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Special Issue "Adipokines 2.0"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 July 2019).

Special Issue Editor

Prof. Dr. Christa Büchler
E-Mail Website
Guest Editor
Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany
Tel. +49-941-944-7009; Fax: +49-941-944-7016
Interests: adipose tissue; obesity; non-alcoholic fatty liver disease; hepatocellular carcinoma; chemerin
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Special Issue Information

Dear Colleagues,

This Special Issue, “Adipokines 2.0”, will cover a selection of recent research topics and current review articles related to the role of adipokines in health and disease. Up-to-date review articles, commentaries, and experimental papers are all welcome.

Adipokines are released from white adipose tissues and act in an autocrine, paracrine, or endocrine manner. Systemic adipokine levels have emerged as promising biomarkers in various diseases. Over the past decade, associations among adipokines and obesity, cardiovascular disease, type 2 diabetes, cancer, fertility, and many more have been identified. Further research has focused on the role of these proteins in rheumatoid arthritis, inflammatory bowel disease, kidney disease, chronic liver injury, systemic lupus erythematosus, and asthma, just to refer to few of them. There is evidence that brown adipose tissue has its own set of secreted hormones, which may be named “brown adipokines”. These factors seem to enhance energy expenditure. Adipokine receptors are less well characterized, and analysis of their tissue distribution and biological activities awaits further investigation.

Prof. Dr. Christa Büchler
Guest Editor

Manuscript Submission Information

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Keywords

  • adipocyte
  • white adipose tissue
  • brown adipose tissue
  • obesity
  • inflammation
  • metabolic diseases
  • cancer
  • adipokine
  • adipokine receptor
  • drugs

Published Papers (19 papers)

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Research

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Open AccessArticle
Correlative Study on Impaired Prostaglandin E2 Regulation in Epicardial Adipose Tissue and Its Role in Maladaptive Cardiac Remodeling via EPAC2 and ST2 Signaling in Overweight Cardiovascular Disease Subjects
Int. J. Mol. Sci. 2020, 21(2), 520; https://doi.org/10.3390/ijms21020520 - 14 Jan 2020
Abstract
There is recent evidence that the dysfunctional responses of a peculiar visceral fat deposit known as epicardial adipose tissue (EAT) can directly promote cardiac enlargement in the case of obesity. Here, we observed a newer molecular pattern associated with LV dysfunction mediated by [...] Read more.
There is recent evidence that the dysfunctional responses of a peculiar visceral fat deposit known as epicardial adipose tissue (EAT) can directly promote cardiac enlargement in the case of obesity. Here, we observed a newer molecular pattern associated with LV dysfunction mediated by prostaglandin E2 (PGE2) deregulation in EAT in a cardiovascular disease (CVD) population. A series of 33 overweight CVD males were enrolled and their EAT thickness, LV mass, and volumes were measured by echocardiography. Blood, plasma, EAT, and SAT biopsies were collected for molecular and proteomic assays. Our data show that PGE2 biosynthetic enzyme (PTGES-2) correlates with echocardiographic parameters of LV enlargement: LV diameters, LV end diastolic volume, and LV masses. Moreover, PTGES-2 is directly associated with EPAC2 gene (r = 0.70, p < 0.0001), known as a molecular inducer of ST2/IL-33 mediators involved in maladaptive heart remodelling. Furthermore, PGE2 receptor 3 (PTEGER3) results are downregulated and its expression is inversely associated with ST2/IL-33 expression. Contrarily, PGE2 receptor 4 (PTGER4) is upregulated in EAT and directly correlates with ST2 molecular expression. Our data suggest that excessive body fatness can shift the EAT transcriptome to a pro-tissue remodelling profile, may be driven by PGE2 deregulation, with consequent promotion of EPAC2 and ST2 signalling. Full article
(This article belongs to the Special Issue Adipokines 2.0)
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Open AccessArticle
Adiponectin Reverses the Hypothalamic Microglial Inflammation during Short-Term Exposure to Fat-Rich Diet
Int. J. Mol. Sci. 2019, 20(22), 5738; https://doi.org/10.3390/ijms20225738 - 15 Nov 2019
Abstract
Adiponectin, an adipokine derived from the adipose tissue, manifests anti-inflammatory effects in the metabolically active organs and is, therefore, beneficial in various metabolic diseases associated with inflammation. However, the role of adiponectin in alleviating the hypothalamic inflammation connected to the pathogenesis of obesity [...] Read more.
