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Review

Metabolic Adaptation in Obesity and Type II Diabetes: Myokines, Adipokines and Hepatokines

1
Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea
2
Department of Functional Genomics, University of Science and Technology (UST), Daejeon 34141, Korea
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2017, 18(1), 8; https://doi.org/10.3390/ijms18010008
Received: 10 October 2016 / Revised: 24 November 2016 / Accepted: 12 December 2016 / Published: 22 December 2016
(This article belongs to the Special Issue Diabetic Complications: Pathophysiology, Mechanisms, and Therapies)

Abstract

:
Obesity and type II diabetes are characterized by insulin resistance in peripheral tissues. A high caloric intake combined with a sedentary lifestyle is the leading cause of these conditions. Whole-body insulin resistance and its improvement are the result of the combined actions of each insulin-sensitive organ. Among the fundamental molecular mechanisms by which each organ is able to communicate and engage in cross-talk are cytokines or peptides which stem from secretory organs. Recently, it was reported that several cytokines or peptides are secreted from muscle (myokines), adipose tissue (adipokines) and liver (hepatokines) in response to certain nutrition and/or physical activity conditions. Cytokines exert autocrine, paracrine or endocrine effects for the maintenance of energy homeostasis. The present review is focused on the relationship and cross-talk amongst muscle, adipose tissue and the liver as secretory organs in metabolic diseases.

1. Introduction

Metabolic disease is characterized by insulin resistance in peripheral tissues. Impaired insulin action increases hepatic glucose production, decreases muscle glucose uptake, and promotes lipid accumulation in insulin-sensitive organs such as muscle, liver and fat [1,2,3]. Recent evidence has identified skeletal muscle and the liver, as well as adipocytes, as secretory organs [4,5,6,7]. These metabolic organs communicate with each other regarding the regulation of energy homeostasis and insulin sensitivity. For instance, improved muscle function by exercise can affect whole-body glucose–lipid metabolism and peripheral insulin sensitivity. The manner in which contracting skeletal muscle is able to communicate with other organs and regulate directly or indirectly whole-body energy homeostasis is through myokines that are secreted from muscle and their endocrine effects. This review classifies muscle, liver and adipose tissue as endocrine organs intimately related to metabolic diseases (Figure 1). Here, we introduce myokines, adipokines and hepatokines as involved in the fundamental molecular mechanism that allows communication amongst metabolic organs in the endocrine system.

2. Myokines

A sedentary lifestyle (physical inactivity) increases the risk of metabolic diseases such as obesity and type II diabetes [8,9,10]. Exercise (physical activity) induces metabolic and mitochondrial adaptation to improve energy metabolism and the function of many organs [11,12]. Recently, Stanford et al. described that exercise training obviously increases energy-dissipating beige adipocytes in subcutaneous white adipose tissue (scWAT) in rodents even though its effect is controversial in human subjects [13]. Exercise-trained mice compared to sedentary mice exhibit improved whole-body glucose metabolism and mitochondrial function, indicating that exercise can induce metabolic adaptation to improve whole-body energy metabolism. These findings imply that muscle-derived factor(s) stemming from muscle contraction affect scWAT.
Skeletal muscle is one of the largest organs in the human body, comprising approximately 40% of one’s body weight. Skeletal muscle has been identified as a secretory organ [4]. Contracting muscle produces and releases a variety of cytokines and other peptides, which are collectively termed “myokines”. Myokines mediate muscle growth (myogenesis) and regeneration within the muscle itself and enable communication with other organs such as adipose tissue, liver and pancreas. Because the production of most myokines is affected by muscle contraction, physical inactivity can change the production profile of myokines and their responses. The action of myokines for exercise-induced adaptation in skeletal muscle is responsible for glucose disposal, fatty acid oxidation and lipolysis, suggesting that muscle-derived cytokines (myokines) are important for the prevention and treatment of type II diabetes (Figure 2) [11,12]. Therefore, myokines and their mechanisms can persuasively explain the negative correlation between a sedentary lifestyle and metabolic diseases such as obesity and type II diabetes.

2.1. Irisin

Irisin has been newly identified as a transcriptional co-activator peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC1α)-dependent myokine [14]. PGC1α, a master regulator of muscle energy metabolism, enhances mitochondrial biogenesis and glucose uptake, and also plays a key role in a fiber-type switch to create oxidative fiber [15,16,17,18]. Muscle PGC1α is increased following exercise, and it regulates angiogenesis [19,20,21,22,23]. Overexpression of PGC1α in muscle stimulates the expression of the transmembrane protein fibronectin type III domain-containing 5 (FNDC5) [14]. FNDC5 is cleaved, and the cleaved ectodomain of FNDC5 is secreted from muscle. The circulating cleaved form of FNDC5 is termed irisin. Muscle-derived irisin targets some white adipocytes in white adipose tissue (WAT) and induces transdifferentiation into beige (brite) cells that express uncoupling protein 1 (UCP1) [14,24]. Therefore, irisin can cause weight loss by increasing energy expenditures. The sequential induction of PGC1α, FNDC5, and circulating irisin is increased following exercise in both humans and mice [14,24]. Recently, a FNDC treatment in obese mouse model improved glucose tolerance and induced the expression of mitochondrial genes [14]. Additionally, circulating irisin is positively correlated with muscle mass, whereas it is inversely correlated with fat mass [14]. These findings strongly suggest that irisin is a typical example of factor which provides beneficial effects through exercise-induced metabolic adaptation. On the other hand, unlike studies in rodents, the effects of irisin in humans remain controversial. Irisin can be induced but is not consistently activated by exercise in humans, and skeletal muscle FNDC5 mRNA expression is limited in response to exercise in humans [25,26]. Recently, WAT was identified as an organ that can secrete irisin, and obese patients exhibited high circulating irisin levels [27,28,29,30,31,32,33]. Furthermore, circulating irisin levels in humans were positively correlated with adiposity parameters such as body weight, fat mass, body mass index (BMI), waist-to-hip ratio and homeostasis model assessment of insulin resistance (HOMA-IR) [25,27,28,29,30,31,32,33]. These reports suggest that adiposity would be one of the main contributors to increase circulating irisin levels in humans.

2.2. Fibroblast Growth Factor 21

Fibroblast growth factor 21 (FGF21) was recently identified as a myokine that is produced by skeletal muscle [34,35]. Muscular FGF21 enhances glucose uptake and increases the expression of glucose transporter 1 (GLUT1) in skeletal muscle [36]. The phosphoinositide 3-kinase/protein kinase B (PI3K/AKT1) signaling pathway is linked to muscle hypertrophy [34,35]. Myogenic AKT1 induction leads to increased muscle mass, decreased fat mass, and improved whole body energy metabolism [34]. Furthermore, the expression of FGF21 was increased in the muscle and plasma of skeletal-muscle-specific AKT1 transgenic mice. After acute insulin infusion with a hyperinsulinemic euglycemic clamp, muscular and plasma FGF21 levels were increased, suggesting that insulin stimulates the expression and secretion of muscular FGF21. Recently, it was reported that exercise induces an elevated FGF21 level in plasma and muscle, and that circulating FGF21 increases lipolysis and decreases blood glucose levels [36,37,38,39]. Additionally, the expression of FGF21 was enhanced in the skeletal muscle of mice with muscle-specific deletion of ATF7 (activating transcription factor 7), resulting in increased fatty acid oxidation, lipolysis, and the browning of WAT [40]. Muscle-specific ATF7 knockout mouse also showed resistance against diet-induced obesity and insulin resistance owing to FGF21 induction [40]. Another example that supports FGF21 as a myokine is the elevated expression of FGF21 in skeletal-muscle-specific UCP1 transgenic mice [41]. FGF21 induction in the muscle tissue of UCP1 transgenic mice led to increased plasma levels of FGF21, resulting in increased browning, lipolysis and respiratory capacity in WAT [41]. These findings suggest that myokine FGF21, as a critical metabolic regulator, would be an attractive target molecule for the treatment of type II diabetes and obesity.

2.3. β-Aminoisobutyric Acid

β-aminoisobutyric acid (BAIBA) has been newly identified as a myokine [42]. Begriche et al. found that BAIBA improved obesity and impaired metabolic phenotypes through increased fatty acid oxidation and reduced de novo lipogenesis in a leptin-deficient ob/ob mouse model and in mice fed a high-calorie diet [43]. Recently, BAIBA, as a myokine, was found to be markedly increased in skeletal muscle and serum following exercise [42]. It was shown to mimic the beneficial effects of exercise in energy metabolism [42,43]. Naturally increased BAIBA lowered the levels of circulating blood glucose, triglycerides (TG), and cholesterol without changing the muscle structure (hypertrophy) or muscle strength [42]. It also affected metabolic changes in the liver and in adipose tissue [42,43]. BAIBA is a PGC1α-dependent myokine [42] which is released from muscle when PGC1α is expressed in muscle tissue. Exercise induces PGC1α, which is followed by the activation of peroxisome proliferator-activated receptor α (PPARα). PPARα increases fatty acid breakdown and fat utilization as an energy source in the body. This process is known as the β-oxidation signaling pathway. BAIBA improves hepatic lipid metabolism via PPARα-mediated β-oxidation and contributes to the conversion of energy-storing white adipocytes into energy-burning brown-like beige adipocytes through the activation of PPARα [42]. Furthermore, an administration of BAIBA stimulates fatty acid oxidation via AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor δ (PPARδ) in skeletal muscle [44], and a BAIBA treatment can restore impaired insulin signaling pathways and protect against inflammation in the skeletal muscle of mice fed a high-fat diet [44].

2.4. Interleukin 6

Interleukin 6 (IL-6) is the first myokine that is also known as a protein that is secreted into the blood stream during muscle contraction [45]. Skeletal muscle is the predominant source of IL-6 production [45,46,47]. During muscle contraction, the plasma concentration of IL-6 is increased by up to 100-fold, and a large amount of IL-6 is released into circulating blood [48]. Therefore, contracting skeletal muscle is the main source of circulating IL-6 in response to exercise. On the other hand, IL-6 responds well to acute exercise rather than prolonged exercise, and is increased more during eccentric exercise than during concentric exercise [49]. Muscular IL-6 promotes myogenic differentiation within skeletal muscle itself [50]. It also increases basal and insulin-stimulated glucose uptake levels by inducing the translocation of GLUT4 [46]. AMPK is an attractive therapeutic target for the treatment of obesity and type II diabetes. IL-6 promotes intramuscular and whole-body fatty acid oxidation by the activation of AMPK in both skeletal muscle and adipose tissue [51,52,53]. It also increases glucose uptake via the activation of AMPK. Further, it stimulates lipolysis in skeletal muscle but not in adipose tissue. Consistently, IL-6 knockout mouse exhibit obesity and glucose intolerance [54]. Additionally, IL-6 can function as an anti-inflammatory factor [55,56,57]. It also inhibits lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF) production. Conversely, TNF levels were markedly elevated in IL-6 knockout mice and in anti-IL-6 antibody-treated mice [54,55]. These findings strongly support the contention that muscle-derived IL-6 is beneficial for the regulation of metabolic disorders such as obesity and type II diabetes. Further, muscle-derived IL-6 is associated with endogenous glucose production (hepatic glucose production) during exercise [58,59,60]. It is thought that hepatic regulation by IL-6 is mediated by another cytokine, i.e., the chemokine CXC ligand-1 (CXCL-1) [61]. It is increased in serum, muscle and liver tissues after exercise. Exercise-induced hepatic CXCL-1 was completely reduced in IL-6 knockout mice, and the overexpression of IL-6 in muscle induced CXCL-1 in the liver and serum, suggesting the presence of cross-talk between muscle and liver tissues during exercise. On the other hand, the liver is also known as a source of IL-6 production. Hepatic IL-6 increases glucose release and causes insulin resistance in the liver [60,62,63]. Adipose tissue, the brain and the connective tissue are other sources of IL-6 [64].

2.5. Interleukin 4

Interleukin 4 (IL-4) is a myokine which regulates myoblast fusion with myotubes and the formation and maturation of skeletal muscle [65,66]. IL-4 is expressed in muscle after strength training or by the fusion of myoblasts. Myotubes secrete IL-4, leading to myoblast fusion and growth. IL-4 is also related to muscle hypertrophy. The depletion of IL-4 in muscle cells leads to a reduction in their size and nuclear number.

2.6. Interleukin 7

Interleukin 7 (IL-7) is a cytokine which is involved in the development of T and B cells in the immune system. IL-7 has been identified as a myokine which is released from skeletal muscle cells [67]. It is co-expressed with the myosin heavy chain and is increased during the differentiation of human myotubes and with adaptation to strength training. IL-7 stimulates the cell migration of satellite cells and plays a critical role in myogenesis and muscle hypertrophy.

2.7. Interleukin 8

Interleukin 8 (IL-8) belongs to the CXC family of chemokines that possess neutrophil chemoattractant activity [68,69,70]. Muscle-derived IL-8 also stimulates angiogenesis [70,71]. It can bind to the CXC chemokine receptors CXCR-1 and CXCR-2 [68]. IL-8 exerts chemotactic activity with CXCR-1, whereas it induces angiogenesis via CXCR-2. Exercise markedly increases the expression of IL-8 and its receptor CXCR-2 within muscle itself [72]. Muscle-derived IL-8 exerts autocrine and paracrine activity, and the intramuscular expression of IL-8 is higher in contracting muscle. The plasma level of IL-8 increases in response to exhaustive exercise rather than concentric exercise.

2.8. Interleukin 15

Interleukin-15 (IL-15) belongs to the interleukin-2 (IL-2) superfamily. Its expression is increased in skeletal muscle and serum following strength training [73]. IL-15 is involved in skeletal muscle growth and is closely related to obesity and type II diabetes [74,75,76,77]. Physical inactivity is directly connected with the accumulation of abdominal visceral fat. IL-15 overexpression in mouse muscle reduces visceral fat mass, but not subcutaneous fat mass. It also has anabolic effects on skeletal muscle and reduces adipose tissue mass. Additionally, increased plasma levels of IL-15 in mice significantly reduces body fat mass levels without changes in the lean body mass or levels of other cytokines. These findings suggest that muscle-secreted IL-15 decreases the visceral fat mass via an endocrine system, demonstrating the muscle-fat crosstalk. Further, IL-15 increases glucose uptake in skeletal muscle and in muscle cell lines [77]. In fact, IL-15 administration increases muscle glucose uptake and glucose transporter type 4 (GLUT4) expression, suggesting that IL-15 is a critical mediator of muscle growth, hypertrophy and glucose uptake. Additionally, treadmill exercise enhances the expression of IL-15 in the skeletal muscles of obese rats fed a high-fat diet [78]. IL-15 overexpression in the skeletal muscle of diabetic zucker rats improved glucose intolerance during treadmill exercise. These data demonstrate that exercise-induced IL-15 improves glucose uptake and glucose intolerance and that IL-5 is an attractive target for the treatment of type II diabetes.

2.9. Myostatin

Myostatin is a myokine that is known as growth differentiation factor 8 (GDF-8). Myostatin is a highly conserved member of the transforming growth factor β (TGF-β) protein family [79]. It inhibits muscle growth and differentiation (myogenesis) in an autocrine manner [80]. Myostatin depletion leads to skeletal muscle hypertrophy and a reduction in total body fat [81,82]. Exercise diminishes myostatin expression, whereas obesity augments myostatin levels in muscle and serum [83]. In fact, myoblast isolated from obese patients secretes an excessive amount of myostatin compared to that in normal individuals [84]. Follistatin is also member of the TGF-β superfamily. It acts as an endogenous and natural inhibitor of myostatin in skeletal muscle [85]. However, contracting muscle is not a primary organ responsible for the production of follistatin. Follistatin is a hepatokine rather than a myokine. Swimming exercise in a mouse model markedly increased follistatin levels in plasma and liver tissue [6]. It was thought that the increased circulating level of follistatin may contribute to regulate myostatin levels in skeletal muscle.

2.10. Brain-Derived Neurotrophic Factor

Brain-derived neurotrophic factor (BDNF) is a neurotrophin that functions in neurons through Trk receptor tyrosine kinases [86]. It plays critical roles in neuronal development, synaptic plasticity, neuron growth and survival [87]. In addition, it is important for learning and memory [88,89,90,91]. Therefore, patients with Alzheimer’s disease exhibit reduced expression levels of BDNF in the hippocampus. Approximately 70% to 80% of circulating BDNF is released from the brain. It reduces food intake and lowers blood glucose levels. A low level of circulating BDNF is implicated in obesity, type II diabetes, peripheral insulin resistance and aging [92,93,94,95,96,97,98]. Recently, it has been reported that BDNF could be expressed in skeletal muscle and that it regulates muscle metabolism [95,96,97]. Exercise augments BDNF expression in skeletal muscle. However, muscle-derived BDNF is not released into the blood-stream, and instead displays autocrine/paracrine characteristics. Muscle-contraction-induced BDNF plays important roles in muscle differentiation, development, repair and regeneration. Muscular BDNF also stimulates the phosphorylation of AMPK and acetyl-CoA carboxylase β (ACCβ), and increases fat oxidation. Consequently, the activation of muscular BDNF diminishes the size of peripheral adipose tissue. Furthermore, muscular BDNF enhances glucose utilization in diabetic skeletal muscle [98]. These results indicate that BDNF, as a novel contraction-induced protein, is a potent regulator of glucose and lipid metabolism. Eventually, it will be an attractive target for improvements of metabolic diseases such as type II diabetes and obesity.

2.11. Leukemia Inhibitory Factor

Leukemia inhibitory factor (LIF) is a cytokine that belongs to the IL-6 superfamily. It was first identified in 1988 as a protein secreted from ascites tumor cells [99,100]. LIF is required for platelet formation, the proliferation of hematopoietic cells, and the survival and formation of neurons [101]. Recently, LIF was established as a contraction-induced myokine [102]. It was found to be expressed in skeletal muscle following exercise and to function in an autocrine or paracrine manner. Exercise-induced PI3K/mTOR/AKT1 pathway (mTOR: mammalian target of rapamycin) also regulates LIF expression in muscle [103]. LIF enhances myoblast proliferation via the induction of the transcription factors JunB and c-Myc [104,105,106]. The proliferation of muscle satellite cells plays a key role in muscle hypertrophy and regeneration. LIF regulates myogenic differentiation and muscle satellite cell proliferation via the regulation of c-Jun N-terminal kinase (JNK), Janus kinase (JAK) and signal transducer and activator of transcription 3 (STAT3) [107,108]. Further, LIF enhances myoblast survival in dystrophic muscle, suggesting that it can be an alternative therapeutic target for the treatment of skeletal muscle diseases such as muscular dystrophy [109].

2.12. Secreted Protein Acidic and Rich in Cysteine

Secreted protein acidic and rich in cysteine (SPARC) was initially known as “osteonectin” [110,111,112,113], as SPARC was identified in bone, and most studies of SPARC have been associated with bone. Recently, a secretome analysis of human skeletal muscle cells showed that SPARC is a secretory muscle protein [114]. SPARC is secreted into blood in conjunction with elevated protein expression levels in muscle fiber following strength training [115]. The expression of muscle-secreted SPARC was found to increase during myogenesis [114]. Interestingly, SPARC interacts with AMPK and regulates GLUT4 expression via the activation of AMPK in muscle and muscle cells [116,117]. Muscular AMPK is a critical regulator for the improvement of glucose and lipid metabolism in obesity and type II diabetes. Therefore, it is thought that muscular SPARC may regulate glucose metabolism via AMPK activation. Additionally, SPARC decreases in skeletal muscle with age, and the reduced expression of SPARC in mouse skeletal muscle is linked to muscle atrophy [118].

2.13. Insulin-Like Growth Factor-1 and Fibroblast Growth Factor 2

Insulin-like growth factor 1 (IGF1) and fibroblast growth factor 2 (FGF2) are well-known osteogenic factors that stimulate bone formation. Recently, it was reported that they are osteogenic myokines [119,120]. They were found to be localized in muscle tissue and myotubes, and were present in extracts from crushed muscle. IGF-1 is associated with muscle hypertrophy. FGF2 is also secreted from muscle by wounds and injuries, causing hypertrophy in adjacent muscle cells.