Adiponectin, an adipokine derived from the adipose tissue, manifests anti-inflammatory effects in the metabolically active organs and is, therefore, beneficial in various metabolic diseases associated with inflammation. However, the role of adiponectin in alleviating the hypothalamic inflammation connected to the pathogenesis of obesity has not yet been clearly interrogated. Here, we identified that the systemic administration of adiponectin suppresses the activation of microglia and thereby reverses the hypothalamic inflammation during short-term exposure to a high-fat diet. Additionally, we show that adiponectin induces anti-inflammatory effects in the microglial cell line subjected to an exogenous treatment with a saturated free fatty acid. In conclusion, the current study suggests that adiponectin suppresses the saturated free fatty acid-triggered the hypothalamic inflammation by modulating the microglial activation and thus maintains energy homeostasis. Full article
(This article belongs to the Special Issue Adipokines 2.0)
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Open AccessArticle
Effects of Tocilizumab, an Anti-Interleukin-6 Receptor Antibody, on Serum Lipid and Adipokine Levels in Patients with Rheumatoid Arthritis
Int. J. Mol. Sci. 2019, 20(18), 4633; https://doi.org/10.3390/ijms20184633 - 18 Sep 2019
Cited by 1
Abstract
Patients with rheumatoid arthritis (RA) are at increased risk of cardiovascular disease. Dyslipidemia is a known adverse effect of tocilizumab (TCZ), an anti-interleukin-6 receptor antibody used in RA treatment. We aimed to assess the effect of TCZ on lipid profile and adipokine levels [...] Read more.
Patients with rheumatoid arthritis (RA) are at increased risk of cardiovascular disease. Dyslipidemia is a known adverse effect of tocilizumab (TCZ), an anti-interleukin-6 receptor antibody used in RA treatment. We aimed to assess the effect of TCZ on lipid profile and adipokine levels in RA patients. Height, weight, disease activity scores, lipid profile and atherogenic indices (AI), leptin, adiponectin, resistin, interleukin-6, and high-sensitivity C-reactive protein (CRP) were measured before and four months after initiation of TCZ in 40 RA patients and 40 healthy controls. Following TCZ treatment, total cholesterol, high density lipoprotein (HDL), and triglycerides were significantly elevated, but no significant changes in weight, body mass index (BMI), low density lipoprotein (LDL), and AI were observed. Compared with controls, significantly higher adiponectin levels were measured in the RA group at baseline. Following TCZ treatment, resistin levels and the leptin-to-adiponectin ratio increased, adiponectin levels decreased, and leptin levels remained unchanged. No correlation was found between the change in adipokine serum levels and changes in the disease activity indices, nor the lipid profile. In conclusion, the changes observed suggest a protective role for TCZ on the metabolic and cardiovascular burden associated with RA, but does not provide a mechanistic explanation for this phenomenon. Full article
(This article belongs to the Special Issue Adipokines 2.0)
Open AccessArticle
Glucose Restriction Plus Refeeding in Vitro Induce Changes of the Human Adipocyte Secretome with an Impact on Complement Factors and Cathepsins
Int. J. Mol. Sci. 2019, 20(16), 4055; https://doi.org/10.3390/ijms20164055 - 20 Aug 2019
Abstract
Adipose tissue is a major endocrine organ capable of secreting adipokines with a role in whole-body metabolism. Changes in the secretome profile during the development of obesity is suspected to contribute to the risk of health complications such as those associated with weight [...] Read more.
Adipose tissue is a major endocrine organ capable of secreting adipokines with a role in whole-body metabolism. Changes in the secretome profile during the development of obesity is suspected to contribute to the risk of health complications such as those associated with weight regain after weight loss. However, the number of studies on weight regain is limited and secretome changes during weight regain have hardly been investigated. In an attempt to generate leads for in vivo studies, we have subjected human Simpson Golabi Behmel Syndrome adipocytes to glucose restriction (GR) followed by refeeding (RF) as an in vitro surrogate for weight regain after weight loss. Using LC-MS/MS, we compared the secreted protein profile after GR plus RF with that of normal feeding (NF) to assess the consequences of GR plus RF. We identified 338 secreted proteins of which 49 were described for the first time as being secreted by adipocytes. In addition, comparison between NF and GR plus RF showed 39 differentially secreted proteins. Functional classification revealed GR plus RF-induced changes of enzymes for extracellular matrix modification, complement system factors, cathepsins, and several proteins related to Alzheimer’s disease. These observations can be used as clues to investigate metabolic consequences of weight regain, weight cycling or intermittent fasting. Full article
(This article belongs to the Special Issue Adipokines 2.0)
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Open AccessArticle
Serum Chemerin Does Not Differentiate Colorectal Liver Metastases from Hepatocellular Carcinoma
Int. J. Mol. Sci. 2019, 20(16), 3919; https://doi.org/10.3390/ijms20163919 - 12 Aug 2019
Cited by 2
Abstract
The chemoattractant adipokine chemerin is related to the metabolic syndrome, which is a risk factor for different cancers. Recent studies provide evidence that chemerin is an important molecule in colorectal cancer (CRC) and hepatocellular carcinoma (HCC). Serum chemerin is high in CRC patients [...] Read more.