2.14. Follistatin-Related Protein 1

Follistatin-related protein 1 (FSTL-1) was described as a myokine in 2008 [121]. Myogenic AKT plays an influential role in blood vessel growth and muscle growth [122]. Muscle-specific AKT overexpression increases intramuscular and circulating serum levels of FSTL-1. Increased FSTL-1 enhances the endothelial function and revascularization via the activation of the AKT-eNOS signaling pathway. The expression and secretion of FSTL-1 are also increased in a differentiation-dependent manner in human primary skeletal muscle cells [123]. Additionally, exercise increases circulating FSTL-1 levels; and interferon γ (IFNγ) and IL-1β also stimulate FSTL-1 secretion [123].

2.15. Erythropoietin

Erythropoietin (EPO) was newly classified as a myokine in 2009 [124]. EPO overexpression in mouse skeletal muscle leads to increased levels in circulating blood as well as skeletal muscle. EPO overexpression in the skeletal muscle of obese mice fed a high-fat diet causes weight loss due to the reduced fat mass. These mice exhibited improved fasting insulin levels and better glucose tolerance. Further, the muscular expression of EPO increased fatty acid oxidation in skeletal muscle. Additionally, EPO was found to be produced and secreted from skeletal muscle during and following exercise, affecting neighboring muscle in a paracrine or endocrine fashion [125]. EPO, as a myokine, increases the expression of EPO receptor (EPOR) and the phosphorylation of EPOR-related JAK2, suggesting exercise-induced skeletal muscle adaptation [125]. These data describe the physiological role of EPO as a myokine for the maintenance of metabolic homeostasis.

2.16. Other Myokines

2.16.1. Hepatocyte Growth Factor

Hepatocyte growth factor (HGF) and its receptor c-met are co-localized in activated satellite cells in regions of muscle repair [126]. HGF exists in muscle and in the muscle extracellular matrix, and it is secreted from muscle in the event of a muscle injury [127].

2.16.2. Semaphorin 3A

Semaphorin 3A (Sema3A) is induced by HGF/FGF2 [128]. It is secreted from muscle satellite cells and mediates the early myogenic differentiation of satellite cell-derived myoblasts [129,130].

3. Adipokines

Excess adiposity and adipocyte dysfunction are strongly associated with metabolic diseases such as obesity, type II diabetes and atherosclerosis [131,132]. WAT is an insulin-sensitive organ that stores lipids, and it produces and secretes adipocyte-specific endocrine hormones (adipokines) that can regulate energy balance levels in other peripheral tissues [133]. The main WATs are the two regional depots of visceral and subcutaneous adipose tissues, which have unique expression patterns of adipokines. Subcutaneous white adipose tissue (scWAT) is associated with an insulin sensitive phenotype, whereas visceral white adipose tissue (vWAT) is associated with obesity, type II diabetes, dyslipidemia and insulin resistance [134,135,136,137]. A sedentary lifestyle is directly linked to the accumulation of visceral fat, which is associated with the development of metabolic diseases [8,9,10]. Therefore, methods for consuming energy without physical activity have been spotlighted to promote weight loss. One of them is heat production (thermogenesis) [138,139,140]. Interestingly, there are energy-consuming white adipocytes that exhibit UCP1-dependent thermogenic capacity, similar to brown adipocytes [139,140]. These are beige adipocytes, UCP1-expressing adipocytes in scWAT. Beige adipocytes have been considered as attractive therapeutic targets for the treatment of obesity and type II diabetes, as they are found in WAT, which stores lipids. In this review, we categorize adipokines into the anti-inflammatory and inflammatory types, and describe the roles of adipokines in diet-induced metabolic changes and exercise-induced metabolic adaptation (Figure 3). We also introduce adiponectin and FGF21 as adipokines that lead to the activation of beige cells.

3.1. Anti-Inflammatory Adipokines

3.1.1. Adiponectin

Adiponectin is one of the well-characterized classic adipokines. The gene that codes for adiponectin is located on chromosome 3q27, which is associated with type II diabetes and metabolic syndrome [141,142]. There are at least three homomeric complexes in blood: trimer (LMW: the low-molecular-weight form), hexamer (MMW: the medium-molecular-weight form) and multimer (HMW: the high-molecular-weight form) [143,144]. Among them, the stable HMW form is well-known as a biologically active form for the regulation of glucose homeostasis, insulin sensitivity and metabolic homeostasis [145,146]. Adiponectin expression by adipocytes is decreased in obese individuals and is inhibited by pro-inflammatory cytokines such as TNF and IL-6 and by conditions such as hypoxia and oxidative stress [147,148,149,150,151,152]. The plasma levels of adiponectin were found to be reduced in individuals with obesity, type II diabetes and insulin resistance [153,154,155], and they are also inversely correlated with BMI [156]. In short, increased levels are associated with weight loss, whereas decreased levels are linked to weight gain [157,158]. Chronic cold exposure promotes the production of anti-obese hormone adiponectin in scWAT. Cold-induced adiponectin regulates the thermogenic program through the proliferation of M2 macrophages, leading to the browning of scWAT [159]. Further, adiponectin enhances glucose uptake and fatty acid oxidation in skeletal muscle and suppresses glucose production in the liver via the activation of AMPK [160,161]. Additionally, adiponectin stimulates insulin secretion in vivo, and hypoadiponectinemia causes β-cell dysfunction [162,163,164]. In line with these findings, mice lacking adiponectin exhibit hepatic insulin resistance and exacerbated diet-induced resistance. Adiponectin exerts beneficial effects through the activation of its two receptors, adiponectin receptor 1 (AdipoR1) and adiponectin receptor 2 (AdipoR2) [165,166]. AdipoR1 is expressed in several tissues and is associated with the activation of AMPK, resulting in reduced glucose production and improved insulin resistance. AdipoR2 is mainly expressed in the liver. It is related to the activation of PPARα, which is related to increased fatty acid oxidation and improved insulin sensitivity. Both receptors are related to insulin sensitivity and glucose/lipid metabolism. On the other hand, exercise has controversial effects on adiponectin and plasma adiponectin levels. It was reported that plasma adiponectin levels in obese men were significantly increased by acute aerobic exercise training [167]. In contrast, other reports found that mild or moderate exercise did not affect adiponectin levels, and high-intensity exercise decreased total adiponectin concentrations by reducing LMW and MMW adiponectin levels, but not HMW levels [168,169,170]. These data suggest that the intensity and duration of exercise are important for the regulation of adiponectin levels.

3.1.2. Fibroblast Growth Factor 21

FGF21 was recently introduced as a novel adipokine [171,172,173]. Cold exposure induces FGF21 expression in WAT and brown adipose tissue (BAT), resulting in the thermogenic recruitment of WAT [174,175,176,177]. Adipose-derived FGF21 in an autocrine/paracrine manner increases the expression of uncoupling protein 1 (UCP1) and other thermogenic genes in WAT. Beige adipocytes are UCP1 positive cells in scWAT following cold exposure. FGF21 knockout mice showed a reduced level of beige adipocytes. Similarly, FGF21 induced increased energy expenditure in BAT, and FGF21 stimulated insulin-independent glucose uptake in peripheral tissues. In humans, cold exposure increases circulating FGF21 levels, resulting in the activation of brown adipocytes and lipolysis and the browning of WAT. It has also been reported that adiponectin secreted from adipocytes regulates glucose and lipid metabolism in the liver and muscle in an endocrine fashion [178,179,180,181], while adipose-derived FGF21 stimulates adiponectin expression in WAT and the blood stream [182,183]. However, the beneficial effects of FGF21 on obesity-induced insulin resistance in liver and muscle were not exhibited in adiponectin knockout mouse, suggesting that adiponectin is a downstream effector molecule of FGF21.

3.1.3. Secreted Frizzled-Related Protein 5

Secreted frizzled-related protein 5 (SFRP5) is newly identified as an adipokine with anti-inflammatory effects [184]. SFRP5 is highly expressed in WAT compared to other tissues. It has been reported that the canonical Wnt family suppresses adipogenesis, while non-canonical Wnt5a enhances the inflammatory signaling pathway [185,186,187,188]. SFRP5 expression was decreased, whereas Wnt5a expression was increased in the WAT of obese mice and humans [189]. SFRP5 binds to and inhibits Wnt5a as induced by obesity. SFRP5-depleted mice exhibit insulin resistance and a fatty liver even when they are normoglycemic. Further, SFRP5 depletion under a high-fat and high-sucrose feeding condition enhances macrophage accumulation and the expression of pro-inflammatory cytokines though the Wnt5a-induced activation of inflammatory JNK1. These data suggest that SFRP5 is a beneficial target for mitigating obesity-induced adipose tissue inflammation and metabolic disorder.

3.2. Inflammatory Adipokines

3.2.1. Leptin

Leptin is a classic adipokine which is predominantly secreted from adipocytes into the bloodstream. It is a pro-inflammatory adipokine that has been identified in ob/ob mice (leptin deficient mice) [190,191]. Leptin-deficient ob/ob mice exhibit increased food intake, decreased energy expenditure, dyslipidemia, obesity and insulin resistance. In line with these findings, leptin administration has been shown to improve lipodystrophy and insulin resistance [192,193]. However, there was a positive correlation between leptin levels in blood and adipose masses, and obese individuals have high leptin levels in the blood [194]. Thus, leptin is a well-known marker for obesity. Further, leptin enhances the production of TNF and IL-6 by monocytes [195]. It also promotes the production of reactive oxygen species (ROS) and stimulates cell proliferation and migratory responses in monocytes. In macrophages, leptin stimulates the production of CC-chemokine ligands by activating the JAK2/STAT3 signaling pathway [196]. Leptin levels in adipose tissue and plasma were increased by pro-inflammatory stimuli such as TNF and lipopolysaccharide (LPS) [197,198,199,200]. Chronic inflammation and increased TNFα play an important role in hyperleptinemia in obese individuals with leptin resistance. Several reports have described that leptin mRNA levels in adipose tissue following exercise did not change [201,202,203,204]. However, plasma leptin levels tend to decrease following exercise in patients with type II diabetes [205,206].

3.2.2. Resistin

Resistin is an adipokine that functions as a pro-inflammatory biomarker and a mediator of obesity-related insulin resistance [207]. It is positively correlated with fat mass and causes endothelial dysfunction by enhancing oxidative stress. It has two quaternary forms, i.e., a less abundant trimer and an abundant hexamer [208]. The trimer form is more bioactive and is strongly associated with the induction of hepatic insulin resistance. Resistin-deficient mice exhibit low glucose levels due to the reduction of hepatic glucose production [209]. Resistin-deficient ob/ob mice show improved glucose tolerance and insulin sensitivity, although they showed increased obesity as well [210]. Resistin in the regulation of glucose metabolism is associated with the activation of a suppressor of cytokine signaling 3 (SOCS3), an inhibitor of insulin signaling [211]. Resistin levels in adipocytes and blood are not affected by exercise [212,213]. However, regular weight training reduces plasma resistin levels. Resistin promotes insulin resistance in mice, whereas whether it does so in humans is unclear [214,215,216,217]. Resistin protein synthesis in mice is restricted to adipocytes, while in humans it is generated by macrophages and monocytes, but not adipocytes. Therefore, it is thought that the role of resistin is very different in mice and humans.

3.2.3. Tumor Necrosis Factor α

TNFα is an inflammatory cytokine that is produced by monocytes and macrophages. In obese individuals, macrophage-infiltrated visceral fat is the main site for TNFα production [218,219]. Visceral fat obesity is associated with a reduction of insulin sensitivity and anti-inflammatory cytokines. TNF expression is increased in the adipose tissue of humans and in a mouse model with obesity and type II diabetes [220,221]. TNFα depletion in ob/ob genetic or diet-induced obese mice reduces insulin resistance and improves insulin signaling in adipose tissue and muscle [221]. TNF attenuates the insulin-stimulated tyrosine phosphorylation of insulin receptor (IR) and insulin receptor substrate 1 (IRS1) in adipose tissue and muscle, resulting in the occurrence of insulin resistance. Patients with diabetes had elevated levels of TNFα in plasma and muscle [222,223,224,225,226]. Increased TNFα levels stimulate hepatic fatty acid uptake and increase fat accumulation and ROS production in the liver. Additionally, TNFα enhances the incorporation of fatty acids into diacylglycerol (DAG), suggesting TNFα-induced insulin resistance in skeletal muscle [227]. Exercise reduces circulating plasma levels of TNFα, whereas it does not affect TNFα expression in adipose tissue [228,229,230].

3.2.4. Interleukin 6

IL-6 has both pro-inflammatory effects as an adipokine and anti-inflammatory effects as a myokine [231,232,233,234]. The reason IL-6 can have different functions in different organs would be that induction of IL-6 expression is stimulated by the different inducers and inducing signals in different organs. As mentioned in the myokine section of this review, an increase in the plasma IL-6 level following exercise mainly results from it being secreted from skeletal muscle. Muscle-derived IL-6 improves glucose and lipid metabolism and the insulin signaling pathway. On the other hand, circulating plasma IL-6 levels are elevated in individuals with type II diabetes, obesity and insulin resistance [235,236]. IL-6 as an adipokine is positively related to BMI [237]. It has been reported that one third of the circulating IL-6 level was derived from adipose tissue. Specifically, visceral adipose tissue is an important source of circulating IL-6 in relation to obesity [237,238,239]. The expression of IL-6 in adipose tissue is produced by macrophages and is stimulated by the activation of the nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) signaling pathway. Further, IL-6 impedes insulin signaling and reduces insulin-dependent glucose uptake by the inhibition of GLUT4 and IRS1 expression in adipocytes. Finally, adipocyte-derived IL-6 is related to the occurrence of insulin resistance and metabolic disorder.

3.2.5. Retinol Binding Protein 4

Retinol binding protein 4 (RBP4) is a hepatocyte-secreted factor [240,241,242]. It delivers retinol from the liver to peripheral tissues as a carrier for the transport of retinol (vitamin A alcohol) [242]. Recently, RBP4 was described as an adipokine which is secreted from adipocytes [243]. It is also secreted by macrophages [244]. Adipocyte-derived RBP4 impedes the insulin-induced phosphorylation of IRS1 in an autocrine or paracrine fashion [243]. Further, adipocyte-specific GLUT4 knockout mice exhibit increased adipose expression levels of RBP4 [243]. Increased adipose RBP4 contributes to glucose intolerance and insulin resistance in adipocyte-specific GLUT4 knockout mice. The circulating serum RBP4 level is increased under insulin-resistant conditions. Under insulin resistant conditions, the serum RBP4 level is mainly produced by visceral adipose tissue and is associated with an increased BMI [244,245,246,247,248]. An increased serum level of RBP4 elevates blood pressure and plasma levels of cholesterol and TG. Therefore, RBP4 is considered as a marker of intra-abdominal fat accumulation and obesity-induced inflammation.

3.3. Other Adipokines

3.3.1. Irisin

Adipose tissue, as well as skeletal muscle, is also the main site that can generate and secrete FNDC5/irisin [249,250,251,252]. Irisin secretion from scWAT and vWAT was induced by short-term periods of endurance exercise training, whereas it was decreased by long-term exercise training and fasting [250,251]. Obese animals such as zucker rat and diet-induced obese animal models excessively secreted irisin from WAT [250]. In humans, irisin levels were higher in obese patients compared with normal weight subjects, and body fat mass was positively correlated with circulating irisin levels [252]. These suggest that irisin secreted from WAT might play a role in metabolic pathology related with obesity and insulin resistance.

3.3.2. α2-HS-Glycoprotein (Fetuin-A)

Fetuin-A, one of the liver secretory glycoproteins, stimulates the production of inflammatory cytokines from adipocytes and macrophages [253,254]. Recently, it has been reported that free fatty acid (FFA) enhanced fetuin-A expression, and elevated fetuin-A functioned as an endogenous ligand of Toll-like receptor 4 (TLR4) [255,256,257]. Further, FFA-induced fetuin-A activated TLR4-mediated inflammatory and insulin resistance pathways in adipose tissue [257]. Additionally, FFA-treated adipocytes released fetuin-A into the medium, and lipid-induced fetuin-A increased macrophage migration into adipocyte and adipose tissue [258]. Consistently, expression and secretion of fetuin-A were increased in obese and pro-inflammatory adipose tissues [257,258,259]. It has also been reported that visceral fat expressed and secreted more fetuin-A than subcutaneous fat, and excess secretion of fetuin-A inhibited insulin signaling [260]. These data indicate that fetuin-A is an inflammatory adipokine.

4. Hepatokines

Liver is the main insulin-sensitive organ to be in charge of glucose production [261]. Under insulin-resistant conditions, impaired insulin action promotes hepatic glucose production and decreases glucose uptake in peripheral tissues such as muscle and fat, resulting in hyperglycemia (high blood glucose) [262,263], i.e., type II diabetes. Impaired insulin action promotes excessive fat accumulation [264], that is to say, obesity. Recently, it was reported that hepatokine, a secretory protein released from the liver, could affect muscle and fat metabolic phenotypes in an endocrine-dependent manner (Figure 4) [5]. In this section, we introduce the role of hepatokines in metabolic regulation under insulin-resistant conditions.

4.1. α2-HS-Glycoprotein (Fetuin-A)

Fetuin-A is the first liver-derived protein (hepatokine) to show relationship with metabolic diseases. It is mainly synthesized in the liver and secreted into the bloodstream [265,266,267]. It is a phosphorylated glycoprotein that is also a natural inhibitor of insulin receptor tyrosine kinase, leading to insulin resistance [268,269,270,271,272]. Fetuin-A was positively linked to liver fat accumulation and negatively related to insulin sensitivity [273,274]. Fetuin-A levels are higher in patients with non-alcoholic fatty liver disease (NAFLD) and type II diabetes [275,276,277]. Depletion of fetuin-A improves the insulin signaling pathway in the liver and in skeletal muscle [272]. Fetuin-knockout mice exhibit improved glucose and insulin tolerance and are resistant to high-fat diet-induced weight gain. In hepatocytes, palmitate enhances NF-κB recruitment to the fetuin-A promoter, resulting in increased fetuin-A synthesis and secretion levels [274]. Circulating fetuin-A is also related to hepatic steatosis, impaired glucose tolerance, and insulin resistance [276,277].

4.2. Fibroblast Growth Factor 21

As above mentioned, FGF21 plays roles as a myokine and an adipokine. FGF21 also functions as a hepatokine. FGF21 is predominantly synthesized and expressed in the liver and is secreted into the bloodstream [278]. FGF21, as a fasting-induced hormone, is necessary for adaptive starvation [279]. Hepatic and circulating levels of FGF21 are increased by fasting and a high-fat/low-carbohydrate ketogenic diet [279,280]. FGF21 alleviates endoplasmic reticulum stress or obesity-induced hepatic steatosis [281,282,283,284]. The hepatic knockdown of FGF21 leads to a fatty liver and dyslipidemia, whereas the hepatic expression of FGF21 enhances hepatic lipid oxidation and TG clearance [284]. The hepatic expression of FGF21 can be stimulated by PPARα [285]. Hepatic FGF21, as an endocrine hormone, triggers lipolysis in white adipose tissue, functioning in the brain to reduce physical activity [285].

4.3. Leukocyte Cell-Derived Chemotaxin 2

Leukocyte cell-derived chemotaxin 2 (LECT2) is a factor that is related to hepatic inflammatory signaling and the homeostasis of hepatic natural killer T cells [286,287]. Recently, a DNA chip analysis from liver biopsies of patients with type II diabetes showed a positive correlation between the hepatic LECT2 expression level and BMI, describing a relationship between LECT2 and obesity [288]. Further, high-fat diet feeding increased serum and hepatic LECT2 levels by impeding AMPK activation [288]. On the other hand, exercise reduced hepatic and circulating levels of LECT2 via AMPK activation. LECT2 functioned as a hepatokine connected to obesity through the induction of insulin resistance in skeletal muscle.