The chemoattractant adipokine chemerin is related to the metabolic syndrome, which is a risk factor for different cancers. Recent studies provide evidence that chemerin is an important molecule in colorectal cancer (CRC) and hepatocellular carcinoma (HCC). Serum chemerin is high in CRC patients and low in HCC patients and may serve as a differential diagnostic marker for HCC and liver metastases from CRC. To this end, serum chemerin was measured in 36 patients with CRC metastases, 32 patients with HCC and 49 non-tumor patients by ELISA. Chemerin serum protein levels were, however, similar in the three cohorts. Serum chemerin was higher in hypertensive than normotensive tumor patients but not controls. Cancer patients with hypercholesterolemia or hyperuricemia also had increased serum chemerin. When patients with these comorbidities were excluded from the calculation, chemerin was higher in CRC than HCC patients but did not differ from controls. Chemerin did not correlate with the tumor markers carcinoembryonic antigen, carbohydrate antigen 19-9 and alpha-fetoprotein in both cohorts and was not changed with tumor-node-metastasis stage in HCC. Chemerin was not associated with hepatic fat, liver inflammation and fibrosis. To conclude, systemic chemerin did not discriminate between CRC metastases and HCC. Comorbidities among tumor patients were linked with elevated systemic chemerin. Full article
(This article belongs to the Special Issue Adipokines 2.0)
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Open AccessArticle
Expression of Chemerin and Its Receptors in the Porcine Hypothalamus and Plasma Chemerin Levels during the Oestrous Cycle and Early Pregnancy
Int. J. Mol. Sci. 2019, 20(16), 3887; https://doi.org/10.3390/ijms20163887 - 09 Aug 2019
Abstract
Chemerin (CHEM) may act as an important link integrating energy homeostasis and reproductive functions of females, and its actions are mediated by three receptors: chemokine-like receptor 1 (CMKLR1), G protein-coupled receptor 1 (GPR1), and C-C motif chemokine receptor-like 2 (CCRL2). The aim of [...] Read more.
Chemerin (CHEM) may act as an important link integrating energy homeostasis and reproductive functions of females, and its actions are mediated by three receptors: chemokine-like receptor 1 (CMKLR1), G protein-coupled receptor 1 (GPR1), and C-C motif chemokine receptor-like 2 (CCRL2). The aim of the current study was to compare the expression of CHEM and its receptor (CHEM system) mRNAs (quantitative real-time PCR) and proteins (Western blotting and fluorescent immunohistochemistry) in the selected areas of the porcine hypothalamus responsible for gonadotropin-releasing hormone production and secretion: the mediobasal hypothalamus, preoptic area and stalk median eminence during the oestrous cycle and early pregnancy. Moreover, plasma CHEM concentrations were determined using ELISA. The expression of CHEM system has been demonstrated in the porcine hypothalamus throughout the luteal phase and follicular phase of the oestrous cycle, and during early pregnancy from days 10 to 28. Plasma CHEM levels and concentrations of transcripts and proteins of CHEM system components in the hypothalamus fluctuated throughout pregnancy and the oestrous cycle. Our study was the first experiment to demonstrate the presence of CHEM system mRNAs and proteins in the porcine hypothalamus and the correlations between the expression levels and physiological hormonal milieu related to the oestrous cycle and early pregnancy. Full article
(This article belongs to the Special Issue Adipokines 2.0)
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Open AccessArticle
Ovarian Expression of Adipokines in Polycystic Ovary Syndrome: A Role for Chemerin, Omentin, and Apelin in Follicular Growth Arrest and Ovulatory Dysfunction?
Int. J. Mol. Sci. 2019, 20(15), 3778; https://doi.org/10.3390/ijms20153778 - 02 Aug 2019
Cited by 1
Abstract
Adipokines are a potential link between reproduction and energy metabolism and could partly explain some infertilities related to some pathophysiology, such as polycystic ovary syndrome (PCOS). However, adipokines were predominantly assessed in blood samples, while very little is known concerning their variations in [...] Read more.
Adipokines are a potential link between reproduction and energy metabolism and could partly explain some infertilities related to some pathophysiology, such as polycystic ovary syndrome (PCOS). However, adipokines were predominantly assessed in blood samples, while very little is known concerning their variations in follicular fluid (FF) and ovarian granulosa cells (GCs) of PCOS women. Thus, the objectives of our study were to investigate adiponectin, chemerin, resistin, visfatin, omentin, and apelin ovarian expression in PCOS women in comparison with controls and women with only a polycystic ovary morphology. In total, 78 women undergoing an in vitro fertilization procedure were divided into three groups: 23 PCOS women, 28 women presenting only ≥12 follicles per ovary (ECHO group), and 27 control women. Each group almost equally included normal weight and obese women. Follicular fluid (FF) concentration and granulosa cells (GCs) mRNA expression of adipokines and their receptors were assessed by ELISA and RT-qPCR, respectively. Omentin levels in FF and GC were higher in PCOS than in ECHO and control women, while apelin expression was increased in both PCOS and ECHO groups. FF chemerin concentration was predominant in normal-weight PCOS women compared to BMI (Body Mass Index)-matched ECHO and control women, while GC mRNA levels were higher in the obese PCOS group than in the ECHO one. Compared to PCOS, ECHO women had increased FF adiponectin concentrations and lower plasma AMH levels. The FF concentration of all adipokines was higher in obese subjects except for adiponectin, predominant in normal-weight women. In conclusion, women with PCOS expressed higher GC chemerin and omentin, whereas the ECHO group presented higher levels of FF adiponectin and apelin and lower plasma AMH and LH concentrations. Chemerin, omentin, and apelin expression was differently regulated in women with PCOS, suggesting their possible role in follicular growth arrest and ovulatory dysfunction characterizing PCOS pathogenesis. Full article
(This article belongs to the Special Issue Adipokines 2.0)
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Open AccessArticle
Adipokinome Signatures in Obese Mouse Models Reflect Adipose Tissue Health and Are Associated with Serum Lipid Composition
Int. J. Mol. Sci. 2019, 20(10), 2559; https://doi.org/10.3390/ijms20102559 - 24 May 2019
Cited by 2
Abstract
Adipocyte and hepatic lipid metabolism govern whole-body metabolic homeostasis, whereas a disbalance of de novo lipogenesis (DNL) in fat and liver might lead to obesity, with severe co-morbidities. Nevertheless, some obese people are metabolically healthy, but the “protective” mechanisms are not yet known [...] Read more.
Adipocyte and hepatic lipid metabolism govern whole-body metabolic homeostasis, whereas a disbalance of de novo lipogenesis (DNL) in fat and liver might lead to obesity, with severe co-morbidities. Nevertheless, some obese people are metabolically healthy, but the “protective” mechanisms are not yet known in detail. Especially, the adipocyte-derived molecular mediators that indicate adipose functionality are poorly understood. We studied transgenic mice (alb-SREBP-1c) with a “healthy” obese phenotype, and obob mice with hyperphagia-induced “sick” obesity to analyze the impact of the tissue-specific DNL on the secreted proteins, i.e., the adipokinome, of the primary adipose cells by label-free proteomics. Compared to the control mice, adipose DNL is reduced in both obese mouse models. In contrast, the hepatic DNL is reduced in obob but elevated in alb-SREBP-1c mice. To investigate the relationship between lipid metabolism and adipokinomes, we formulated the “liver-to-adipose-tissue DNL” ratio. Knowledge-based analyses of these results revealed adipocyte functionality with proteins, which was involved in tissue remodeling or metabolism in the alb-SREBP-1c mice and in the control mice, but mainly in fibrosis in the obob mice. The adipokinome in “healthy” obesity is similar to that in a normal condition, but it differs from that in “sick” obesity, whereas the serum lipid patterns reflect the “liver-to-adipose-tissue DNL” ratio and are associated with the adipokinome signature. Full article
(This article belongs to the Special Issue Adipokines 2.0)
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Open AccessArticle
Leptin and Ghrelin in Excessive Gestational Weight Gain—Association between Mothers and Offspring
Int. J. Mol. Sci. 2019, 20(10), 2398; https://doi.org/10.3390/ijms20102398 - 15 May 2019
Abstract
Two-thirds of pregnant women exceed gestational weight gain recommendations. Excessive gestational weight gain (EGWG) appears to be associated with offspring’s complications induced by mechanisms that are still unclear. The aim of this study was to investigate whether umbilical cord leptin (UCL) and ghrelin [...] Read more.