4.4. Selenoprotein P

Selenoprotein P (SeP) is an abundant extracellular glycoprotein [289,290]. It is mainly produced in the liver, and it is released into plasma. A DNA chip analysis of liver biopsies from patients with type II diabetes showed that hepatic SeP expression is linked to insulin resistance [291]. Administration of SeP to mice impeded insulin signaling, and inhibited AMPK activation in the liver [292]. In contrast, depletion of SeP in mice improved insulin sensitivity and glucose tolerance. Further, a palmitate treatment increased SeP expression in hepatocytes, and the AMPK-mediated phosphorylation of FoxO1a inhibited palmitate-induced SeP expression and insulin resistance. Further, circulating SeP levels were increased in patients with NAFLD, type II diabetes and visceral obesity [293,294].

4.5. Chemerin

Chemerin is known as an adipokine associated with obesity [295]. Circulating levels of chemerin are increased in those with NAFLD [296]. Recently, it was reported that chemerin is produced in the liver and contributes to impaired glucose homeostasis [297]. Paigen diet feeding in conjunction with non-alcoholic fatty liver disease due to higher cholesterol contents promotes the hepatic expression of chemerin [298]. Methionine choline-deficient (MCD) diet feeding to induce a severe fatty liver due to a lack of methionine and choline increases chemerin expression levels in the liver [298]. Further, the hepatic expression of chemerin is elevated in patients with NAFLD and non-alcoholic steatohepatitis (NASH) [299]. These findings support the contention that chemerin as a hepatokine is associated with the development of hepatic steatosis.

5. Concluding Remarks

Understanding the regulation of endocrine hormones secreted from each metabolic organ is important for improving metabolic diseases such as obesity and type II diabetes, as metabolic diseases are not a local problem. Metabolic organs secrete cytokines in response to nutrition and physical activity, and communicate with each other for the maintenance of energy homeostasis. In this review, we demonstrate that a sedentary lifestyle combined with excessive calorie intake alters the pattern of cytokine secretion from many organs. As mentioned above, myokines, muscle-derived factors due to muscle contraction, are negatively correlated with a sedentary lifestyle and metabolic disease and are in charge of exercise-induced adaptation. They stimulate glucose disposal, fatty acid oxidation and lipolysis in other metabolic organs as well as in muscle. These reports show the whole-body adaptive effects and the health-promoting effects of exercise-induced myokines. There were a few in-depth studies to identify novel myokines and to determine their physiological functions [300,301,302]. Secretome analysis using DNA microarray and proteomics approaches identified novel exercise-induced myokines such as CX3CL1 and CCL2 [300,301]. As a lipid vesicle delivery system for exercise-induced molecules, exosomes and/or microvesicles containing exerkines (exercise-induced peptides and nucleic acids, lipids and microRNA species) facilitate the exchange of these exerkines between cells and tissues, and enable exerkines to exert systemic beneficial effects in a stable condition [302]. Indeed, secretome analyses for identifying novel myokines and a newly devised delivery system would provide an effective method for the improvement and treatment of metabolic disease. As mentioned above, myokines such as irisin and IL-6 are additionally known to be secreted by adipocytes [249,303,304]. We termed these proteins adipomyokines. They function as both pro-inflammatory mediators (adipokines) under obese conditions and beneficial effectors (myokines) following exercise. There were efforts to identify adipomyokines by using expression profiling and human secretome data [304]. Candidates for adipomyokines were biological molecules that are related with extracellular matrix (ECM) remodeling and tissue fibrosis. It has been previously reported that excessive ECM deposition in adipose tissues, adipose tissue dysfunction and fibrosis are closely associated with development of obesity-associated insulin resistance and type II diabetes [305,306,307]. Understanding adipose-muscle crosstalk in obesity and type II diabetes, and in exercise-induced metabolic adaptation would provide a more comprehensive view for the maintenance of metabolic homeostasis. Adipokines, adipocyte-derived factors, have both anti-inflammatory and pro-inflammatory effects. An imbalance between the two types of adipokines causes the abnormal expansion of adipose tissue, the leading cause of obesity, and causes local and systemic inflammation. On the other hand, there are two regional depots of adipose tissue. One is scWAT, which is involved in insulin sensitivity. Exercise can increase the production of energy-consuming beige adipocytes in scWAT. The other one is vWAT, which is closely connected to the development of insulin resistance, obesity and type II diabetes. Comparative secretome analysis proved the existence of location-specific secreted proteins in different adipose spots, scWAT and vWAT, by genome-wide mRNA expression profiling and quantitative proteomic approach. These studies support depot-specific metabolic function and distinctive features of scWAT and vWAT [308,309,310,311,312]. Recently, hepatokines, secretory proteins produced in the liver, redefined the liver as an endocrine organ that can affect and communicate with many other organs. Hepatokines play critical roles in hepatic fat accumulation and insulin resistance. However, there remains a lack of research on hepatokines.
This review will provide a better understanding of molecular mechanisms and the progression of metabolic diseases, although it described the roles of myokines, adipokines and hepatokines from skeletal muscle, adipocytes and the liver, respectively, only in a limited manner.

Acknowledgments

We would like to thank Hail Kim, Jae Myung Suh, and Jin Han for their encouragement and helpful advice. This work was supported by grants from Korea Research Institute of Bioscience and Biotechnology (KRIBB) and from the Research Program (Grant Nos. 2012M3A9C7050101, 2015M3A9D7029882 and 2016R1C1B2010257) through the National Research Foundation of Korea.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Wilcox, G. Insulin and insulin resistance. Clin. Biochem. Rev. 2005, 26, 19–39. [Google Scholar] [PubMed]
  2. Oakes, N.D.; Cooney, G.J.; Camilleri, S.; Chisholm, D.J.; Kraegen, E.W. Mechanisms of liver and muscle insulin resistance induced by chronic high-fat feeding. Diabetes 1997, 46, 1768–1774. [Google Scholar] [CrossRef] [PubMed]
  3. Rask-Madsen, C.; Kahn, C.R. Tissue-specific insulin signaling, metabolic syndrome, and cardiovascular disease. Arterioscler. Thromb. Vasc. Biol. 2012, 32, 2052–2059. [Google Scholar] [CrossRef] [PubMed]
  4. Febbraio, M.A.; Pedersen, B.K. Contraction-induced myokine production and release: Is skeletal muscle an endocrine organ? Exerc. Sport Sci. Rev. 2005, 33, 114–119. [Google Scholar] [CrossRef] [PubMed]
  5. Stefan, N.; Häring, H.U. The role of hepatokines in metabolism. Nat. Rev. Endocrinol. 2013, 9, 144–152. [Google Scholar] [CrossRef] [PubMed]
  6. Hansen, J.; Brandt, C.; Nielsen, A.R.; Hojman, P.; Whitham, M.; Febbraio, M.A.; Pedersen, B.K.; Plomgaard, P. Exercise induces a marked increase in plasma follistatin: Evidence that follistatin is a contraction-induced hepatokine. Endocrinology 2011, 152, 164–171. [Google Scholar] [CrossRef] [PubMed]
  7. Itoh, N. FGF21 as a Hepatokine, Adipokine, and Myokine in Metabolism and Diseases. Front. Endocrinol. 2014, 5, 107. [Google Scholar] [CrossRef] [PubMed]
  8. Hu, F.B. Sedentary lifestyle and risk of obesity and type 2 diabetes. Lipids 2003, 38, 103–108. [Google Scholar] [CrossRef] [PubMed]
  9. Edwardson, C.L.; Gorely, T.; Davies, M.J.; Gray, L.J.; Khunti, K.; Wilmot, E.G.; Yates, T.; Biddle, S.J. Association of sedentary behaviour with metabolic syndrome: A meta-analysis. PLoS ONE 2012, 7, e34916. [Google Scholar] [CrossRef] [PubMed]
  10. Pietiläinen, K.H.; Kaprio, J.; Borg, P.; Plasqui, G.; Yki-Järvinen, H.; Kujala, U.M.; Rose, R.J.; Westerterp, K.R.; Rissanen, A. Physical inactivity and obesity: A vicious circle. Obesity 2008, 16, 409–414. [Google Scholar] [CrossRef] [PubMed]
  11. Egan, B.; Zierath, J.R. Exercise metabolism and the molecular regulation of skeletal muscle adaptation. Cell Metab. 2013, 17, 162–184. [Google Scholar] [CrossRef] [PubMed]
  12. Drake, J.C.; Wilson, R.J.; Yan, Z. Molecular mechanisms for mitochondrial adaptation to exercise training in skeletal muscle. FASEB J. 2016, 30, 13–22. [Google Scholar] [CrossRef] [PubMed]
  13. Stanford, K.I.; Middelbeek, R.J.; Goodyear, L.J. Exercise Effects on White Adipose Tissue: Beiging and Metabolic Adaptations. Diabetes 2015, 64, 2361–2368. [Google Scholar] [CrossRef] [PubMed]
  14. Boström, P.; Wu, J.; Jedrychowski, M.P.; Korde, A.; Ye, L.; Lo, J.C.; Rasbach, K.A.; Boström, E.A.; Choi, J.H.; Long, J.Z.; et al. A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature 2012, 481, 463–468. [Google Scholar] [CrossRef] [PubMed][Green Version]
  15. Scarpulla, R.C. Metabolic control of mitochondrial biogenesis through the PGC-1 family regulatory network. Biochim. Biophys. Acta 2011, 1813, 1269–1278. [Google Scholar] [CrossRef] [PubMed]
  16. Fernandez-Marcos, P.J.; Auwerx, J. Regulation of PGC-1α, a nodal regulator of mitochondrial biogenesis. Am. J. Clin. Nutr. 2011, 93, 884S–890S. [Google Scholar] [CrossRef] [PubMed]
  17. Michael, L.F.; Wu, Z.; Cheatham, R.B.; Puigserver, P.; Adelmant, G.; Lehman, J.J.; Kelly, D.P.; Spiegelman, B.M. Restoration of insulin-sensitive glucose transporter (GLUT4) gene expression in muscle cells by the transcriptional coactivator PGC-1. Proc. Natl. Acad. Sci. USA 2001, 98, 3820–3825. [Google Scholar] [CrossRef] [PubMed]
  18. Schuler, M.; Ali, F.; Chambon, C.; Duteil, D.; Bornert, J.M.; Tardivel, A.; Desvergne, B.; Wahli, W.; Chambon, P.; Metzger, D. PGC1α expression is controlled in skeletal muscles by PPARβ, whose ablation results in fiber-type switching, obesity, and type 2 diabetes. Cell Metab. 2006, 4, 407–414. [Google Scholar] [CrossRef] [PubMed]
  19. Baar, K.; Wende, A.R.; Jones, T.E.; Marison, M.; Nolte, L.A.; Chen, M.; Kelly, D.P.; Holloszy, J.O. Adaptations of skeletal muscle to exercise: Rapid increase in the transcriptional coactivator PGC-1. FASEB J. 2002, 16, 1879–1886. [Google Scholar] [CrossRef] [PubMed]
  20. Pilegaard, H.; Saltin, B.; Neufer, P.D. Exercise induces transient transcriptional activation of the PGC-1α gene in human skeletal muscle. J. Physiol. 2003, 546, 851–858. [Google Scholar] [CrossRef] [PubMed]
  21. Terada, S.; Kawanaka, K.; Goto, M.; Shimokawa, T.; Tabata, I. Effects of high-intensity intermittent swimming on PGC-1αprotein expression in rat skeletal muscle. Acta Physiol. Scand. 2005, 184, 59–65. [Google Scholar] [CrossRef] [PubMed]
  22. Russell, A.P.; Feilchenfeldt, J.; Schreiber, S.; Praz, M.; Crettenand, A.; Gobelet, C.; Meier, C.A.; Bell, D.R.; Kralli, A.; Giacobino, J.P.; et al. Endurance training in humans leads to fiber type-specific increases in levels of peroxisome proliferator-activated receptor-gamma coactivator-1 and peroxisome proliferator-activated receptor-alpha in skeletal muscle. Diabetes 2003, 52, 2874–2881. [Google Scholar] [CrossRef] [PubMed]
  23. Chinsomboon, J.; Ruas, J.; Gupta, R.K.; Thom, R.; Shoag, J.; Rowe, G.C.; Sawada, N.; Raghuram, S.; Arany, Z. The transcriptional coactivator PGC-1α mediates exercise-induced angiogenesis in skeletal muscle. Proc. Natl. Acad. Sci. USA 2009, 106, 21401–21406. [Google Scholar] [CrossRef] [PubMed]
  24. Castillo-Quan, J.I. From white to brown fat through the PGC-1α-dependent myokine irisin: Implications for diabetes and obesity. Dis. Models Mech. 2012, 5, 293–295. [Google Scholar] [CrossRef] [PubMed]
  25. Huh, J.Y.; Panagiotou, G.; Mougios, V.; Brinkoetter, M.; Vamvini, M.T.; Schneider, B.E.; Mantzoros, C.S. FNDC5 and irisin in humans: I. Predictors of circulating concentrations in serum and plasma and II. mRNA expression and circulating concentrations in response to weight loss and exercise. Metabolism 2012, 61, 1725–1738. [Google Scholar] [CrossRef] [PubMed]
  26. Timmons, J.A.; Baar, K.; Davidsen, P.K.; Atherton, P.J. Is irisin a human exercise gene? Nature 2012, 488, E9–E10. [Google Scholar] [CrossRef] [PubMed]
  27. Crujeiras, A.B.; Pardo, M.; Arturo, R.R.; Navas-Carretero, S.; Zulet, M.A.; Martínez, J.A.; Casanueva, F.F. Longitudinal variation of circulating irisin after an energy restriction-induced weight loss and following weight regain in obese men and women. Am. J. Hum. Biol. 2014, 26, 198–207. [Google Scholar] [CrossRef] [PubMed]
  28. Stengel, A.; Hofmann, T.; Goebel-Stengel, M.; Elbelt, U.; Kobelt, P.; Klapp, B.F. Circulating levels of irisin in patients with anorexia nervosa and different stages of obesity—Correlation with body mass index. Peptides 2013, 39, 125–130. [Google Scholar] [CrossRef] [PubMed]
  29. Pardo, M.; Crujeiras, A.B.; Amil, M.; Aguera, Z.; Jiménez-Murcia, S.; Baños, R.; Botella, C.; de la Torre, R.; Estivill, X.; Fagundo, A.B.; et al. Association of irisin with fat mass, resting energy expenditure, and daily activity in conditions of extreme body mass index. Int. J. Endocrinol. 2014, 2014, 857270. [Google Scholar] [CrossRef] [PubMed]
  30. Moreno-Navarrete, J.M.; Ortega, F.; Serrano, M.; Guerra, E.; Pardo, G.; Tinahones, F.; Ricart, W.; Fernández-Real, J.M. Irisin is expressed and produced by human muscle and adipose tissue in association with obesity and insulin resistance. J. Clin. Endocrinol. Metab. 2013, 98, E769–E778. [Google Scholar] [CrossRef] [PubMed]
  31. Boström, P.A.; Fernández-Real, J.M.; Mantzoros, C. Irisin in humans: Recent advances and questions for future research. Metabolism 2014, 63, 178–180. [Google Scholar] [CrossRef] [PubMed]
  32. Elbelt, U.; Hofmann, T.; Stengel, A. Irisin: What promise does it hold? Curr. Opin. Clin. Nutr. Metab. Care 2013, 16, 541–547. [Google Scholar] [CrossRef] [PubMed]
  33. Shoukry, A.; Shalaby, S.M.; El-Arabi Bdeer, S.; Mahmoud, A.A.; Mousa, M.M.; Khalifa, A. Circulating serum irisin levels in obesity and type 2 diabetes mellitus. IUBMB Life 2016, 68, 544–556. [Google Scholar] [CrossRef] [PubMed]
  34. Izumiya, Y.; Bina, H.A.; Ouchi, N.; Akasaki, Y.; Kharitonenkov, A.; Walsh, K. FGF21 is an Akt-regulated myokine. FEBS Lett. 2008, 582, 3805–3810. [Google Scholar] [CrossRef] [PubMed]
  35. Hojman, P.; Pedersen, M.; Nielsen, A.R.; Krogh-Madsen, R.; Yfanti, C.; Akerstrom, T.; Nielsen, S.; Pedersen, B.K. Fibroblast growth factor-21 is induced in human skeletal muscles by hyperinsulinemia. Diabetes 2009, 58, 2797–2801. [Google Scholar] [CrossRef] [PubMed]
  36. Mashili, F.L.; Austin, R.L.; Deshmukh, A.S.; Fritz, T.; Caidahl, K.; Bergdahl, K.; Zierath, J.R.; Chibalin, A.V.; Moller, D.E.; Kharitonenkov, A.; et al. Direct effects of FGF21 on glucose uptake in human skeletal muscle: Implications for type 2 diabetes and obesity. Diabetes Metab. Res. Rev. 2011, 27, 286–297. [Google Scholar] [CrossRef] [PubMed]
  37. Luo, Y.; McKeehan, W.L. Stressed Liver and Muscle Call on Adipocytes with FGF21. Front. Endocrinol. 2013, 4, 194. [Google Scholar] [CrossRef] [PubMed]
  38. Cuevas-Ramos, D.; Almeda-Valdes, P.; Meza-Arana, C.E.; Brito-Cordova, G.; Gomez-Perez, F.J.; Mehta, R.; Oseguera-Moguel, J.; Aguilar-Salinas, C.A. Exercise increases serum fibroblast growth factor 21 (FGF21) levels. PLoS ONE 2012, 7, e38022. [Google Scholar] [CrossRef] [PubMed]
  39. Kim, K.H.; Kim, S.H.; Min, Y.K.; Yang, H.M.; Lee, J.B.; Lee, M.S. Acute exercise induces FGF21 expression in mice and in healthy humans. PLoS ONE 2013, 8, e63517. [Google Scholar] [CrossRef] [PubMed]
  40. Kim, K.H.; Jeong, Y.T.; Oh, H.; Kim, S.H.; Cho, J.M.; Kim, Y.N.; Kim, S.S.; Kim, do.H.; Hur, K.Y.; Kim, H.K.; et al. Autophagy deficiency leads to protection from obesity and insulin resistance by inducing FGF21 as a mitokine. Nat. Med. 2013, 19, 83–92. [Google Scholar] [CrossRef] [PubMed]
  41. Keipert, S.; Ost, M.; Johann, K.; Imber, F.; Jastroch, M.; van Schothorst, E.M.; Keijer, J.; Klaus, S. Skeletal muscle mitochondrial uncoupling drives endocrine cross-talk through the induction of FGF21 as a myokine. Am. J. Physiol. Endocrinol. Metab. 2014, 306, E469–E482. [Google Scholar] [CrossRef] [PubMed]
  42. Roberts, L.D.; Bostrom, P.; O’Sullivan, J.F.; Schinzel, R.T.; Lewis, G.D.; Dejam, A.; Lee, Y.K.; Palma, M.J.; Calhoun, S.; Georgiadi, A.; et al. β-Aminoisobutyric acid induces browning of white fat and hepatic beta-oxidation and is inversely correlated with cardiometabolic risk factors. Cell Metab. 2014, 19, 96–108. [Google Scholar] [CrossRef] [PubMed]
  43. Begriche, K.; Massart, J.; Abbey-Toby, A.; Igoudjil, A.; Lettéron, P.; Fromenty, B. Beta-aminoisobutyric acid prevents diet-induced obesity in mice with partial leptin deficiency. Obesity 2008, 16, 2053–2067. [Google Scholar] [CrossRef] [PubMed]
  44. Jung, T.W.; Hwang, H.J.; Hong, H.C.; Yoo, H.J.; Baik, S.H.; Choi, K.M. BAIBA attenuates insulin resistance and inflammation induced by palmitate or a high fat diet via an AMPK-PPARδ-dependent pathway in mice. Diabetologia 2015, 58, 2096–2105. [Google Scholar] [CrossRef] [PubMed]
  45. Pedersen, B.K.; Fischer, C.P. Beneficial health effects of exercise—The role of IL-6 as a myokine. Trends Pharmacol. Sci. 2007, 28, 152–156. [Google Scholar] [CrossRef] [PubMed]
  46. Pedersen, B.K. IL-6 signalling in exercise and disease. Biochem. Soc. Trans. 2007, 35, 1295–1297. [Google Scholar] [CrossRef] [PubMed]
  47. Pedersen, B.K.; Hoffman-Goetz, L. Exercise and the immune system: Regulation, integration, and adaptation. Physiol. Rev. 2000, 80, 1055–1081. [Google Scholar] [PubMed]
  48. Rosendal, L.; Søgaard, K.; Kjaer, M.; Sjøgaard, G.; Langberg, H.; Kristiansen, J. Increase in interstitial interleukin-6 of human skeletal muscle with repetitive low-force exercise. J. Appl. Physiol. 2005, 98, 477–481. [Google Scholar] [CrossRef] [PubMed]
  49. Pedersen, B.K. Special feature for the Olympics: Effects of exercise on the immune system: Exercise and cytokines. Immunol. Cell Biol. 2000, 78, 532–535. [Google Scholar] [CrossRef] [PubMed]
  50. Hoene, M.; Runge, H.; Häring, H.U.; Schleicher, E.D.; Weigert, C. Interleukin-6 promotes myogenic differentiation of mouse skeletal muscle cells: Role of the STAT3 pathway. Am. J. Physiol. Cell Physiol. 2013, 304, C128–C136. [Google Scholar] [CrossRef] [PubMed]
  51. Carey, A.L.; Steinberg, G.R.; Macaulay, S.L.; Thomas, W.G.; Holmes, A.G.; Ramm, G.; Prelovsek, O.; Hohnen-Behrens, C.; Watt, M.J.; James, D.E.; et al. Interleukin-6 increases insulin-stimulated glucose disposal in humans and glucose uptake and fatty acid oxidation in vitro via AMP-activated protein kinase. Diabetes 2006, 55, 2688–2697. [Google Scholar] [CrossRef] [PubMed]
  52. Ruderman, N.B.; Keller, C.; Richard, A.M.; Saha, A.K.; Luo, Z.; Xiang, X.; Giralt, M.; Ritov, V.B.; Menshikova, E.V.; Kelley, D.E.; et al. Interleukin-6 regulation of AMP-activated protein kinase. Potential role in the systemic response to exercise and prevention of the metabolic syndrome. Diabetes 2006, 55, S48–S54. [Google Scholar] [CrossRef] [PubMed]
  53. Kelly, M.; Gauthier, M.S.; Saha, A.K.; Ruderman, N.B. Activation of AMP-activated protein kinase by interleukin-6 in rat skeletal muscle: Association with changes in cAMP, energy state, and endogenous fuel mobilization. Diabetes 2009, 58, 1953–1960. [Google Scholar] [CrossRef] [PubMed]
  54. Wallenius, V.; Wallenius, K.; Ahrén, B.; Rudling, M.; Carlsten, H.; Dickson, S.L.; Ohlsson, C.; Jansson, J.O. Interleukin-6-deficient mice develop mature-onset obesity. Nat. Med. 2002, 8, 75–79. [Google Scholar] [CrossRef] [PubMed]
  55. Xing, Z.; Gauldie, J.; Cox, G.; Baumann, H.; Jordana, M.; Lei, X.F.; Achong, M.K. IL-6 is an antiinflammatory cytokine required for controlling local or systemic acute inflammatory responses. J. Clin. Investig. 1998, 101, 311–320. [Google Scholar] [CrossRef] [PubMed]
  56. Pedersen, B.K.; Fischer, C.P. Physiological roles of muscle-derived interleukin-6 in response to exercise. Curr. Opin. Clin. Nutr. Metab. Care 2007, 10, 265–271. [Google Scholar] [CrossRef] [PubMed]
  57. Pedersen, B.K.; Steensberg, A.; Schjerling, P. Muscle-derived interleukin-6: Possible biological effects. J. Physiol. 2001, 536, 329–337. [Google Scholar] [CrossRef] [PubMed]
  58. Febbraio, M.A.; Hiscock, N.; Sacchetti, M.; Fischer, C.P.; Pedersen, B.K. Interleukin-6 is a novel factor mediating glucose homeostasis during skeletal muscle contraction. Diabetes 2004, 53, 1643–1648. [Google Scholar] [CrossRef] [PubMed]
  59. Steensberg, A.; van Hall, G.; Osada, T.; Sacchetti, M.; Saltin, B.; Klarlund, P.B. Production of interleukin-6 in contracting human skeletal muscles can account for the exercise-induced increase in plasma interleukin-6. J. Physiol. 2000, 529, 237–242. [Google Scholar] [CrossRef] [PubMed]
  60. Ritchie, D.G. Interleukin 6 stimulates hepatic glucose release from prelabeled glycogen pools. Am. J. Physiol. 1990, 258, E57–E64. [Google Scholar] [PubMed]
  61. Pedersen, L.; Pilegaard, H.; Hansen, J.; Brandt, C.; Adser, H.; Hidalgo, J.; Olesen, J.; Pedersen, B.K.; Hojman, P. Exercise-induced liver chemokine CXCL-1 expression is linked to muscle-derived interleukin-6 expression. J. Physiol. 2011, 589, 1409–1420. [Google Scholar] [CrossRef] [PubMed]
  62. Klover, P.J.; Zimmers, T.A.; Koniaris, L.G.; Mooney, R.A. Chronic exposure to interleukin-6 causes hepatic insulin resistance in mice. Diabetes 2003, 52, 2784–2789. [Google Scholar] [CrossRef] [PubMed]
  63. Kim, J.H.; Kim, J.E.; Liu, H.Y.; Cao, W.; Chen, J. Regulation of interleukin-6-induced hepatic insulin resistance by mammalian target of rapamycin through the STAT3-SOCS3 pathway. J. Biol. Chem. 2008, 283, 708–715. [Google Scholar] [CrossRef] [PubMed]
  64. Pedersen, B.K.; Febbraio, M. Muscle-derived interleukin-6—A possible link between skeletal muscle, adipose tissue, liver, and brain. Brain Behav. Immun. 2005, 19, 371–376. [Google Scholar] [CrossRef] [PubMed]
  65. Prokopchuk, O.; Liu, Y.; Wang, L.; Wirth, K.; Schmidtbleicher, D.; Steinacker, J.M. Skeletal muscle IL-4, IL-4Rα, IL-13 and IL-13Rα1 expression and response to strength training. Exerc. Immunol. Rev. 2007, 13, 67–75. [Google Scholar] [PubMed]
  66. Horsley, V.; Jansen, K.M.; Mills, S.T.; Pavlath, G.K. IL-4 acts as a myoblast recruitment factor during mammalian muscle growth. Cell 2003, 113, 483–494. [Google Scholar] [CrossRef]
  67. Haugen, F.; Norheim, F.; Lian, H.; Wensaas, A.J.; Dueland, S.; Berg, O.; Funderud, A.; Skålhegg, B.S.; Raastad, T.; Drevon, C.A. IL-7 is expressed and secreted by human skeletal muscle cells. Am. J. Physiol. Cell Physiol. 2010, 298, C807–C816. [Google Scholar] [CrossRef] [PubMed]
  68. Baggiolini, M. Chemokines in pathology and medicine. J. Intern. Med. 2001, 250, 91–104. [Google Scholar] [CrossRef] [PubMed]
  69. Pedersen, B.K.; Febbraio, M.A. Muscle as an endocrine organ: Focus on muscle-derived interleukin-6. Physiol. Rev. 2008, 88, 1379–1406. [Google Scholar] [CrossRef] [PubMed]
  70. Belperio, J.A.; Keane, M.P.; Arenberg, D.A.; Addison, C.L.; Ehlert, J.E.; Burdick, M.D.; Strieter, R.M. CXC chemokines in angiogenesis. J. Leukoc. Biol. 2000, 68, 1–8. [Google Scholar] [PubMed]
  71. Koch, A.E.; Polverini, P.J.; Kunkel, S.L.; Harlow, L.A.; DiPietro, L.A.; Elner, V.M.; Elner, S.G.; Strieter, R.M. Interleukin-8 as a macrophage-derived mediator of angiogenesis. Science 1992, 258, 1798–1801. [Google Scholar] [CrossRef] [PubMed]
  72. Frydelund-Larsen, L.; Penkowa, M.; Akerstrom, T.; Zankari, A.; Nielsen, S.; Pedersen, B.K. Exercise induces interleukin-8 receptor (CXCR2) expression in human skeletal muscle. Exp. Physiol. 2007, 92, 233–240. [Google Scholar] [CrossRef] [PubMed]