Two-thirds of pregnant women exceed gestational weight gain recommendations. Excessive gestational weight gain (EGWG) appears to be associated with offspring’s complications induced by mechanisms that are still unclear. The aim of this study was to investigate whether umbilical cord leptin (UCL) and ghrelin (UCG) concentrations are altered in full-term neonates born to EGWG mothers and whether neonatal anthropometric measurements correlate with UCL and UCG levels and maternal serum ghrelin and leptin as well as urine ghrelin concentrations. The study subjects were divided into two groups, 28 healthy controls and 38 patients with EGWG. Lower UCL and UCG levels were observed in neonates born to healthy mothers but only in male newborns. In the control group UCG concentrations correlated positively with neonatal birth weight, body length and head circumference. In the control group maternal serum ghrelin levels correlated negatively with neonatal birth weight, body length and head circumference as well as positively with chest circumference. In the EGWG group UCG concentrations correlated negatively with neonatal birth weight and birth body length. UCL correlated positively with birth body length in EGWG group and negatively with head circumference in the control group. In conclusion, EGWG is associated with disturbances in UCL and UCG concentrations. Full article
(This article belongs to the Special Issue Adipokines 2.0)
Open AccessArticle
Umbilical Cord SFRP5 Levels of Term Newborns in Relation to Normal and Excessive Gestational Weight Gain
Int. J. Mol. Sci. 2019, 20(3), 595; https://doi.org/10.3390/ijms20030595 - 30 Jan 2019
Cited by 2
Abstract
Among the new adipokines, secreted frizzled-related protein 5 (SFRP5) is considered to prevent obesity and insulin resistance. The umbilical cord SFRP5 levels have not yet been investigated. The main aim of the study was to investigate whether the umbilical cord SFRP5 concentrations are [...] Read more.
Among the new adipokines, secreted frizzled-related protein 5 (SFRP5) is considered to prevent obesity and insulin resistance. The umbilical cord SFRP5 levels have not yet been investigated. The main aim of the study was to investigate whether the umbilical cord SFRP5 concentrations are altered in term neonates born to mothers with excessive gestational weight gain (EGWG). Two groups of subjects were selected depending on their gestational weight gain, i.e. 28 controls and 38 patients with EGWG. Umbilical cord and maternal serum SFRP5 levels were lower in the EGWG group. Umbilical cord SFRP5 concentrations were directly associated with the maternal serum SFRP5, hemoglobin A1c and lean tissue index, umbilical cord leptin levels, as well as newborns’ anthropometric measurements in the EGWG subjects. In multiple linear regression models performed in all the study participants, umbilical cord SFRP5 concentrations depended positively on the maternal serum SFRP5, ghrelin, and leptin levels and negatively on the umbilical cord ghrelin levels, low-density lipoprotein cholesterol, pre-pregnancy body mass index, and gestational weight gain. EGWG is associated with disturbances in SFRP5 concentrations. Obstetricians and midwives should pay attention to nutrition and weight management during pregnancy. Full article
(This article belongs to the Special Issue Adipokines 2.0)
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Review

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Open AccessReview
Metabolic Health—The Role of Adipo-Myokines
Int. J. Mol. Sci. 2019, 20(24), 6159; https://doi.org/10.3390/ijms20246159 - 06 Dec 2019
Abstract
Obesity is now a worldwide epidemic. In recent years, different phenotypes of obesity, ranging from metabolically healthy normal weight to metabolically unhealthy obese, were described. Although there is no standardized definition for these phenotypes or for metabolic health, the influence of lifestyle and [...] Read more.
Obesity is now a worldwide epidemic. In recent years, different phenotypes of obesity, ranging from metabolically healthy normal weight to metabolically unhealthy obese, were described. Although there is no standardized definition for these phenotypes or for metabolic health, the influence of lifestyle and early-life factors is undisputed. In this context, the ratio of muscle-to-fat tissue seems to play a crucial role. Both adipose tissue and skeletal muscle are highly heterogeneous endocrine organs secreting several hormones, with myokines and adipokines being involved in local autocrine/paracrine interactions and crosstalk with other tissues. Some of these endocrine factors are secreted by both tissues and are, therefore, termed adipo-myokines. High (cardiorespiratory) fitness as a surrogate parameter for an active lifestyle is epidemiologically linked to “better” metabolic health, even in the obese; this may be partly due to the role of adipo-myokines and the crosstalk between adipose and muscle tissue. Therefore, it is essential to consider (cardiovascular) fitness in the definition of metabolically healthy obese/metabolic health and to perform longitudinal studies in this regard. A better understanding of both the (early-life) lifestyle factors and the underlying mechanisms that mediate different phenotypes is necessary for the tailored prevention and personalized treatment of obesity. Full article
(This article belongs to the Special Issue Adipokines 2.0)
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Open AccessReview
The Novel Perspectives of Adipokines on Brain Health
Int. J. Mol. Sci. 2019, 20(22), 5638; https://doi.org/10.3390/ijms20225638 - 11 Nov 2019
Abstract
First seen as a fat-storage tissue, the adipose tissue is considered as a critical player in the endocrine system. Precisely, adipose tissue can produce an array of bioactive factors, including cytokines, lipids, and extracellular vesicles, which target various systemic organ systems to regulate [...] Read more.