  73. Nielsen, A.R.; Mounier, R.; Plomgaard, P.; Mortensen, O.H.; Penkowa, M.; Speerschneider, T.; Pilegaard, H.; Pedersen, B.K. Expression of interleukin-15 in human skeletal muscle effect of exercise and muscle fibre type composition. J. Physiol. 2007, 584, 305–312. [Google Scholar] [CrossRef] [PubMed]
  74. Nielsen, A.R.; Hojman, P.; Erikstrup, C.; Fischer, C.P.; Plomgaard, P.; Mounier, R.; Mortensen, O.H.; Broholm, C.; Taudorf, S.; Krogh-Madsen, R.; et al. Association between interleukin-15 and obesity: Interleukin-15 as a potential regulator of fat mass. J. Clin. Endocrinol. Metab. 2008, 93, 4486–4493. [Google Scholar] [CrossRef] [PubMed]
  75. Quinn, L.S.; Anderson, B.G.; Strait-Bodey, L.; Stroud, A.M.; Argilés, J.M. Oversecretion of interleukin-15 from skeletal muscle reduces adiposity. Am. J. Physiol. Endocrinol. Metab. 2009, 296, E191–E202. [Google Scholar] [CrossRef] [PubMed]
  76. Argilés, J.M.; López-Soriano, F.J.; Busquets, S. Therapeutic potential of interleukin-15: A myokine involved in muscle wasting and adiposity. Drug Discov. Today 2009, 14, 208–213. [Google Scholar] [CrossRef] [PubMed]
  77. Busquets, S.; Figueras, M.; Almendro, V.; López-Soriano, F.J.; Argilés, J.M. Interleukin-15 increases glucose uptake in skeletal muscle. An antidiabetogenic effect of the cytokine. Biochim. Biophys. Acta 2006, 1760, 1613–1617. [Google Scholar] [CrossRef] [PubMed]
  78. Yang, H.; Chang, J.; Chen, W.; Zhao, L.; Qu, B.; Tang, C.; Qi, Y.; Zhang, J. Treadmill exercise promotes interleukin 15 expression in skeletal muscle and interleukin 15 receptor alpha expression in adipose tissue of high-fat diet rats. Endocrine 2013, 43, 579–585. [Google Scholar] [CrossRef] [PubMed]
  79. McPherron, A.C.; Lawler, A.M.; Lee, S.J. Regulation of skeletal muscle mass in mice by a new TGF-β superfamily member. Nature 1997, 387, 83–90. [Google Scholar] [CrossRef] [PubMed]
  80. Allen, D.L.; Cleary, A.S.; Speaker, K.J.; Lindsay, S.F.; Uyenishi, J.; Reed, J.M.; Madden, M.C.; Mehan, R.S. Myostatin, activin receptor IIb, and follistatin-like-3 gene expression are altered in adipose tissue and skeletal muscle of obese mice. Am. J. Physiol. Endocrinol. Metab. 2008, 294, E918–E927. [Google Scholar] [CrossRef] [PubMed]
  81. Guo, T.; Jou, W.; Chanturiya, T.; Portas, J.; Gavrilova, O.; McPherron, A.C. Myostatin inhibition in muscle, but not adipose tissue, decreases fat mass and improves insulin sensitivity. PLoS ONE 2009, 4, e4937. [Google Scholar] [CrossRef] [PubMed]
  82. McPherron, A.C.; Lee, S.J. Suppression of body fat accumulation in myostatin-deficient mice. J. Clin. Investig. 2002, 109, 595–601. [Google Scholar] [CrossRef] [PubMed]
  83. Allen, D.L.; Hittel, D.S.; McPherron, A.C. Expression and function of myostatin in obesity, diabetes, and exercise adaptation. Med. Sci. Sports Exerc. 2011, 43, 1828–1835. [Google Scholar] [CrossRef] [PubMed]
  84. Hittel, D.S.; Berggren, J.R.; Shearer, J.; Boyle, K.; Houmard, J.A. Increased secretion and expression of myostatin in skeletal muscle from extremely obese women. Diabetes 2009, 58, 30–38. [Google Scholar] [CrossRef] [PubMed]
  85. Rodino-Klapac, L.R.; Haidet, A.M.; Kota, J.; Handy, C.; Kaspar, B.K.; Mendell, J.R. Inhibition of myostatin with emphasis on follistatin as a therapy for muscle disease. Muscle Nerve 2009, 39, 283–296. [Google Scholar] [CrossRef] [PubMed]
  86. Hofer, M.M.; Barde, Y.A. Brain-derived neurotrophic factor prevents neuronal death in vivo. Nature 1988, 331, 261–262. [Google Scholar] [CrossRef] [PubMed]
  87. Mattson, M.P.; Maudsley, S.; Martin, B. BDNF and 5-HT: A dynamic duo in age-related neuronal plasticity and neurodegenerative disorders. Trends Neurosci. 2004, 27, 589–594. [Google Scholar] [CrossRef] [PubMed]
  88. Tyler, W.J.; Alonso, M.; Bramham, C.R.; Pozzo-Miller, L.D. From acquisition to consolidation: On the role of brain-derived neurotrophic factor signaling in hippocampal-dependent learning. Learn. Mem. 2002, 9, 224–237. [Google Scholar] [CrossRef] [PubMed]
  89. Connor, B.; Young, D.; Yan, Q.; Faull, R.L.; Synek, B.; Dragunow, M. Brain-derived neurotrophic factor is reduced in Alzheimer’s disease. Brain Res. Mol. Brain Res. 1997, 49, 71–81. [Google Scholar] [CrossRef]
  90. Rasmussen, P.; Brassard, P.; Adser, H.; Pedersen, M.V.; Leick, L.; Hart, E.; Secher, N.H.; Pedersen, B.K.; Pilegaard, H. Evidence for a release of brain-derived neurotrophic factor from the brain during exercise. Exp. Physiol. 2009, 94, 1062–1069. [Google Scholar] [CrossRef] [PubMed]
  91. Zuccato, C.; Cattaneo, E. Brain-derived neurotrophic factor in neurodegenerative diseases. Nat. Rev. Neurol. 2009, 5, 311–322. [Google Scholar] [CrossRef] [PubMed]
  92. Krabbe, K.S.; Nielsen, A.R.; Krogh-Madsen, R.; Plomgaard, P.; Rasmussen, P.; Erikstrup, C.; Fischer, C.P.; Lindegaard, B.; Petersen, A.M.; Taudorf, S.; et al. Brain-derived neurotrophic factor (BDNF) and type 2 diabetes. Diabetologia 2007, 50, 431–438. [Google Scholar] [CrossRef] [PubMed]
  93. Komulainen, P.; Pedersen, M.; Hänninen, T.; Bruunsgaard, H.; Lakka, T.A.; Kivipelto, M.; Hassinen, M.; Rauramaa, T.H.; Pedersen, B.K.; Rauramaa, R. BDNF is a novel marker of cognitive function in ageing women: The DR’s EXTRA Study. Neurobiol. Learn. Mem. 2008, 90, 596–603. [Google Scholar] [CrossRef] [PubMed]
  94. Krabbe, K.S.; Mortensen, E.L.; Avlund, K.; Pedersen, A.N.; Pedersen, B.K.; Jørgensen, T.; Bruunsgaard, H. Brain-derived neurotrophic factor predicts mortality risk in older women. J. Am. Geriatr. Soc. 2009, 57, 1447–1452. [Google Scholar] [CrossRef] [PubMed]
  95. Matthews, V.B.; Aström, M.B.; Chan, M.H.; Bruce, C.R.; Krabbe, K.S.; Prelovsek, O.; Akerström, T.; Yfanti, C.; Broholm, C.; Mortensen, O.H.; et al. Brain-derived neurotrophic factor is produced by skeletal muscle cells in response to contraction and enhances fat oxidation via activation of AMP-activated protein kinase. Diabetologia 2009, 52, 1409–1418. [Google Scholar] [CrossRef] [PubMed]
  96. Pedersen, B.K.; Pedersen, M.; Krabbe, K.S.; Bruunsgaard, H.; Matthews, V.B.; Febbraio, M.A. Role of exercise-induced brain-derived neurotrophic factor production in the regulation of energy homeostasis in mammals. Exp. Physiol. 2009, 94, 1153–1160. [Google Scholar] [CrossRef] [PubMed]
  97. Pedersen, B.K. Exercise-induced myokines and their role in chronic diseases. Brain Behav. Immun. 2011, 25, 811–816. [Google Scholar] [CrossRef] [PubMed]
  98. Yamanaka, M.; Tsuchida, A.; Nakagawa, T.; Nonomura, T.; Ono-Kishino, M.; Sugaru, E.; Noguchi, H.; Taiji, M. Brain-derived neurotrophic factor enhances glucose utilization in peripheral tissues of diabetic mice. Diabetes Obes. Metab. 2007, 9, 59–64. [Google Scholar] [CrossRef] [PubMed]
  99. Hilton, D.J.; Nicola, N.A.; Metcalf, D. Purification of a murine leukemia inhibitory factor from Krebs ascites cells. Anal. Biochem. 1988, 173, 359–367. [Google Scholar] [CrossRef]
  100. Heinrich, P.C.; Behrmann, I.; Müller-Newen, G.; Schaper, F.; Graeve, L. Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. Biochem. J. 1998, 334, 297–314. [Google Scholar] [CrossRef] [PubMed]
  101. Metcalf, D. The unsolved enigmas of leukemia inhibitory factor. Stem Cells 2003, 21, 5–14. [Google Scholar] [CrossRef] [PubMed]
  102. Broholm, C.; Pedersen, B.K. Leukaemia inhibitory factor—An exercise-induced myokine. Exerc. Immunol. Rev. 2010, 16, 77–85. [Google Scholar] [PubMed]
  103. Broholm, C.; Laye, M.J.; Brandt, C.; Vadalasetty, R.; Pilegaard, H.; Pedersen, B.K.; Scheele, C. LIF is a contraction-induced myokine stimulating human myocyte proliferation. J. Appl. Physiol. 2011, 111, 251–259. [Google Scholar] [CrossRef] [PubMed]
  104. Alter, J.; Rozentzweig, D.; Bengal, E. Inhibition of myoblast differentiation by tumor necrosis factor alpha is mediated by c-Jun N-terminal kinase 1 and leukemia inhibitory factor. J. Biol. Chem. 2008, 283, 23224–23234. [Google Scholar] [CrossRef] [PubMed]
  105. Diao, Y.; Wang, X.; Wu, Z. SOCS1, SOCS3, and PIAS1 promote myogenic differentiation by inhibiting the leukemia inhibitory factor-induced JAK1/STAT1/STAT3 pathway. Mol. Cell. Biol. 2009, 29, 5084–5093. [Google Scholar] [CrossRef] [PubMed]
  106. Sun, L.; Ma, K.; Wang, H.; Xiao, F.; Gao, Y.; Zhang, W.; Wang, K.; Gao, X.; Ip, N.; Wu, Z. JAK1-STAT1-STAT3, a key pathway promoting proliferation and preventing premature differentiation of myoblasts. J. Cell Biol. 2007, 179, 129–138. [Google Scholar] [CrossRef] [PubMed]
  107. Broholm, C.; Mortensen, O.H.; Nielsen, S.; Akerstrom, T.; Zankari, A.; Dahl, B.; Pedersen, B.K. Exercise induces expression of leukaemia inhibitory factor in human skeletal muscle. J. Physiol. 2008, 586, 2195–2201. [Google Scholar] [CrossRef] [PubMed]
  108. Kurek, J.B.; Bower, J.J.; Romanella, M.; Koentgen, F.; Murphy, M.; Austin, L. The role of leukemia inhibitory factor in skeletal muscle regeneration. Muscle Nerve 1997, 20, 815–822. [Google Scholar] [CrossRef]
  109. Hunt, L.C.; Anthea Coles, C.; Gorman, C.M.; Tudor, E.M.; Smythe, G.M.; White, J.D. Alterations in the expression of leukemia inhibitory factor following exercise: Comparisons between wild-type and mdx muscles. PLoS Curr. 2011, 3, RRN1277. [Google Scholar] [CrossRef] [PubMed]
  110. Shimokawa, H. Osteonectin, a new protein. Nihon Shika Ishikai Zasshi 1984, 37, 487–491. [Google Scholar] [PubMed]
  111. Termine, J.D.; Robey, P.G.; Fisher, L.W.; Shimokawa, H.; Drum, M.A.; Conn, K.M.; Hawkins, G.R.; Cruz, J.B.; Thompson, K.G. Osteonectin, bone proteoglycan, and phosphophoryn defects in a form of bovine osteogenesis imperfecta. Proc. Natl. Acad. Sci. USA 1984, 81, 2213–2217. [Google Scholar] [CrossRef] [PubMed]
  112. Shimokawa, N. Osteonectin—Non-collagenous protein of the bone. Kokubyo Gakkai Zasshi 1984, 51, 460. [Google Scholar] [PubMed]
  113. Holland, P.W.; Harper, S.J.; McVey, J.H.; Hogan, B.L. In vivo expression of mRNA for the Ca++-binding protein SPARC (osteonectin) revealed by in situ hybridization. J. Cell Biol. 1987, 105, 473–482. [Google Scholar] [CrossRef] [PubMed]
  114. Norheim, F.; Raastad, T.; Thiede, B.; Rustan, A.C.; Drevon, C.A.; Haugen, F. Proteomic identification of secreted proteins from human skeletal muscle cells and expression in response to strength training. Am. J. Physiol. Endocrinol. Metab. 2011, 301, E1013–E1021. [Google Scholar] [CrossRef] [PubMed]
  115. Aoi, W.; Naito, Y.; Takagi, T.; Tanimura, Y.; Takanami, Y.; Kawai, Y.; Sakuma, K.; Hang, L.P.; Mizushima, K.; Hirai, Y.; et al. A novel myokine, secreted protein acidic and rich in cysteine (SPARC), suppresses colon tumorigenesis via regular exercise. Gut 2013, 62, 882–889. [Google Scholar] [CrossRef] [PubMed]
  116. Song, H.; Guan, Y.; Zhang, L.; Li, K.; Dong, C. SPARC interacts with AMPK and regulates GLUT4 expression. Biochem. Biophys. Res. Commun. 2010, 396, 961–966. [Google Scholar] [CrossRef] [PubMed]
  117. Jager, S.; Handschin, C.; St-Pierre, J.; Spiegelman, B.M. AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1α. Proc. Natl. Acad. Sci. USA 2007, 104, 12017–12022. [Google Scholar] [CrossRef] [PubMed][Green Version]
  118. Nakamura, K.; Nakano, S.; Miyoshi, T.; Yamanouchi, K.; Nishihara, M. Loss of SPARC in mouse skeletal muscle causes myofiber atrophy. Muscle Nerve 2013, 48, 791–799. [Google Scholar] [CrossRef] [PubMed]
  119. Hamrick, M.W. A role for myokines in muscle-bone interactions. Exerc. Sport Sci. Rev. 2011, 39, 43–47. [Google Scholar] [CrossRef] [PubMed]
  120. Hamrick, M.W.; McNeil, P.L.; Patterson, S.L. Role of muscle-derived growth factors in bone formation. J. Musculoskelet. Neuronal Interact. 2010, 10, 64–70. [Google Scholar] [PubMed]
  121. Ouchi, N.; Oshima, Y.; Ohashi, K.; Higuchi, A.; Ikegami, C.; Izumiya, Y.; Walsh, K. Follistatin-like 1, a secreted muscle protein, promotes endothelial cell function and revascularization in ischemic tissue through a nitric-oxide synthase-dependent mechanism. J. Biol. Chem. 2008, 283, 32802–32811. [Google Scholar] [CrossRef] [PubMed]
  122. Takahashi, A.; Kureishi, Y.; Yang, J.; Luo, Z.; Guo, K.; Mukhopadhyay, D.; Ivashchenko, Y.; Branellec, D.; Walsh, K. Myogenic Akt signaling regulates blood vessel recruitment during myofiber growth. Mol. Cell. Biol. 2002, 22, 4803–4814. [Google Scholar] [CrossRef] [PubMed]
  123. Gorgens, S.W.; Raschke, S.; Holven, K.B.; Jensen, J.; Eckardt, K.; Eckel, J. Regulation of follistatin-like protein 1 expression and secretion in primary human skeletal muscle cells. Arch. Physiol. Biochem. 2013, 119, 75–80. [Google Scholar] [CrossRef] [PubMed]
  124. Hojman, P.; Brolin, C.; Gissel, H.; Brandt, C.; Zerahn, B.; Pedersen, B.K.; Gehl, J. Erythropoietin over-expression protects against diet-induced obesity in mice through increased fat oxidation in muscles. PLoS ONE 2009, 4, e5894. [Google Scholar] [CrossRef] [PubMed]
  125. Rundqvist, H.; Rullman, E.; Sundberg, C.J.; Fischer, H.; Eisleitner, K.; Stahlberg, M.; Sundblad, P.; Jansson, E.; Gustafsson, T. Activation of the erythropoietin receptor in human skeletal muscle. Eur. J. Endocrinol. 2009, 161, 427–434. [Google Scholar] [CrossRef] [PubMed]
  126. Tatsumi, R.; Anderson, J.E.; Nevoret, C.J.; Halevy, O.; Allen, R.E. HGF/SF is present in normal adult skeletal muscle and is capable of activating satellite cells. Dev. Biol. 1998, 194, 114–128. [Google Scholar] [CrossRef] [PubMed]
  127. Tatsumi, R.; Allen, R.E. Active hepatocyte growth factor is present in skeletal muscle extracellular matrix. Muscle Nerve 2004, 30, 654–658. [Google Scholar] [CrossRef] [PubMed]
  128. Tatsumi, R.; Sankoda, Y.; Anderson, J.E.; Sato, Y.; Mizunoya, W.; Shimizu, N.; Suzuki, T.; Yamada, M.; Rhoads, R.P., Jr.; Ikeuchi, Y.; et al. Possible implication of satellite cells in regenerative motoneuritogenesis: HGF upregulates neural chemorepellent Sema3A during myogenic differentiation. Am. J. Physiol. Cell Physiol. 2009, 297, C238–C252. [Google Scholar] [CrossRef] [PubMed]
  129. Sakaguchi, S.; Shono, J.; Suzuki, T.; Sawano, S.; Anderson, J.E.; Do, M.K.; Ohtsubo, H.; Mizunoya, W.; Sato, Y.; Nakamura, M.; et al. Implication of anti-inflammatory macrophages in regenerative moto-neuritogenesis: Promotion of myoblast migration and neural chemorepellent semaphorin 3A expression in injured muscle. Int. J. Biochem. Cell Biol. 2014, 54, 272–285. [Google Scholar] [CrossRef] [PubMed]
  130. Sato, Y.; Do, M.K.; Suzuki, T.; Ohtsubo, H.; Mizunoya, W.; Nakamura, M.; Furuse, M.; Ikeuchi, Y.; Tatsumi, R. Satellite cells produce neural chemorepellent semaphorin 3A upon muscle injury. Anim. Sci. J. 2013, 84, 185–189. [Google Scholar] [CrossRef] [PubMed]
  131. Guilherme, A.; Virbasius, J.V.; Puri, V.; Czech, M.P. Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes. Nat. Rev. Mol. Cell Biol. 2008, 9, 367–377. [Google Scholar] [CrossRef] [PubMed]
  132. Gustafson, B. Adipose tissue, inflammation and atherosclerosis. J. Atheroscler. Thromb. 2010, 17, 332–341. [Google Scholar] [CrossRef] [PubMed]
  133. Stephens, J.M. The fat controller: Adipocyte development. PLoS Biol. 2012, 10, e1001436. [Google Scholar] [CrossRef] [PubMed]
  134. Wang, Y.; Rimm, E.B.; Stampfer, M.J.; Willett, W.C.; Hu, F.B. Comparison of abdominal adiposity and overall obesity in predicting risk of type 2 diabetes among men. Am. J. Clin. Nutr. 2005, 81, 555–563. [Google Scholar] [PubMed]
  135. Zhang, C.; Rexrode, K.M.; van Dam, R.M.; Li, T.Y.; Hu, F.B. Abdominal obesity and the risk of all-cause, cardiovascular, and cancer mortality: Sixteen years of follow-up in US women. Circulation 2008, 117, 1658–1667. [Google Scholar] [CrossRef] [PubMed]
  136. Misra, A.; Garg, A.; Abate, N.; Peshock, R.M.; Stray-Gundersen, J.; Grundy, S.M. Relationship of anterior and posterior subcutaneous abdominal fat to insulin sensitivity in nondiabetic men. Obes. Res. 1997, 5, 93–99. [Google Scholar] [CrossRef] [PubMed]
  137. Snijder, M.B.; Dekker, J.M.; Visser, M.; Bouter, L.M.; Stehouwer, C.D.; Kostense, P.J.; Yudkin, J.S.; Heine, R.J.; Nijpels, G.; Seidell, J.C. Associations of hip and thigh circumferences independent of waist circumference with the incidence of type 2 diabetes: The Hoorn Study. Am. J. Clin. Nutr. 2003, 77, 1192–1197. [Google Scholar] [PubMed]
  138. Schoeller, D.A. The importance of clinical research: The role of thermogenesis in human obesity. Am. J. Clin. Nutr. 2001, 73, 511–516. [Google Scholar] [PubMed]
  139. Wu, J.; Cohen, P.; Spiegelman, B.M. Adaptive thermogenesis in adipocytes: Is beige the new brown? Genes Dev. 2013, 27, 234–250. [Google Scholar] [CrossRef] [PubMed]
  140. Harms, M.; Seale, P. Brown and beige fat: Development, function and therapeutic potential. Nat. Med. 2013, 19, 1252–1263. [Google Scholar] [CrossRef] [PubMed]
  141. Hara, K.; Boutin, P.; Mori, Y.; Tobe, K.; Dina, C.; Yasuda, K.; Yamauchi, T.; Otabe, S.; Okada, T.; Eto, K.; et al. Genetic variation in the gene encoding adiponectin is associated with an increased risk of type 2 diabetes in the Japanese population. Diabetes 2002, 51, 536–540. [Google Scholar] [CrossRef] [PubMed]
  142. Kissebah, A.H.; Sonnenberg, G.E.; Myklebust, J.; Goldstein, M.; Broman, K.; James, R.G.; Marks, J.A.; Krakower, G.R.; Jacob, H.J.; Weber, J.; et al. Quantitative trait loci on chromosomes 3 and 17 influence phenotypes of the metabolic syndrome. Proc. Natl. Acad. Sci. USA 2000, 97, 14478–14483. [Google Scholar] [CrossRef] [PubMed]
  143. Pajvani, U.B.; Du, X.; Combs, T.P.; Berg, A.H.; Rajala, M.W.; Schulthess, T.; Engel, J.; Brownlee, M.; Scherer, P.E. Structure-function studies of the adipocyte-secreted hormone Acrp30/adiponectin. Implications for metabolic regulation and bioactivity. J. Biol. Chem. 2003, 278, 9073–9085. [Google Scholar] [CrossRef] [PubMed]
  144. Tsao, T.S.; Murrey, H.E.; Hug, C.; Lee, D.H.; Lodish, H.F. Oligomerization state-dependent activation of NF-κB signaling pathway by adipocyte complement-related protein of 30 kDa (Acrp30). J. Biol. Chem. 2002, 277, 29359–29362. [Google Scholar] [CrossRef] [PubMed]