First seen as a fat-storage tissue, the adipose tissue is considered as a critical player in the endocrine system. Precisely, adipose tissue can produce an array of bioactive factors, including cytokines, lipids, and extracellular vesicles, which target various systemic organ systems to regulate metabolism, homeostasis, and immune response. The global effects of adipokines on metabolic events are well defined, but their impacts on brain function and pathology remain poorly defined. Receptors of adipokines are widely expressed in the brain. Mounting evidence has shown that leptin and adiponectin can cross the blood–brain barrier, while evidence for newly identified adipokines is limited. Significantly, adipocyte secretion is liable to nutritional and metabolic states, where defective circuitry, impaired neuroplasticity, and elevated neuroinflammation are symptomatic. Essentially, neurotrophic and anti-inflammatory properties of adipokines underlie their neuroprotective roles in neurodegenerative diseases. Besides, adipocyte-secreted lipids in the bloodstream can act endocrine on the distant organs. In this article, we have reviewed five adipokines (leptin, adiponectin, chemerin, apelin, visfatin) and two lipokines (palmitoleic acid and lysophosphatidic acid) on their roles involving in eating behavior, neurotrophic and neuroprotective factors in the brain. Understanding and regulating these adipokines can lead to novel therapeutic strategies to counteract metabolic associated eating disorders and neurodegenerative diseases, thus promote brain health. Full article
(This article belongs to the Special Issue Adipokines 2.0)
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Open AccessReview
The Role of Adipokines as Circulating Biomarkers in Critical Illness and Sepsis
Int. J. Mol. Sci. 2019, 20(19), 4820; https://doi.org/10.3390/ijms20194820 - 28 Sep 2019
Abstract
Sepsis represents a major global health burden. Early diagnosis of sepsis as well as guiding early therapeutic decisions in septic patients still represent major clinical challenges. In this context, a whole plethora of different clinical and serum-based markers have been tested regarding their [...] Read more.
Sepsis represents a major global health burden. Early diagnosis of sepsis as well as guiding early therapeutic decisions in septic patients still represent major clinical challenges. In this context, a whole plethora of different clinical and serum-based markers have been tested regarding their potential for early detection of sepsis and their ability to stratify patients according to their probability to survive critical illness and sepsis. Adipokines represent a fast-growing class of proteins that have gained an increasing interest with respect to their potential to modulate immune responses in inflammatory and infectious diseases. We review current knowledge on the role of different adipokines in diagnostic work-up and risk stratification of sepsis as well as critical illness. We discuss recent data from animal models as well as from clinical studies and finally highlight the limitations of these analyses that currently prevent the use of adipokines as biomarkers in daily practice. Full article
(This article belongs to the Special Issue Adipokines 2.0)
Open AccessReview
More Than an Adipokine: The Complex Roles of Chemerin Signaling in Cancer
Int. J. Mol. Sci. 2019, 20(19), 4778; https://doi.org/10.3390/ijms20194778 - 26 Sep 2019
Abstract
Chemerin is widely recognized as an adipokine, with diverse biological roles in cellular differentiation and metabolism, as well as a leukocyte chemoattractant. Research investigating the role of chemerin in the obesity–cancer relationship has provided evidence both for pro- and anti-cancer effects. The tumor-promoting [...] Read more.
Chemerin is widely recognized as an adipokine, with diverse biological roles in cellular differentiation and metabolism, as well as a leukocyte chemoattractant. Research investigating the role of chemerin in the obesity–cancer relationship has provided evidence both for pro- and anti-cancer effects. The tumor-promoting effects of chemerin primarily involve direct effects on migration, invasion, and metastasis as well as growth and proliferation of cancer cells. Chemerin can also promote tumor growth via the recruitment of tumor-supporting mesenchymal stromal cells and stimulation of angiogenesis pathways in endothelial cells. In contrast, the majority of evidence supports that the tumor-suppressing effects of chemerin are immune-mediated and result in a shift from immunosuppressive to immunogenic cell populations within the tumor microenvironment. Systemic chemerin and chemerin produced within the tumor microenvironment may contribute to these effects via signaling through CMKLR1 (chemerin1), GPR1 (chemerin2), and CCLR2 on target cells. As such, inhibition or activation of chemerin signaling could be beneficial as a therapeutic approach depending on the type of cancer. Additional studies are required to determine if obesity influences cancer initiation or progression through increased adipose tissue production of chemerin and/or altered chemerin processing that leads to changes in chemerin signaling in the tumor microenvironment. Full article
(This article belongs to the Special Issue Adipokines 2.0)
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Open AccessReview
Involvement of Novel Adipokines, Chemerin, Visfatin, Resistin and Apelin in Reproductive Functions in Normal and Pathological Conditions in Humans and Animal Models
Int. J. Mol. Sci. 2019, 20(18), 4431; https://doi.org/10.3390/ijms20184431 - 09 Sep 2019
Cited by 1
Abstract
It is well known that adipokines are endocrine factors that are mainly secreted by white adipose tissue. Their central role in energy metabolism is currently accepted. More recently, their involvement in fertility regulation and the development of some reproductive disorders has been suggested. [...] Read more.
It is well known that adipokines are endocrine factors that are mainly secreted by white adipose tissue. Their central role in energy metabolism is currently accepted. More recently, their involvement in fertility regulation and the development of some reproductive disorders has been suggested. Data concerning the role of leptin and adiponectin, the two most studied adipokines, in the control of the reproductive axis are consistent. In recent years, interest has grown about some novel adipokines, chemerin, visfatin, resistin and apelin, which have been found to be strongly associated with obesity and insulin-resistance. Here, we will review their expression and role in male and female reproduction in humans and animal models. According to accumulating evidence, they could regulate the secretion of GnRH (Gonadotropin-Releasing Hormone), gonadotropins and steroids. Furthermore, their expression and that of their receptors (if known), has been demonstrated in the human and animal hypothalamo-pituitary-gonadal axis. Like leptin and adiponectin, these novel adipokines could thus represent metabolic sensors that are able to regulate reproductive functions according to energy balance changes. Therefore, after investigating their role in normal fertility, we will also discuss their possible involvement in some reproductive troubles known to be associated with features of metabolic syndrome, such as polycystic ovary syndrome, gestational diabetes mellitus, preeclampsia and intra-uterine growth retardation in women, and sperm abnormalities and testicular pathologies in men. Full article
(This article belongs to the Special Issue Adipokines 2.0)
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Open AccessReview
The Adipokine Network in Rheumatic Joint Diseases
Int. J. Mol. Sci. 2019, 20(17), 4091; https://doi.org/10.3390/ijms20174091 - 22 Aug 2019
Cited by 2
Abstract
Rheumatic diseases encompass a diverse group of chronic disorders that commonly affect musculoskeletal structures. Osteoarthritis (OA) and rheumatoid arthritis (RA) are the two most common, leading to considerable functional limitations and irreversible disability when patients are unsuccessfully treated. Although the specific causes of [...] Read more.
Rheumatic diseases encompass a diverse group of chronic disorders that commonly affect musculoskeletal structures. Osteoarthritis (OA) and rheumatoid arthritis (RA) are the two most common, leading to considerable functional limitations and irreversible disability when patients are unsuccessfully treated. Although the specific causes of many rheumatic conditions remain unknown, it is generally accepted that immune mechanisms and/or uncontrolled inflammatory responses are involved in their etiology and symptomatology. In this regard, the bidirectional communication between neuroendocrine and immune system has been demonstrated to provide a homeostatic network that is involved in several pathological conditions. Adipokines represent a wide variety of bioactive, immune and inflammatory mediators mainly released by adipocytes that act as signal molecules in the neuroendocrine-immune interactions. Adipokines can also be synthesized by synoviocytes, osteoclasts, osteoblasts, chondrocytes and inflammatory cells in the joint microenvironment, showing potent modulatory properties on different effector cells in OA and RA pathogenesis. Effects of adiponectin, leptin, resistin and visfatin on local and systemic inflammation are broadly described. However, more recently, other adipokines, such as progranulin, chemerin, lipocalin-2, vaspin, omentin-1 and nesfatin, have been recognized to display immunomodulatory actions in rheumatic diseases. This review highlights the latest relevant findings on the role of the adipokine network in the pathophysiology of OA and RA. Full article
(This article belongs to the Special Issue Adipokines 2.0)
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Open AccessReview
Chemerin and Cancer
Int. J. Mol. Sci. 2019, 20(15), 3750; https://doi.org/10.3390/ijms20153750 - 31 Jul 2019
Cited by 3
Abstract
Chemerin is a multifunctional adipokine with established roles in inflammation, adipogenesis and glucose homeostasis. Increasing evidence suggest an important function of chemerin in cancer. Chemerin’s main cellular receptors, chemokine-like receptor 1 (CMKLR1), G-protein coupled receptor 1 (GPR1) and C-C chemokine receptor-like 2 (CCRL2) [...] Read more.