  145. Pajvani, U.B.; Hawkins, M.; Combs, T.P.; Rajala, M.W.; Doebber, T.; Berger, J.P.; Wagner, J.A.; Wu, M.; Knopps, A.; Xiang, A.H.; et al. Complex distribution, not absolute amount of adiponectin, correlates with thiazolidinedione-mediated improvement in insulin sensitivity. J. Biol. Chem. 2004, 279, 12152–12162. [Google Scholar] [CrossRef] [PubMed]
  146. Oh, D.K.; Ciaraldi, T.; Henry, R.R. Adiponectin in health and disease. Diabetes Obes. Metab. 2007, 9, 282–289. [Google Scholar] [CrossRef] [PubMed]
  147. Ouchi, N.; Kihara, S.; Funahashi, T.; Matsuzawa, Y.; Walsh, K. Obesity, adiponectin and vascular inflammatory disease. Curr. Opin. Lipidol. 2003, 14, 561–566. [Google Scholar] [CrossRef] [PubMed]
  148. Berg, A.H.; Scherer, P.E. Adipose tissue, inflammation, and cardiovascular disease. Circ. Res. 2005, 96, 939–949. [Google Scholar] [CrossRef] [PubMed]
  149. Moschen, A.R.; Wieser, V.; Tilg, H. Adiponectin: Key player in the adipose tissue-liver crosstalk. Curr. Med. Chem. 2012, 19, 5467–5473. [Google Scholar] [CrossRef] [PubMed]
  150. Ryo, M.; Nakamura, T.; Kihara, S.; Kumada, M.; Shibazaki, S.; Takahashi, M.; Nagai, M.; Matsuzawa, Y.; Funahashi, T. Adiponectin as a biomarker of the metabolic syndrome. Circ. J. 2004, 68, 975–981. [Google Scholar] [CrossRef] [PubMed]
  151. Hosogai, N.; Fukuhara, A.; Oshima, K.; Miyata, Y.; Tanaka, S.; Segawa, K.; Furukawa, S.; Tochino, Y.; Komuro, R.; Matsuda, M.; et al. Adipose tissue hypoxia in obesity and its impact on adipocytokine dysregulation. Diabetes 2007, 56, 901–911. [Google Scholar] [CrossRef] [PubMed]
  152. Ohashi, K.; Ouchi, N.; Matsuzawa, Y. Anti-inflammatory and anti-atherogenic properties of adiponectin. Biochimie 2012, 94, 2137–2142. [Google Scholar] [CrossRef] [PubMed]
  153. Mather, K.J.; Funahashi, T.; Matsuzawa, Y.; Edelstein, S.; Bray, G.A.; Kahn, S.E.; Crandall, J.; Marcovina, S.; Goldstein, B.; Goldberg, R.; et al. Adiponectin, change in adiponectin, and progression to diabetes in the Diabetes Prevention Program. Diabetes 2008, 57, 980–986. [Google Scholar] [CrossRef] [PubMed]
  154. Snijder, M.B.; Heine, R.J.; Seidell, J.C.; Bouter, L.M.; Stehouwer, C.D.; Nijpels, G.; Funahashi, T.; Matsuzawa, Y.; Shimomura, I.; Dekker, J.M. Associations of adiponectin levels with incident impaired glucose metabolism and type 2 diabetes in older men and women: The Hoorn study. Diabetes Care 2006, 29, 2498–2503. [Google Scholar] [CrossRef] [PubMed][Green Version]
  155. Krakoff, J.; Funahashi, T.; Stehouwer, C.D.; Schalkwijk, C.G.; Tanaka, S.; Matsuzawa, Y.; Kobes, S.; Tataranni, P.A.; Hanson, R.L.; Knowler, W.C.; et al. Inflammatory markers, adiponectin, and risk of type 2 diabetes in the Pima Indian. Diabetes Care 2003, 26, 1745–1751. [Google Scholar] [CrossRef] [PubMed]
  156. Mazaki-Tovi, S.; Kanety, H.; Sivan, E. Adiponectin and human pregnancy. Curr. Diabetes Rep. 2005, 5, 278–281. [Google Scholar] [CrossRef]
  157. Yang, W.S.; Lee, W.J.; Funahashi, T.; Tanaka, S.; Matsuzawa, Y.; Chao, C.L.; Chen, C.L.; Tai, T.Y.; Chuang, L.M. Weight reduction increases plasma levels of an adipose-derived anti-inflammatory protein, adiponectin. J. Clin. Endocrinol. Metab. 2001, 86, 3815–3819. [Google Scholar] [CrossRef] [PubMed]
  158. Mavri, A.; Poredos, P.; Suran, D.; Gaborit, B.; Juhan-Vague, I.; Poredos, P. Effect of diet-induced weight loss on endothelial dysfunction: Early improvement after the first week of dieting. Heart Vessels 2011, 26, 31–38. [Google Scholar] [CrossRef] [PubMed]
  159. Hui, X.; Gu, P.; Zhang, J.; Nie, T.; Pan, Y.; Wu, D.; Feng, T.; Zhong, C.; Wang, Y.; Lam, K.S.; et al. Adiponectin Enhances Cold-Induced Browning of Subcutaneous Adipose Tissue via Promoting M2 Macrophage Proliferation. Cell Metab. 2015, 22, 279–290. [Google Scholar] [CrossRef] [PubMed]
  160. Tomas, E.; Tsao, T.S.; Saha, A.K.; Murrey, H.E.; Zhang, C.; Itani, S.I.; Lodish, H.F.; Ruderman, N.B. Enhanced muscle fat oxidation and glucose transport by ACRP30 globular domain: Acetyl-CoA carboxylase inhibition and AMP-activated protein kinase activation. Proc. Natl. Acad. Sci. USA 2002, 99, 16309–16313. [Google Scholar] [CrossRef] [PubMed]
  161. Yamauchi, T.; Kamon, J.; Minokoshi, Y.; Ito, Y.; Waki, H.; Uchida, S.; Yamashita, S.; Noda, M.; Kita, S.; Ueki, K.; et al. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat. Med. 2002, 8, 1288–1295. [Google Scholar] [CrossRef] [PubMed]
  162. Yamauchi, T.; Iwabu, M.; Okada-Iwabu, M.; Kadowaki, T. Adiponectin receptors: A review of their structure, function and how they work. Best Pract. Res. Clin. Endocrinol. Metab. 2014, 28, 15–23. [Google Scholar] [CrossRef] [PubMed]
  163. Okamoto, M.; Ohara-Imaizumi, M.; Kubota, N.; Hashimoto, S.; Eto, K.; Kanno, T.; Kubota, T.; Wakui, M.; Nagai, R.; Noda, M.; et al. Adiponectin induces insulin secretion in vitro and in vivo at a low glucose concentration. Diabetologia 2008, 51, 827–835. [Google Scholar] [CrossRef] [PubMed]
  164. Musso, G.; Gambino, R.; Biroli, G.; Carello, M.; Fagà, E.; Pacini, G.; de Michieli, F.; Cassader, M.; Durazzo, M.; Rizzetto, M.; et al. Hypoadiponectinemia predicts the severity of hepatic fibrosis and pancreatic Beta-cell dysfunction in nondiabetic nonobese patients with nonalcoholic steatohepatitis. Am. J. Gastroenterol. 2005, 100, 2438–2446. [Google Scholar] [CrossRef] [PubMed]
  165. Yamauchi, T.; Kamon, J.; Ito, Y.; Tsuchida, A.; Yokomizo, T.; Kita, S.; Sugiyama, T.; Miyagishi, M.; Hara, K.; Tsunoda, M.; et al. Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature 2003, 423, 762–769. [Google Scholar] [CrossRef] [PubMed]
  166. Yamauchi, T.; Nio, Y.; Maki, T.; Kobayashi, M.; Takazawa, T.; Iwabu, M.; Okada-Iwabu, M.; Kawamoto, S.; Kubota, N.; Kubota, T.; et al. Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions. Nat. Med. 2007, 13, 332–339. [Google Scholar] [CrossRef] [PubMed]
  167. Saunders, T.J.; Palombella, A.; McGuire, K.A.; Janiszewski, P.M.; Després, J.P.; Ross, R. Acute exercise increases adiponectin levels in abdominally obese men. J. Nutr. Metab. 2012, 2012, 148729. [Google Scholar] [CrossRef] [PubMed]
  168. Ferguson, M.A.; White, L.J.; McCoy, S.; Kim, H.W.; Petty, T.; Wilsey, J. Plasma adiponectin response to acute exercise in healthy subjects. Eur. J. Appl. Physiol. 2004, 91, 324–329. [Google Scholar] [CrossRef] [PubMed]
  169. Punyadeera, C.; Zorenc, A.H.; Koopman, R.; McAinch, A.J.; Smit, E.; Manders, R.; Keizer, H.A.; Cameron-Smith, D.; van Loon, L.J. The effects of exercise and adipose tissue lipolysis on plasma adiponectin concentration and adiponectin receptor expression in human skeletal muscle. Eur. J. Endocrinol. 2005, 152, 427–436. [Google Scholar] [CrossRef] [PubMed]
  170. Numao, S.; Katayama, Y.; Hayashi, Y.; Matsuo, T.; Tanaka, K. Influence of acute aerobic exercise on adiponectin oligomer concentrations in middle-aged abdominally obese men. Metabolism 2011, 60, 186–194. [Google Scholar] [CrossRef] [PubMed]
  171. Ohta, H.; Itoh, N. Roles of FGFs as Adipokines in Adipose Tissue Development, Remodeling, and Metabolism. Front. Endocrinol. 2014, 5, 18. [Google Scholar] [CrossRef] [PubMed][Green Version]
  172. Lee, P.; Werner, C.D.; Kebebew, E.; Celi, F.S. Functional thermogenic beige adipogenesis is inducible in human neck fat. Int. J. Obes. (Lond.) 2014, 38, 170–176. [Google Scholar] [CrossRef] [PubMed]
  173. Mraz, M.; Bartlova, M.; Lacinova, Z.; Michalsky, D.; Kasalicky, M.; Haluzikova, D.; Matoulek, M.; Dostalova, I.; Humenanska, V.; Haluzik, M. Serum concentrations and tissue expression of a novel endocrine regulator fibroblast growth factor-21 in patients with type 2 diabetes and obesity. Clin. Endocrinol. 2009, 71, 369–375. [Google Scholar] [CrossRef] [PubMed]
  174. Fisher, F.M.; Kleiner, S.; Douris, N.; Fox, E.C.; Mepani, R.J.; Verdeguer, F.; Wu, J.; Kharitonenkov, A.; Flier, J.S.; Maratos-Flier, E.; et al. FGF21 regulates PGC-1α and browning of white adipose tissues in adaptive thermogenesis. Genes Dev. 2012, 26, 271–281. [Google Scholar] [CrossRef] [PubMed]
  175. Hondares, E.; Iglesias, R.; Giralt, A.; Gonzalez, F.J.; Giralt, M.; Mampel, T.; Villarroya, F. Thermogenic activation induces FGF21 expression and release in brown adipose tissue. J. Biol. Chem. 2011, 286, 12983–12990. [Google Scholar] [CrossRef] [PubMed]
  176. Lee, P.; Linderman, J.D.; Smith, S.; Brychta, R.J.; Wang, J.; Idelson, C.; Perron, R.M.; Werner, C.D.; Phan, G.Q.; Kammula, U.S.; et al. Irisin and FGF21 are cold-induced endocrine activators of brown fat function in humans. Cell Metab. 2014, 19, 302–309. [Google Scholar] [CrossRef] [PubMed]
  177. Lee, P.; Brychta, R.J.; Linderman, J.; Smith, S.; Chen, K.Y.; Celi, F.S. Mild cold exposure modulates fibroblast growth factor 21 (FGF21) diurnal rhythm in humans: Relationship between FGF21 levels, lipolysis, and cold-induced thermogenesis. J. Clin. Endocrinol. Metab. 2013, 98, 98–102. [Google Scholar] [CrossRef] [PubMed]
  178. Park, P.H.; Sanz-Garcia, C.; Nagy, L.E. Adiponectin as an anti-fibrotic and anti-inflammatory adipokine in the liver. Curr. Pathobiol. Rep. 2015, 3, 243–252. [Google Scholar] [CrossRef] [PubMed]
  179. Dong, Z.; Su, L.; Esmaili, S.; Iseli, T.J.; Ramezani-Moghadam, M.; Hu, L.; Xu, A.; George, J.; Wang, J. Adiponectin attenuates liver fibrosis by inducing nitric oxide production of hepatic stellate cells. J. Mol. Med. 2015, 93, 1327–1339. [Google Scholar] [CrossRef] [PubMed]
  180. Silva, T.E.; Colombo, G.; Schiavon, L.L. Adiponectin: A multitasking player in the field of liver diseases. Diabetes. Metab. 2014, 40, 95–107. [Google Scholar] [CrossRef] [PubMed]
  181. Palanivel, R.; Ganguly, R.; Turdi, S.; Xu, A.; Sweeney, G. Adiponectin stimulates Rho-mediated actin cytoskeleton remodeling and glucose uptake via APPL1 in primary cardiomyocytes. Metabolism 2014, 63, 1363–1373. [Google Scholar] [CrossRef] [PubMed]
  182. Lin, Z.; Tian, H.; Lam, K.S.; Lin, S.; Hoo, R.C.; Konishi, M.; Itoh, N.; Wang, Y.; Bornstein, S.R.; Xu, A.; et al. Adiponectin mediates the metabolic effects of FGF21 on glucose homeostasis and insulin sensitivity in mice. Cell Metab. 2013, 17, 779–789. [Google Scholar] [CrossRef] [PubMed]
  183. Holland, W.L.; Adams, A.C.; Brozinick, J.T.; Bui, H.H.; Miyauchi, Y.; Kusminski, C.M.; Bauer, S.M.; Wade, M.; Singhal, E.; Cheng, C.C.; et al. An FGF21-adiponectin-ceramide axis controls energy expenditure and insulin action in mice. Cell Metab. 2013, 17, 790–797. [Google Scholar] [CrossRef] [PubMed]
  184. Ouchi, N.; Higuchi, A.; Ohashi, K.; Oshima, Y.; Gokce, N.; Shibata, R.; Akasaki, Y.; Shimono, A.; Walsh, K. Sfrp5 is an anti-inflammatory adipokine that modulates metabolic dysfunction in obesity. Science 2010, 329, 454–457. [Google Scholar] [CrossRef] [PubMed]
  185. Ross, S.E.; Hemati, N.; Longo, K.A.; Bennett, C.N.; Lucas, P.C.; Erickson, R.L.; MacDougald, O.A. Inhibition of adipogenesis by Wnt signaling. Science 2000, 289, 950–953. [Google Scholar] [CrossRef] [PubMed]
  186. Zhao, Y.; Zhang, C.; Huang, Y.; Yu, Y.; Li, R.; Li, M.; Liu, N.; Liu, P.; Qiao, J. Up-regulated expression of WNT5a increases inflammation and oxidative stress via PI3K/AKT/NF-κB signaling in the granulosa cells of PCOS patients. J. Clin. Endocrinol. Metab. 2015, 100, 201–211. [Google Scholar] [CrossRef] [PubMed]
  187. Catalán, V.; Gómez-Ambrosi, J.; Rodríguez, A.; Pérez-Hernández, A.I.; Gurbindo, J.; Ramírez, B.; Méndez-Giménez, L.; Rotellar, F.; Valentí, V.; Moncada, R.; et al. Activation of noncanonical Wnt signaling through WNT5A in visceral adipose tissue of obese subjects is related to inflammation. J. Clin. Endocrinol. Metab. 2014, 99, 1407–1417. [Google Scholar] [CrossRef] [PubMed]
  188. Bilkovski, R.; Schulte, D.M.; Oberhauser, F.; Mauer, J.; Hampel, B.; Gutschow, C.; Krone, W.; Laudes, M. Adipose tissue macrophages inhibit adipogenesis of mesenchymal precursor cells via wnt-5a in humans. Int. J. Obes. 2011, 35, 1450–1454. [Google Scholar] [CrossRef] [PubMed]
  189. Schulte, D.M.; Müller, N.; Neumann, K.; Oberhäuser, F.; Faust, M.; Güdelhöfer, H.; Brandt, B.; Krone, W.; Laudes, M. Pro-inflammatory wnt5a and anti-inflammatory sFRP5 are differentially regulated by nutritional factors in obese human subjects. PLoS ONE 2012, 7, e32437. [Google Scholar] [CrossRef] [PubMed]
  190. Zhang, Y.; Proenca, R.; Maffei, M.; Barone, M.; Leopold, L.; Friedman, J.M. Positional cloning of the mouse obese gene and its human homologue. Nature 1994, 372, 425–432. [Google Scholar] [CrossRef] [PubMed]
  191. Myers, M.G.; Cowley, M.A.; Münzberg, H. Mechanisms of leptin action and leptin resistance. Annu. Rev. Physiol. 2008, 70, 537–556. [Google Scholar] [CrossRef] [PubMed]
  192. Shimomura, I.; Hammer, R.E.; Ikemoto, S.; Brown, M.S.; Goldstein, J.L. Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy. Nature 1999, 401, 73–76. [Google Scholar] [PubMed]
  193. Oral, E.A.; Simha, V.; Ruiz, E.; Andewelt, A.; Premkumar, A.; Snell, P.; Wagner, A.J.; DePaoli, A.M.; Reitman, M.L.; Taylor, S.I.; et al. Leptin-replacement therapy for lipodystrophy. N. Engl. J. Med. 2002, 346, 570–578. [Google Scholar] [CrossRef] [PubMed]
  194. Friedman, J.M.; Halaas, J.L. Leptin and the regulation of body weight in mammals. Nature 1998, 395, 763–770. [Google Scholar] [CrossRef] [PubMed]
  195. Santos-Alvarez, J.; Goberna, R.; Sánchez-Margalet, V. Human leptin stimulates proliferation and activation of human circulating monocytes. Cell. Immunol. 1999, 194, 6–11. [Google Scholar] [CrossRef] [PubMed]
  196. Kiguchi, N.; Maeda, T.; Kobayashi, Y.; Fukazawa, Y.; Kishioka, S. Leptin enhances CC-chemokine ligand expression in cultured murine macrophage. Biochem. Biophys. Res. Commun. 2009, 384, 311–315. [Google Scholar] [CrossRef] [PubMed]
  197. Zarkesh-Esfahani, H.; Pockley, A.G.; Wu, Z.; Hellewell, P.G.; Weetman, A.P.; Ross, R.J. Leptin indirectly activates human neutrophils via induction of TNF-α. J. Immunol. 2004, 172, 1809–1814. [Google Scholar] [CrossRef] [PubMed]
  198. Grunfeld, C.; Zhao, C.; Fuller, J.; Pollack, A.; Moser, A.; Friedman, J.; Feingold, K.R. Endotoxin and cytokines induce expression of leptin, the ob gene product, in hamsters. J. Clin. Investig. 1996, 97, 2152–2157. [Google Scholar] [CrossRef] [PubMed]
  199. Kirchgessner, T.G.; Uysal, K.T.; Wiesbrock, S.M.; Marino, M.W.; Hotamisligil, G.S. Tumor necrosis factor-alpha contributes to obesity-related hyperleptinemia by regulating leptin release from adipocytes. J. Clin. Investig. 1997, 100, 2777–2782. [Google Scholar] [CrossRef] [PubMed]
  200. Mantzoros, C.S.; Moschos, S.; Avramopoulos, I.; Kaklamani, V.; Liolios, A.; Doulgerakis, D.E.; Griveas, I.; Katsilambros, N.; Flier, J.S. Leptin concentrations in relation to body mass index and the tumor necrosis factor-alpha system in humans. J. Clin. Endocrinol. Metab. 1997, 82, 3408–3413. [Google Scholar] [PubMed]
  201. Christiansen, T.; Paulsen, S.K.; Bruun, J.M.; Pedersen, S.B.; Richelsen, B. Exercise training versus diet-induced weight-loss on metabolic risk factors and inflammatory markers in obese subjects: A 12-week randomized intervention study. Am. J. Physiol. Endocrinol. Metab. 2010, 298, 824–831. [Google Scholar] [CrossRef] [PubMed]
  202. Polak, J.; Klimcakova, E.; Moro, C.; Viguerie, N.; Berlan, M.; Hejnova, J.; Richterova, B.; Kraus, I.; Langin, D.; Stich, V. Effect of aerobic training on plasma levels and subcutaneous abdominal adipose tissue gene expression of adiponectin, leptin, interleukin 6, and tumor necrosis factor alpha in obese women. Metabolism 2006, 55, 1375–1381. [Google Scholar] [CrossRef] [PubMed]
  203. Keller, P.; Keller, C.; Steensberg, A.; Robinson, L.E.; Pedersen, B.K. Leptin gene expression and systemic levels in healthy men: Effect of exercise, carbohydrate, interleukin-6, and epinephrine. J. Appl. Physiol. 2005, 98, 1805–1812. [Google Scholar] [CrossRef] [PubMed]
  204. Varady, K.A.; Bhutani, S.; Church, E.C.; Phillips, S.A. Adipokine responses to acute resistance exercise in trained and untrained men. Med. Sci. Sports Exerc. 2010, 42, 456–462. [Google Scholar] [CrossRef] [PubMed]
  205. Kanaley, J.A.; Fenicchia, L.M.; Miller, C.S.; Ploutz-Synder, L.L.; Weinstock, R.S.; Carhart, R.; Azevedo, J.L., Jr. Resting leptin responses to acute and chronic resistance training in type 2 diabetic men and women. Int. J. Obes. Relat. Metab. Disord. 2001, 25, 1474–1480. [Google Scholar] [CrossRef] [PubMed]
  206. Barwell, N.D.; Malkova, D.; Moran, C.N.; Cleland, S.J.; Packard, C.J.; Zammit, V.A.; Gill, J.M. Exercise training has greater effects on insulin sensitivity in daughters of patients with type 2 diabetes than in women with no family history of diabetes. Diabetologia 2008, 51, 1912–1919. [Google Scholar] [CrossRef] [PubMed]
  207. Codoñer-Franch, P.; Alonso-Iglesias, E. Resistin: Insulin resistance to malignancy. Clin. Chim. Acta 2015, 438, 46–54. [Google Scholar] [CrossRef] [PubMed]
  208. Patel, S.D.; Rajala, M.W.; Rossetti, L.; Scherer, P.E.; Shapiro, L. Disulfide-dependent multimeric assembly of resistin family hormones. Science 2004, 304, 1154–1158. [Google Scholar] [CrossRef] [PubMed]
  209. Banerjee, R.R.; Rangwala, S.M.; Shapiro, J.S.; Rich, A.S.; Rhoades, B.; Qi, Y.; Wang, J.; Rajala, M.W.; Pocai, A.; Scherer, P.E.; et al. Regulation of fasted blood glucose by resistin. Science 2004, 303, 1195–1198. [Google Scholar] [CrossRef] [PubMed]
  210. Qi, Y.; Nie, Z.; Lee, Y.S.; Singhal, N.S.; Scherer, P.E.; Lazar, M.A.; Ahima, R.S. Loss of resistin improves glucose homeostasis in leptin deficiency. Diabetes 2006, 55, 3083–3090. [Google Scholar] [CrossRef] [PubMed]
  211. Steppan, C.M.; Wang, J.; Whiteman, E.L.; Birnbaum, M.J.; Lazar, M.A. Activation of SOCS-3 by resistin. Mol. Cell. Biol. 2005, 25, 1569–1575. [Google Scholar] [CrossRef] [PubMed]
  212. Jamurtas, A.Z.; Theocharis, V.; Koukoulis, G.; Stakias, N.; Fatouros, I.G.; Kouretas, D.; Koutedakis, Y. The effects of acute exercise on serum adiponectin and resistin levels and their relation to insulin sensitivity in overweight males. Eur. J. Appl. Physiol. 2006, 97, 122–126. [Google Scholar] [CrossRef] [PubMed][Green Version]
  213. de Luis, D.A.; Aller, R.; Izaola, O.; Sagrado, M.G.; Conde, R. Influence of ALA54THR polymorphism of fatty acid binding protein 2 on lifestyle modification response in obese subjects. Ann. Nutr. Metab. 2006, 50, 354–360. [Google Scholar] [CrossRef] [PubMed]
  214. Heilbronn, L.K.; Rood, J.; Janderova, L.; Albu, J.B.; Kelley, D.E.; Ravussin, E.; Smith, S.R. Relationship between serum resistin concentrations and insulin resistance in nonobese, obese, and obese diabetic subjects. J. Clin. Endocrinol. Metab. 2004, 89, 1844–1848. [Google Scholar] [CrossRef] [PubMed]
  215. Lee, J.H.; Chan, J.L.; Yiannakouris, N.; Kontogianni, M.; Estrada, E.; Seip, R.; Orlova, C.; Mantzoros, C.S. Circulating resistin levels are not associated with obesity or insulin resistance in humans and are not regulated by fasting or leptin administration: Cross-sectional and interventional studies in normal, insulin-resistant, and diabetic subjects. J. Clin. Endocrinol. Metab. 2003, 88, 4848–4856. [Google Scholar] [CrossRef] [PubMed]
  216. Steppan, C.M.; Bailey, S.T.; Bhat, S.; Brown, E.J.; Banerjee, R.R.; Wright, C.M.; Patel, H.R.; Ahima, R.S.; Lazar, M.A. The hormone resistin links obesity to diabetes. Nature 2001, 409, 307–312. [Google Scholar] [CrossRef] [PubMed]
  217. Savage, D.B.; Sewter, C.P.; Klenk, E.S.; Segal, D.G.; Vidal-Puig, A.; Considine, R.V.; O’Rahilly, S. Resistin/Fizz3 expression in relation to obesity and peroxisome proliferator-activated receptor-gamma action in humans. Diabetes 2001, 50, 2199–2202. [Google Scholar] [CrossRef] [PubMed]
  218. Gastaldelli, A.; Basta, G. Ectopic fat and cardiovascular disease: What is the link? Nutr. Metab. Cardiovasc. Dis. 2010, 20, 481–490. [Google Scholar] [CrossRef] [PubMed]
  219. Hotamisligil, G.S.; Shargill, N.S.; Spiegelman, B.M. Adipose expression of tumor necrosis factor-alpha: Direct role in obesity-linked insulin resistance. Science 1993, 259, 87–91. [Google Scholar] [CrossRef] [PubMed]
  220. Kern, P.A.; Saghizadeh, M.; Ong, J.M.; Bosch, R.J.; Deem, R.; Simsolo, R.B. The expression of tumor necrosis factor in human adipose tissue. Regulation by obesity, weight loss, and relationship to lipoprotein lipase. J. Clin. Investig. 1995, 95, 2111–2119. [Google Scholar] [CrossRef] [PubMed]
  221. Uysal, K.T.; Wiesbrock, S.M.; Marino, M.W.; Hotamisligil, G.S. Protection from obesity-induced insulin resistance in mice lacking TNF-α function. Nature 1997, 389, 610–614. [Google Scholar] [PubMed]
  222. Mishima, Y.; Kuyama, A.; Tada, A.; Takahashi, K.; Ishioka, T.; Kibata, M. Relationship between serum tumor necrosis factor-alpha and insulin resistance in obese men with Type 2 diabetes mellitus. Diabetes Res. Clin. Pract. 2001, 52, 119–123. [Google Scholar] [CrossRef]
  223. Winkler, G.; Salamon, F.; Harmos, G.; Salamon, D.; Speer, G.; Szekeres, O.; Hajós, P.; Kovács, M.; Simon, K.; Cseh, K. Elevated serum tumor necrosis factor-alpha concentrations and bioactivity in Type 2 diabetics and patients with android type obesity. Diabetes Res. Clin. Pract. 1998, 42, 169–174. [Google Scholar] [CrossRef]
  224. Saghizadeh, M.; Ong, J.M.; Garvey, W.T.; Henry, R.R.; Kern, P.A. The expression of TNF α by human muscle. Relationship to insulin resistance. J. Clin. Investig. 1996, 97, 1111–1116. [Google Scholar] [CrossRef] [PubMed]
  225. Berk, P.D.; Zhou, S.L.; Bradbury, M.; Stump, D.; Kiang, C.L.; Isola, L.M. Regulated membrane transport of free fatty acids in adipocytes: Role in obesity and non-insulin dependent diabetes mellitus. Trans. Am. Clin. Climatol. Assoc. 1997, 108, 26–40. [Google Scholar] [PubMed]
  226. Schulze-Osthoff, K.; Bakker, A.C.; Vanhaesebroeck, B.; Beyaert, R.; Jacob, W.A.; Fiers, W. Cytotoxic activity of tumor necrosis factor is mediated by early damage of mitochondrial functions. Evidence for the involvement of mitochondrial radical generation. J. Biol. Chem. 1992, 267, 5317–5323. [Google Scholar] [PubMed]
  227. Bruce, C.R.; Dyck, D.J. Cytokine regulation of skeletal muscle fatty acid metabolism: Effect of interleukin-6 and tumor necrosis factor-alpha. Am. J. Physiol. Endocrinol. Metab. 2004, 287, 616–621. [Google Scholar] [CrossRef] [PubMed]
  228. Christiansen, T.; Bruun, J.M.; Paulsen, S.K.; Olholm, J.; Overgaard, K.; Pedersen, S.B.; Richelsen, B. Acute exercise increases circulating inflammatory markers in overweight and obese compared with lean subjects. Eur. J. Appl. Physiol. 2013, 113, 1635–1642. [Google Scholar] [CrossRef] [PubMed]
  229. Kondo, T.; Kobayashi, I.; Murakami, M. Effect of exercise on circulating adipokine levels in obese young women. Endocr. J. 2006, 53, 189–195. [Google Scholar] [CrossRef] [PubMed]
  230. Phillips, M.D.; Patrizi, R.M.; Cheek, D.J.; Wooten, J.S.; Barbee, J.J.; Mitchell, J.B. Resistance training reduces subclinical inflammation in obese, postmenopausal women. Med. Sci. Sports Exerc. 2012, 44, 2099–2110. [Google Scholar] [CrossRef] [PubMed]
  231. Raschke, S.; Eckardt, K.; Holven, K.B.; Jensen, J.; Eckel, J. Identification and validation of novel contraction-regulated myokines released from primary human skeletal muscle cells. PLoS ONE 2013, 8, e62008. [Google Scholar] [CrossRef] [PubMed]
  232. Dandona, P.; Aljada, A.; Bandyopadhyay, A. Inflammation: The link between insulin resistance, obesity and diabetes. Trends Immunol. 2004, 25, 4–7. [Google Scholar] [CrossRef] [PubMed]
  233. Duncan, B.B.; Schmidt, M.I.; Pankow, J.S.; Ballantyne, C.M.; Couper, D.; Vigo, A.; Hoogeveen, R.; Folsom, A.R.; Heiss, G. Atherosclerosis Risk in Communities Study. Low-grade systemic inflammation and the development of type 2 diabetes: The atherosclerosis risk in communities study. Diabetes 2003, 52, 1799–1805. [Google Scholar] [CrossRef] [PubMed]
  234. Kern, P.A.; Ranganathan, S.; Li, C.; Wood, L.; Ranganathan, G. Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance. Am. J. Physiol. Endocrinol. Metab. 2001, 280, 745–751. [Google Scholar]
  235. Vozarova, B.; Weyer, C.; Hanson, K.; Tataranni, P.A.; Bogardus, C.; Pratley, R.E. Circulating interleukin-6 in relation to adiposity, insulin action, and insulin secretion. Obes. Res. 2001, 9, 414–417. [Google Scholar] [CrossRef] [PubMed]
  236. Oberhauser, F.; Schulte, D.M.; Faust, M.; Güdelhöfer, H.; Hahn, M.; Müller, N.; Neumann, K.; Krone, W.; Laudes, M. Weight loss due to a very low calorie diet differentially affects insulin sensitivity and interleukin-6 serum levels in nondiabetic obese human subjects. Horm. Metab. Res. 2012, 44, 465–470. [Google Scholar] [CrossRef] [PubMed]
  237. Moschen, A.R.; Molnar, C.; Geiger, S.; Graziadei, I.; Ebenbichler, C.F.; Weiss, H.; Kaser, S.; Kaser, A.; Tilg, H. Anti-inflammatory effects of excessive weight loss: Potent suppression of adipose interleukin 6 and tumour necrosis factor alpha expression. Gut 2010, 59, 1259–1264. [Google Scholar] [CrossRef] [PubMed]
  238. Fried, S.K.; Bunkin, D.A.; Greenberg, A.S. Omental and subcutaneous adipose tissues of obese subjects release interleukin-6: Depot difference and regulation by glucocorticoid. J. Clin. Endocrinol. Metab. 1998, 83, 847–850. [Google Scholar] [CrossRef] [PubMed]
  239. Rotter, V.; Nagaev, I.; Smith, U. Interleukin-6 (IL-6) induces insulin resistance in 3T3-L1 adipocytes and is, like IL-8 and tumor necrosis factor-alpha, overexpressed in human fat cells from insulin-resistant subjects. J. Biol. Chem. 2003, 278, 45777–45784. [Google Scholar] [CrossRef] [PubMed]
  240. Ma, X.; Zhou, Z.; Chen, Y.; Wu, Y.; Liu, Y. RBP4 functions as a hepatokine in the regulation of glucose metabolism by the circadian clock in mice. Diabetologia 2016, 59, 354–362. [Google Scholar] [CrossRef] [PubMed]
  241. Maher, J.J. Retinol binding protein 4 and fatty liver: A direct link? Hepatology 2013, 58, 477–479. [Google Scholar] [CrossRef] [PubMed]
  242. Quadro, L.; Blaner, W.S.; Salchow, D.J.; Vogel, S.; Piantedosi, R.; Gouras, P.; Freeman, S.; Cosma, M.P.; Colantuoni, V.; Gottesman, M.E. Impaired retinal function and vitamin A availability in mice lacking retinol-binding protein. EMBO J. 1999, 18, 4633–4644. [Google Scholar] [CrossRef] [PubMed]
  243. Broch, M.; Ramírez, R.; Auguet, M.T.; Alcaide, M.J.; Aguilar, C.; Garcia-Espana, A.; Richart, C. Macrophages are novel sites of expression and regulation of retinol binding protein-4 (RBP4). Physiol. Res. 2010, 59, 299–303. [Google Scholar] [PubMed]
  244. Yang, Q.; Graham, T.E.; Mody, N.; Preitner, F.; Peroni, O.D.; Zabolotny, J.M.; Kotani, K.; Quadro, L.; Kahn, B.B. Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes. Nature 2005, 436, 356–362. [Google Scholar] [CrossRef] [PubMed]
  245. Ost, A.; Danielsson, A.; Lidén, M.; Eriksson, U.; Nystrom, F.H.; Strålfors, P. Retinol-binding protein-4 attenuates insulin-induced phosphorylation of IRS1 and ERK1/2 in primary human adipocytes. FASEB J. 2007, 21, 3696–3704. [Google Scholar] [CrossRef] [PubMed]
  246. Klöting, N.; Graham, T.E.; Berndt, J.; Kralisch, S.; Kovacs, P.; Wason, C.J.; Fasshauer, M.; Schön, M.R.; Stumvoll, M.; Blüher, M.; et al. Serum retinol-binding protein is more highly expressed in visceral than in subcutaneous adipose tissue and is a marker of intra-abdominal fat mass. Cell Metab. 2007, 6, 79–87. [Google Scholar] [CrossRef] [PubMed]
  247. Graham, T.E.; Yang, Q.; Blüher, M.; Hammarstedt, A.; Ciaraldi, T.P.; Henry, R.R.; Wason, C.J.; Oberbach, A.; Jansson, P.A.; Smith, U.; et al. Retinol-binding protein 4 and insulin resistance in lean, obese, and diabetic subjects. N. Engl. J. Med. 2006, 354, 2552–2563. [Google Scholar] [CrossRef] [PubMed]
  248. Balagopal, P.; Graham, T.E.; Kahn, B.B.; Altomare, A.; Funanage, V.; George, D. Reduction of elevated serum retinol binding protein in obese children by lifestyle intervention: Association with subclinical inflammation. J. Clin. Endocrinol. Metab. 2007, 92, 1971–1974. [Google Scholar] [CrossRef] [PubMed]
  249. Varela-Rodríguez, B.M.; Pena-Bello, L.; Juiz-Valiña, P.; Vidal-Bretal, B.; Cordido, F.; Sangiao-Alvarellos, S. FNDC5 expression and circulating irisin levels are modified by diet and hormonal conditions in hypothalamus, adipose tissue and muscle. Sci. Rep. 2016, 6, 29898. [Google Scholar] [CrossRef] [PubMed]
  250. Roca-Rivada, A.; Castelao, C.; Senin, L.L.; Landrove, M.O.; Baltar, J.; Belén Crujeiras, A.; Seoane, L.M.; Casanueva, F.F.; Pardo, M. FNDC5/irisin is not only a myokine but also an adipokine. PLoS ONE 2013, 8, e60563. [Google Scholar] [CrossRef] [PubMed]
  251. Rodríguez, A.; Becerril, S.; Ezquerro, S.; Méndez-Giménez, L.; Frühbeck, G. Cross-talk between adipokines and myokines in fat browning. Acta Physiol. 2016. [Google Scholar] [CrossRef] [PubMed]
  252. Crujeiras, A.B.; Pardo, M.; Casanueva, F.F. Irisin: ‘Fat’ or artefact. Clin. Endocrinol. 2015, 82, 467–474. [Google Scholar] [CrossRef] [PubMed]
  253. Stefan, N.; Fritsche, A.; Weikert, C.; Boeing, H.; Joost, H.G.; Häring, H.U.; Schulze, M.B. Plasma fetuin-A levels and the risk of type 2 diabetes. Diabetes 2008, 57, 2762–2767. [Google Scholar] [CrossRef] [PubMed]
  254. Ix, J.H.; Sharma, K. Mechanisms linking obesity, chronic kidney disease, and fatty liver disease: The roles of fetuin-A, adiponectin, and AMPK. J. Am. Soc. Nephrol. 2010, 21, 406–412. [Google Scholar] [CrossRef] [PubMed]
  255. Dasgupta, S.; Bhattacharya, S.; Biswas, A.; Majumdar, S.S.; Mukhopadhyay, S.; Ray, S.; Bhattacharya, S. NF-κB mediates lipid-induced fetuin-A expression in hepatocytes that impairs adipocyte function effecting insulin resistance. Biochem. J. 2010, 429, 451–462. [Google Scholar] [CrossRef] [PubMed]
  256. Hennige, A.M.; Staiger, H.; Wicke, C.; Machicao, F.; Fritsche, A.; Häring, H.U.; Stefan, N. Fetuin-A induces cytokine expression and suppresses adiponectin production. PLoS ONE 2008, 3, e1765. [Google Scholar] [CrossRef] [PubMed]
  257. Pal, D.; Dasgupta, S.; Kundu, R.; Maitra, S.; Das, G.; Mukhopadhyay, S.; Ray, S.; Majumdar, S.S.; Bhattacharya, S. Fetuin-A acts as an endogenous ligand of TLR4 to promote lipid-induced insulin resistance. Nat. Med. 2012, 18, 1279–1285. [Google Scholar] [CrossRef] [PubMed]
  258. Chatterjee, P.; Seal, S.; Mukherjee, S.; Kundu, R.; Mukherjee, S.; Ray, S.; Mukhopadhyay, S.; Majumdar, S.S.; Bhattacharya, S. Adipocyte fetuin-A contributes to macrophage migration into adipose tissue and polarization of macrophages. J. Biol. Chem. 2013, 288, 28324–28330. [Google Scholar] [CrossRef] [PubMed]
  259. Jialal, I.; Devaraj, S.; Bettaieb, A.; Haj, F.; Adams-Huet, B. Increased adipose tissue secretion of Fetuin-A, lipopolysaccharide-binding protein and high-mobility group box protein 1 in metabolic syndrome. Atherosclerosis 2015, 241, 130–137. [Google Scholar] [CrossRef] [PubMed]
  260. Pérez-Sotelo, D.; Roca-Rivada, A.; Larrosa-García, M.; Castelao, C.; Baamonde, I.; Baltar, J.; Crujeiras, A.B.; Seoane, L.M.; Casanueva, F.F.; Pardo, M. Visceral and subcutaneous adipose tissue express and secrete functional alpha2hsglycoprotein (fetuin a) especially in obesity. Endocrine 2016. [Google Scholar] [CrossRef] [PubMed]
  261. Nordlie, R.C.; Foster, J.D.; Lange, A.J. Regulation of glucose production by the liver. Annu. Rev. Nutr. 1999, 19, 379–406. [Google Scholar] [CrossRef] [PubMed]
  262. Roden, M. Hepatic glucose production and insulin resistance. Wien. Med. Wochenschr. 2008, 158, 558–561. [Google Scholar] [CrossRef] [PubMed]
  263. Beck-Nielsen, H.; Hother-Nielsen, O.; Staehr, P. Is hepatic glucose production increased in type 2 diabetes mellitus? Curr. Diabetes Rep. 2002, 2, 231–236. [Google Scholar] [CrossRef]
  264. Kahn, B.B.; Flier, J.S. Obesity and insulin resistance. J. Clin. Investig. 2000, 106, 473–481. [Google Scholar] [CrossRef] [PubMed]
  265. Nie, Z. Fetuin: Its enigmatic property of growth promotion. Am. J. Physiol. 1992, 263, C551–C562. [Google Scholar] [PubMed]
  266. Brown, W.M.; Saunders, N.R.; Møllgård, K.; Dziegielewska, K.M. Fetuin—An old friend revisited. Bioessays 1992, 14, 749–755. [Google Scholar] [CrossRef] [PubMed]
  267. Denecke, B.; Gräber, S.; Schäfer, C.; Heiss, A.; Wöltje, M.; Jahnen-Dechent, W. Tissue distribution and activity testing suggest a similar but not identical function of fetuin-B and fetuin-A. Biochem. J. 2003, 376, 135–145. [Google Scholar] [CrossRef] [PubMed]
  268. Auberger, P.; Falquerho, L.; Contreres, J.O.; Pages, G.; Le, C.G.; Rossi, B.; Le, C.A. Characterization of a natural inhibitor of the insulin receptor tyrosine kinase: CDNA cloning, purification, and anti-mitogenic activity. Cell 1989, 58, 631–640. [Google Scholar] [CrossRef]
  269. Rauth, G.; Pöschke, O.; Fink, E.; Eulitz, M.; Tippmer, S.; Kellerer, M.; Häring, H.U.; Nawratil, P.; Haasemann, M.; Jahnen-Dechent, W.; et al. The nucleotide and partial amino acid sequences of rat fetuin. Identity with the natural tyrosine kinase inhibitor of the rat insulin receptor. Eur. J. Biochem. 1992, 204, 523–529. [Google Scholar] [CrossRef] [PubMed][Green Version]
  270. Srinivas, P.R.; Wagner, A.S.; Reddy, L.V.; Deutsch, D.D.; Leon, M.A.; Goustin, A.S.; Grunberger, G. Serum alpha 2-HS-glycoprotein is an inhibitor of the human insulin receptor at the tyrosine kinase level. Mol. Endocrinol. 1993, 7, 1445–1455. [Google Scholar] [PubMed]
  271. Mathews, S.T.; Chellam, N.; Srinivas, P.R.; Cintron, V.J.; Leon, M.A.; Goustin, A.S.; Grunberger, G. Alpha2-HSG, a specific inhibitor of insulin receptor autophosphorylation, interacts with the insulin receptor. Mol. Cell. Endocrinol. 2000, 164, 87–98. [Google Scholar] [CrossRef]
  272. Mathews, S.T.; Singh, G.P.; Ranalletta, M.; Cintron, V.J.; Qiang, X.; Goustin, A.S.; Jen, K.L.; Charron, M.J.; Jahnen-Dechent, W.; Grunberger, G. Improved insulin sensitivity and resistance to weight gain in mice null for the Ahsg gene. Diabetes 2002, 51, 2450–2458. [Google Scholar] [CrossRef] [PubMed]
  273. Stefan, N.; Hennige, A.M.; Staiger, H.; Machann, J.; Schick, F.; Kröber, S.M.; Machicao, F.; Fritsche, A.; Häring, H.U. Alpha2-Heremans-Schmid glycoprotein/fetuin-A is associated with insulin resistance and fat accumulation in the liver in humans. Diabetes Care 2006, 29, 853–857. [Google Scholar] [CrossRef] [PubMed]
  274. Jung, T.W.; Youn, B.S.; Choi, H.Y.; Lee, S.Y.; Hong, H.C.; Yang, S.J.; Yoo, H.J.; Kim, B.H.; Baik, S.H.; Choi, K.M. Salsalate and adiponectin ameliorate hepatic steatosis by inhibition of the hepatokine fetuin-A. Biochem. Pharmacol. 2013, 86, 960–969. [Google Scholar] [CrossRef] [PubMed]
  275. Reinehr, T.; Roth, C.L. Fetuin-A and its relation to metabolic syndrome and fatty liver disease in obese children before and after weight loss. J. Clin. Endocrinol. Metab. 2008, 93, 4479–4485. [Google Scholar] [CrossRef] [PubMed]
  276. Mori, K.; Emoto, M.; Yokoyama, H.; Araki, T.; Teramura, M.; Koyama, H.; Shoji, T.; Inaba, M.; Nishizawa, Y. Association of serum fetuin-A with insulin resistance in type 2 diabetic and nondiabetic subjects. Diabetes Care 2006, 29, 468. [Google Scholar] [CrossRef] [PubMed]
  277. Ix, J.H.; Wassel, C.L.; Kanaya, A.M.; Vittinghoff, E.; Johnson, K.C.; Koster, A.; Cauley, J.A.; Harris, T.B.; Cummings, S.R.; Shlipak, M.G. Fetuin-A and incident diabetes mellitus in older persons. JAMA 2008, 300, 182–188. [Google Scholar] [CrossRef] [PubMed]
  278. Emanuelli, B.; Vienberg, S.G.; Smyth, G.; Cheng, C.; Stanford, K.I.; Arumugam, M.; Michael, M.D.; Adams, A.C.; Kharitonenkov, A.; Kahn, C.R. Interplay between FGF21 and insulin action in the liver regulates metabolism. J. Clin. Investig. 2015, 124, 515–527. [Google Scholar] [CrossRef] [PubMed]
  279. Fazeli, P.K.; Lun, M.; Kim, S.M.; Bredella, M.A.; Wright, S.; Zhang, Y.; Lee, H.; Catana, C.; Klibanski, A.; Patwari, P.; et al. FGF21 and the late adaptive response to starvation in humans. J. Clin. Investig. 2015, 125, 4601–4611. [Google Scholar] [CrossRef] [PubMed]
  280. Dushay, J.; Chui, P.C.; Gopalakrishnan, G.S.; Varela-Rey, M.; Crawley, M.; Fisher, F.M.; Badman, M.K.; Martinez-Chantar, M.L.; Maratos-Flier, E. Increased fibroblast growth factor 21 in obesity and nonalcoholic fatty liver disease. Gastroenterology 2010, 139, 456–463. [Google Scholar] [CrossRef] [PubMed]