Chemerin is a multifunctional adipokine with established roles in inflammation, adipogenesis and glucose homeostasis. Increasing evidence suggest an important function of chemerin in cancer. Chemerin’s main cellular receptors, chemokine-like receptor 1 (CMKLR1), G-protein coupled receptor 1 (GPR1) and C-C chemokine receptor-like 2 (CCRL2) are expressed in most normal and tumor tissues. Chemerin’s role in cancer is considered controversial, since it is able to exert both anti-tumoral and tumor-promoting effects, which are mediated by different mechanisms like recruiting innate immune defenses or activation of endothelial angiogenesis. For this review article, original research articles on the role of chemerin and its receptors in cancer were considered, which are listed in the PubMed database. Additionally, we included meta-analyses of publicly accessible DNA microarray data to elucidate the association of expression of chemerin and its receptors in tumor tissues with patients’ survival. Full article
(This article belongs to the Special Issue Adipokines 2.0)
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Open AccessReview
Annexins in Adipose Tissue: Novel Players in Obesity
Int. J. Mol. Sci. 2019, 20(14), 3449; https://doi.org/10.3390/ijms20143449 - 13 Jul 2019
Abstract
Obesity and the associated comorbidities are a growing health threat worldwide. Adipose tissue dysfunction, impaired adipokine activity, and inflammation are central to metabolic diseases related to obesity. In particular, the excess storage of lipids in adipose tissues disturbs cellular homeostasis. Amongst others, organelle [...] Read more.
Obesity and the associated comorbidities are a growing health threat worldwide. Adipose tissue dysfunction, impaired adipokine activity, and inflammation are central to metabolic diseases related to obesity. In particular, the excess storage of lipids in adipose tissues disturbs cellular homeostasis. Amongst others, organelle function and cell signaling, often related to the altered composition of specialized membrane microdomains (lipid rafts), are affected. Within this context, the conserved family of annexins are well known to associate with membranes in a calcium (Ca2+)- and phospholipid-dependent manner in order to regulate membrane-related events, such as trafficking in endo- and exocytosis and membrane microdomain organization. These multiple activities of annexins are facilitated through their diverse interactions with a plethora of lipids and proteins, often in different cellular locations and with consequences for the activity of receptors, transporters, metabolic enzymes, and signaling complexes. While increasing evidence points at the function of annexins in lipid homeostasis and cell metabolism in various cells and organs, their role in adipose tissue, obesity and related metabolic diseases is still not well understood. Annexin A1 (AnxA1) is a potent pro-resolving mediator affecting the regulation of body weight and metabolic health. Relevant for glucose metabolism and fatty acid uptake in adipose tissue, several studies suggest AnxA2 to contribute to coordinate glucose transporter type 4 (GLUT4) translocation and to associate with the fatty acid transporter CD36. On the other hand, AnxA6 has been linked to the control of adipocyte lipolysis and adiponectin release. In addition, several other annexins are expressed in fat tissues, yet their roles in adipocytes are less well examined. The current review article summarizes studies on the expression of annexins in adipocytes and in obesity. Research efforts investigating the potential role of annexins in fat tissue relevant to health and metabolic disease are discussed. Full article
(This article belongs to the Special Issue Adipokines 2.0)
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Open AccessReview
Chemerin Isoforms and Activity in Obesity
Int. J. Mol. Sci. 2019, 20(5), 1128; https://doi.org/10.3390/ijms20051128 - 05 Mar 2019
Cited by 6
Abstract
Overweight and adiposity are risk factors for several diseases, like type 2 diabetes and cancer. White adipose tissue is a major source for adipokines, comprising a diverse group of proteins exerting various functions. Chemerin is one of these proteins whose systemic levels are [...] Read more.
Overweight and adiposity are risk factors for several diseases, like type 2 diabetes and cancer. White adipose tissue is a major source for adipokines, comprising a diverse group of proteins exerting various functions. Chemerin is one of these proteins whose systemic levels are increased in obesity. Chemerin is involved in different physiological and pathophysiological processes and it regulates adipogenesis, insulin sensitivity, and immune response, suggesting a vital role in metabolic health. The majority of serum chemerin is biologically inert. Different proteases are involved in the C-terminal processing of chemerin and generate diverse isoforms that vary in their activity. Distribution of chemerin variants was analyzed in adipose tissues and plasma of lean and obese humans and mice. The Tango bioassay, which is suitable to monitor the activation of the beta-arrestin 2 pathway, was used to determine the ex-vivo activation of chemerin receptors by systemic chemerin. Further, the expression of the chemerin receptors was analyzed in adipose tissue, liver, and skeletal muscle. Present investigations assume that increased systemic chemerin in human obesity is not accompanied by higher biologic activity. More research is needed to fully understand the pathways that control chemerin processing and chemerin signaling. Full article
(This article belongs to the Special Issue Adipokines 2.0)
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