  281. Kim, S.H.; Kim, K.H.; Kim, H.K.; Kim, M.J.; Back, S.H.; Konishi, M.; Itoh, N.; Lee, M.S. Fibroblast growth factor 21 participates in adaptation to endoplasmic reticulum stress and attenuates obesity-induced hepatic metabolic stress. Diabetologia 2015, 58, 809–818. [Google Scholar] [CrossRef] [PubMed]
  282. Jiang, S.; Yan, C.; Fang, Q.C.; Shao, M.L.; Zhang, Y.L.; Liu, Y.; Deng, Y.P.; Shan, B.; Liu, J.Q.; Li, H.T.; et al. Fibroblast growth factor 21 is regulated by the IRE1α-XBP1 branch of the unfolded protein response and counteracts endoplasmic reticulum stress-induced hepatic steatosis. J. Biol. Chem. 2014, 289, 29751–29765. [Google Scholar] [CrossRef] [PubMed]
  283. Fisher, F.M.; Chui, P.C.; Nasser, I.A.; Popov, Y.; Cunniff, J.C.; Lundasen, T.; Kharitonenkov, A.; Schuppan, D.; Flier, J.S.; Maratos-Flier, E. Fibroblast growth factor 21 limits lipotoxicity by promoting hepatic fatty acid activation in mice on methionine and choline-deficient diets. Gastroenterology 2014, 147, 1073–1083. [Google Scholar] [CrossRef] [PubMed]
  284. Badman, M.K.; Pissios, P.; Kennedy, A.R.; Koukos, G.; Flier, J.S.; Maratos-Flier, E. Hepatic fibroblast growth factor 21 is regulated by PPARα and is a key mediator of hepatic lipid metabolism in ketotic states. Cell Metab. 2007, 5, 426–437. [Google Scholar] [CrossRef] [PubMed]
  285. Inagaki, T.; Dutchak, P.; Zhao, G.; Ding, X.; Gautron, L.; Parameswara, V.; Li, Y.; Goetz, R.; Mohammadi, M.; Esser, V.; et al. Endocrine regulation of the fasting response by PPARα-mediated induction of fibroblast growth factor 21. Cell Metab. 2007, 5, 415–425. [Google Scholar] [CrossRef] [PubMed]
  286. Anson, M.; Crain-Denoyelle, A.M.; Baud, V.; Chereau, F.; Gougelet, A.; Terris, B.; Yamagoe, S.; Colnot, S.; Viguier, M.; Perret, C.; et al. Oncogenic beta-catenin triggers an inflammatory response that determines the aggressiveness of hepatocellular carcinoma in mice. J. Clin. Investig. 2012, 122, 586–599. [Google Scholar] [CrossRef] [PubMed]
  287. Saito, T.; Okumura, A.; Watanabe, H.; Asano, M.; Ishida-Okawara, A.; Sakagami, J.; Sudo, K.; Hatano-Yokoe, Y.; Bezbradica, J.S.; Joyce, S.; et al. Increase in hepatic NKT cells in leukocyte cell-derived chemotaxin 2-deficient mice contributes to severe concanavalin A-induced hepatitis. J. Immunol. 2004, 173, 579–585. [Google Scholar] [CrossRef] [PubMed]
  288. Lan, F.; Misu, H.; Chikamoto, K.; Takayama, H.; Kikuchi, A.; Mohri, K.; Takata, N.; Hayashi, H.; Matsuzawa-Nagata, N.; Takeshita, Y.; et al. LECT2 functions as a hepatokine that links obesity to skeletal muscle insulin resistance. Diabetes 2014, 63, 1649–1664. [Google Scholar] [CrossRef] [PubMed]
  289. Carlson, B.A.; Novoselov, S.V.; Kumaraswamy, E.; Lee, B.J.; Anver, M.R.; Gladyshev, V.N.; Hatfield, D.L. Specific excision of the selenocysteine tRNA[Ser]Sec (Trsp) gene in mouse liver demonstrates an essential role of selenoproteins in liver function. J. Biol. Chem. 2004, 279, 8011–8017. [Google Scholar] [CrossRef] [PubMed]
  290. Burk, R.F.; Hill, K.E. Selenoprotein P: An extracellular protein with unique physical characteristics and a role in selenium homeostasis. Annu. Rev. Nutr. 2005, 25, 215–235. [Google Scholar] [CrossRef] [PubMed]
  291. Misu, H.; Takamura, T.; Takayama, H.; Hayashi, H.; Matsuzawa-Nagata, N.; Kurita, S.; Ishikura, K.; Ando, H.; Takeshita, Y.; Ota, T.; et al. A liver-derived secretory protein, selenoprotein P, causes insulin resistance. Cell Metab. 2010, 12, 483–495. [Google Scholar] [CrossRef] [PubMed]
  292. Jung, T.W.; Choi, H.Y.; Lee, S.Y.; Hong, H.C.; Yang, S.J.; Yoo, H.J.; Youn, B.S.; Baik, S.H.; Choi, K.M. Salsalate and Adiponectin Improve Palmitate-Induced Insulin Resistance via Inhibition of Selenoprotein P through the AMPK-FOXO1α Pathway. PLoS ONE 2013, 8, e66529. [Google Scholar] [CrossRef] [PubMed]
  293. Choi, H.Y.; Hwang, S.Y.; Lee, C.H.; Hong, H.C.; Yang, S.J.; Yoo, H.J.; Seo, J.A.; Kim, S.G.; Kim, N.H.; Baik, S.H.; et al. Increased selenoprotein P levels in subjects with visceral obesity and nonalcoholic fatty liver disease. Diabetes Metab. J. 2013, 37, 63–71. [Google Scholar] [CrossRef] [PubMed]
  294. Yang, S.J.; Hwang, S.Y.; Choi, H.Y.; Yoo, H.J.; Seo, J.A.; Kim, S.G.; Kim, N.H.; Baik, S.H.; Choi, D.S.; Choi, K.M. Serum selenoprotein P levels in patients with type 2 diabetes and prediabetes: Implications for insulin resistance, inflammation, and atherosclerosis. J. Clin. Endocrinol. Metab. 2011, 96, E1325–E1329. [Google Scholar] [CrossRef] [PubMed]
  295. Bozaoglu, K.; Bolton, K.; McMillan, J.; Zimmet, P.; Jowett, J.; Collier, G.; Walder, K.; Segal, D. Chemerin is a novel adipokine associated with obesity and metabolic syndrome. Endocrinology 2007, 148, 4687–4694. [Google Scholar] [CrossRef] [PubMed]
  296. Kukla, M.; Zwirska-Korczala, K.; Hartleb, M.; Waluga, M.; Chwist, A.; Kajor, M.; Ciupinska-Kajor, M.; Berdowska, A.; Wozniak-Grygiel, E.; Buldak, R. Serum chemerin and vaspin in non-alcoholic fatty liver disease. Scand. J. Gastroenterol. 2010, 45, 235–242. [Google Scholar] [CrossRef] [PubMed]
  297. Ernst, M.C.; Issa, M.; Goralski, K.B.; Sinal, C.J. Chemerin exacerbates glucose intolerance in mouse models of obesity and diabetes. Endocrinology 2010, 151, 1998–2007. [Google Scholar] [CrossRef] [PubMed]
  298. Krautbauer, S.; Wanninger, J.; Eisinger, K.; Hader, Y.; Beck, M.; Kopp, A.; Schmid, A.; Weiss, T.S.; Dorn, C.; Buechler, C. Chemerin is highly expressed in hepatocytes and is induced in non-alcoholic steatohepatitis liver. Exp. Mol. Pathol. 2013, 95, 199–205. [Google Scholar] [CrossRef] [PubMed]
  299. Docke, S.; Lock, J.F.; Birkenfeld, A.L.; Hoppe, S.; Lieske, S.; Rieger, A.; Raschzok, N.; Sauer, I.M.; Florian, S.; Osterhoff, M.A.; et al. Elevated hepatic chemerin mRNA expression in human non-alcoholic fatty liver disease. Eur. J. Endocrinol. 2013, 169, 547–557. [Google Scholar] [CrossRef] [PubMed]
  300. Catoire, M.; Mensink, M.; Kalkhoven, E.; Schrauwen, P.; Kersten, S. Identification of human exercise-induced myokines using secretome analysis. Physiol. Genom. 2014, 46, 256–267. [Google Scholar] [CrossRef] [PubMed]
  301. Weigert, C.; Lehmann, R.; Hartwig, S.; Lehr, S. The secretome of the working human skeletal muscle—A promising opportunity to combat the metabolic disaster? Proteom. Clin. Appl. 2014, 8, 5–18. [Google Scholar] [CrossRef] [PubMed]
  302. Safdar, A.; Saleem, A.; Tarnopolsky, M.A. The potential of endurance exercise-derived exosomes to treat metabolic diseases. Nat. Rev. Endocrinol. 2016, 12, 504–517. [Google Scholar] [CrossRef] [PubMed]
  303. Raschke, S.; Eckel, J. Adipo-myokines: Two sides of the same coin—Mediators of inflammation and mediators of exercise. Mediat. Inflamm. 2013, 2013, 320724. [Google Scholar] [CrossRef] [PubMed]
  304. Schering, L.; Hoene, M.; Kanzleiter, T.; Jahnert, M.; Wimmers, K.; Klaus, S.; Eckel, J.; Weigert, C.; Schurmann, A.; Maak, S.; et al. Identification of novel putative adipomyokines by a cross-species annotation of secretomes and expression profiles. Arch. Physiol. Biochem. 2015, 121, 194–205. [Google Scholar] [CrossRef] [PubMed]
  305. Lin, D.; Chun, T.H.; Kang, L. Adipose extracellular matrix remodelling in obesity and insulin resistance. Biochem. Pharmacol. 2016, 119, 8–16. [Google Scholar] [CrossRef] [PubMed][Green Version]
  306. Williams, A.S.; Kang, L.; Wasserman, D.H. The extracellular matrix and insulin resistance. Trends Endocrinol. Metab. 2015, 26, 357–366. [Google Scholar] [CrossRef] [PubMed]
  307. Henninger, A.M.; Eliasson, B.; Jenndahl, L.E.; Hammarstedt, A. Adipocyte hypertrophy, inflammation and fibrosis characterize subcutaneous adipose tissue of healthy, non-obese subjects predisposed to type 2 diabetes. PLoS ONE 2014, 9, e105262. [Google Scholar] [CrossRef] [PubMed]
  308. Lee, M.J.; Wu, Y.; Fried, S.K. Adipose tissue heterogeneity: Implication of depot differences in adipose tissue for obesity complications. Mol. Asp. Med. 2013, 34, 1–11. [Google Scholar] [CrossRef] [PubMed]
  309. Perrini, S.; Ficarella, R.; Picardi, E.; Cignarelli, A.; Barbaro, M.; Nigro, P.; Peschechera, A.; Palumbo, O.; Carella, M.; De Fazio, M.; et al. Differences in gene expression and cytokine release profiles highlight the heterogeneity of distinct subsets of adipose tissue-derived stem cells in the subcutaneous and visceral adipose tissue in humans. PLoS ONE 2013, 8, e57892. [Google Scholar] [CrossRef] [PubMed]
  310. Roca-Rivada, A.; Alonso, J.; Al-Massadi, O.; Castelao, C.; Peinado, J.R.; Seoane, L.M.; Casanueva, F.F.; Pardo, M. Secretome analysis of rat adipose tissues shows location-specific roles for each depot type. J. Proteom. 2011, 74, 1068–1079. [Google Scholar] [CrossRef] [PubMed]
  311. Roca-Rivada, A.; Bravo, S.B.; Pérez-Sotelo, D.; Alonso, J.; Castro, A.I.; Baamonde, I.; Baltar, J.; Casanueva, F.F.; Pardo, M. CILAIR-based secretome analysis of obese visceral and subcutaneous adipose tissues reveals distinctive ECM remodeling and inflammation mediators. Sci. Rep. 2015, 5, 12214. [Google Scholar] [CrossRef] [PubMed]
  312. Zhu, Y.; Tchkonia, T.; Stout, M.B.; Giorgadze, N.; Wang, L.; Li, P.W.; Heppelmann, C.J.; Bouloumié, A.; Jensen, M.D.; Bergen, H.R., 3rd; et al. Inflammation and the depot-specific secretome of human preadipocytes. Obesity 2015, 23, 989–999. [Google Scholar] [CrossRef] [PubMed]
Figure 1. Obesity and type II diabetes are characterized by insulin resistance in peripheral tissues. Under insulin-resistant conditions, impaired insulin action enhances hepatic glucose production. Obese adipose tissue secretes adipokines that induce a pathogenic and pro-inflammatory environment. Exercise-induced myokines may prevent the harmful effects of pro-inflammatory adipokines and hepatokines. FFA: free fatty acid.
Figure 1. Obesity and type II diabetes are characterized by insulin resistance in peripheral tissues. Under insulin-resistant conditions, impaired insulin action enhances hepatic glucose production. Obese adipose tissue secretes adipokines that induce a pathogenic and pro-inflammatory environment. Exercise-induced myokines may prevent the harmful effects of pro-inflammatory adipokines and hepatokines. FFA: free fatty acid.
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Figure 2. Exercise-induced myokines play critical roles in beneficial metabolic adaptations. Contracting skeletal muscles release myokines, and promote hypertrophy and myogenesis within muscle itself. The action of myokines for exercise-induced metabolic adaptation is responsible for promoting glucose uptake, glucose disposal, lipolysis, β-oxidation, angiogenesis, and revascularization. Subsequently, they exert systemic effects that improve lipid and glucose metabolism in white adipose tissue (WAT) and the liver. Specifically, muscular irisin, β-aminoisobutyric acid (BAIBA) and fibroblast growth factor 21 (FGF21) lead to the induction of “browning” in WAT that can counteract obesity and its associated metabolic diseases. UCP1: uncoupling protein 1; PGC1α: peroxisome proliferator-activated receptor gamma coactivator 1-α; FSTL-1: follistatin-related protein 1; LIF: leukemia inhibitory factor; BDNF: brain-derived neurotrophic factor; SPARC: secreted protein acidic and rich in cysteine; AMPK: AMP-activated protein kinase; PPARδ: peroxisome proliferator-activated receptor delta; GLUT1: glucose transporter 1; GLUT4: glucose transporter 4; CXCR-2: CXC chemokine receptor-2; CXCL-1: CXC chemokine ligand-1; EPO: erythropoietin; HGF: hepatocyte growth factor; Sema3A: semaphorin 3A; IGF-1: insulin-like growth factor 1; FGF2: fibroblast growth factor 2.
Figure 2. Exercise-induced myokines play critical roles in beneficial metabolic adaptations. Contracting skeletal muscles release myokines, and promote hypertrophy and myogenesis within muscle itself. The action of myokines for exercise-induced metabolic adaptation is responsible for promoting glucose uptake, glucose disposal, lipolysis, β-oxidation, angiogenesis, and revascularization. Subsequently, they exert systemic effects that improve lipid and glucose metabolism in white adipose tissue (WAT) and the liver. Specifically, muscular irisin, β-aminoisobutyric acid (BAIBA) and fibroblast growth factor 21 (FGF21) lead to the induction of “browning” in WAT that can counteract obesity and its associated metabolic diseases. UCP1: uncoupling protein 1; PGC1α: peroxisome proliferator-activated receptor gamma coactivator 1-α; FSTL-1: follistatin-related protein 1; LIF: leukemia inhibitory factor; BDNF: brain-derived neurotrophic factor; SPARC: secreted protein acidic and rich in cysteine; AMPK: AMP-activated protein kinase; PPARδ: peroxisome proliferator-activated receptor delta; GLUT1: glucose transporter 1; GLUT4: glucose transporter 4; CXCR-2: CXC chemokine receptor-2; CXCL-1: CXC chemokine ligand-1; EPO: erythropoietin; HGF: hepatocyte growth factor; Sema3A: semaphorin 3A; IGF-1: insulin-like growth factor 1; FGF2: fibroblast growth factor 2.
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Figure 3. Adipokines are characterized by both pro-inflammatory and anti-inflammatory activities. Obesity increases the production of pro-inflammatory cytokines such as leptin, resistin, tumor necrosis factor α (TNFα), interleukin 6 (IL-6) and retinol binding protein 4 (RBP4) from adipose tissue. These cytokines are associated with the development of insulin resistance and metabolic abnormalities in local and peripheral tissues. On the other hand, anti-inflammatory adipokines (including adiponectin, FGF21 and SFRP5) can be stimulated by cold shock and exercise, including UCP1 expression in WAT and promoting the browning of WAT (beige). Anti-inflammatory adipokines for metabolic adaptation act systemically in an endocrine manner. They mitigate impaired lipid and glucose metabolism in the liver, muscle and pancreas, leading to improved whole-body insulin sensitivity levels. Therefore, understating the mechanism by which the balance between pro-inflammatory and anti-inflammatory adipokines can be maintained would provide a clue for researchers looking to prevent obesity and related metabolic diseases. LPS: lipopolysaccharide; SOCS3: suppressor of cytokine signaling 3; SFRP5: secreted frizzled-related protein 5; AdipoR1: adiponectin receptor 1; AdipoR2: adiponectin receptor 2.
Figure 3. Adipokines are characterized by both pro-inflammatory and anti-inflammatory activities. Obesity increases the production of pro-inflammatory cytokines such as leptin, resistin, tumor necrosis factor α (TNFα), interleukin 6 (IL-6) and retinol binding protein 4 (RBP4) from adipose tissue. These cytokines are associated with the development of insulin resistance and metabolic abnormalities in local and peripheral tissues. On the other hand, anti-inflammatory adipokines (including adiponectin, FGF21 and SFRP5) can be stimulated by cold shock and exercise, including UCP1 expression in WAT and promoting the browning of WAT (beige). Anti-inflammatory adipokines for metabolic adaptation act systemically in an endocrine manner. They mitigate impaired lipid and glucose metabolism in the liver, muscle and pancreas, leading to improved whole-body insulin sensitivity levels. Therefore, understating the mechanism by which the balance between pro-inflammatory and anti-inflammatory adipokines can be maintained would provide a clue for researchers looking to prevent obesity and related metabolic diseases. LPS: lipopolysaccharide; SOCS3: suppressor of cytokine signaling 3; SFRP5: secreted frizzled-related protein 5; AdipoR1: adiponectin receptor 1; AdipoR2: adiponectin receptor 2.
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Figure 4. Hepatokines are closely related to the development of abnormal glucose and lipid metabolism in those with obesity. Most hepatokines, including fetuin-A, selenoprotein P (SeP), chemerin and leukocyte cell-derived chemotaxin 2 (LECT2), increase hepatic fat accumulation and activate inflammatory signaling in the liver. Further, they exacerbate hepatic glucose metabolism and insulin signaling. On the other hand, FGF21, as a hepatokine, promotes lipid oxidation, inhibits hepatic steatosis, and improves obesity-induced insulin resistance. Moreover, hepatic FGF21 stimulates lipolysis and improves obesity-induced insulin resistance in WAT.
Figure 4. Hepatokines are closely related to the development of abnormal glucose and lipid metabolism in those with obesity. Most hepatokines, including fetuin-A, selenoprotein P (SeP), chemerin and leukocyte cell-derived chemotaxin 2 (LECT2), increase hepatic fat accumulation and activate inflammatory signaling in the liver. Further, they exacerbate hepatic glucose metabolism and insulin signaling. On the other hand, FGF21, as a hepatokine, promotes lipid oxidation, inhibits hepatic steatosis, and improves obesity-induced insulin resistance. Moreover, hepatic FGF21 stimulates lipolysis and improves obesity-induced insulin resistance in WAT.
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MDPI and ACS Style

Oh, K.-J.; Lee, D.S.; Kim, W.K.; Han, B.S.; Lee, S.C.; Bae, K.-H. Metabolic Adaptation in Obesity and Type II Diabetes: Myokines, Adipokines and Hepatokines. Int. J. Mol. Sci. 2017, 18, 8. https://doi.org/10.3390/ijms18010008

AMA Style

Oh K-J, Lee DS, Kim WK, Han BS, Lee SC, Bae K-H. Metabolic Adaptation in Obesity and Type II Diabetes: Myokines, Adipokines and Hepatokines. International Journal of Molecular Sciences. 2017; 18(1):8. https://doi.org/10.3390/ijms18010008

Chicago/Turabian Style

Oh, Kyoung-Jin, Da Som Lee, Won Kon Kim, Baek Soo Han, Sang Chul Lee, and Kwang-Hee Bae. 2017. "Metabolic Adaptation in Obesity and Type II Diabetes: Myokines, Adipokines and Hepatokines" International Journal of Molecular Sciences 18, no. 1: 8. https://doi.org/10.3390/ijms18010008

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