Search Results (10)

α-Tocopherol-13′-carboxychromanol (α-T-13′-COOH) is an endogenously formed bioactive α-tocopherol metabolite that limits inflammation and has been proposed to exert lipid metabolism-regulatory, pro-apoptotic, and anti-tumoral properties at micromolar concentrations. The mechanisms underlying these cell stress-associated responses are, however, poorly understood. Here, we show that the induction of G₀/G₁ cell cycle arrest and apoptosis in macrophages triggered by α-T-13′-COOH is associated with the suppressed proteolytic activation of the lipid anabolic transcription factor sterol regulatory element-binding protein (SREBP)1 and with decreased cellular levels of stearoyl-CoA desaturase (SCD)1. In turn, the fatty acid composition of neutral lipids and phospholipids shifts from monounsaturated to saturated fatty acids, and the concentration of the stress-preventive, pro-survival lipokine 1,2-dioleoyl-sn-glycero-3-phospho-(1′-myo-inositol) [PI(18:1/18:1)] decreases. The selective inhibition of SCD1 mimics the pro-apoptotic and anti-proliferative activity of α-T-13′-COOH, and the provision of the SCD1 product oleic acid (C18:1) prevents α-T-13′-COOH-induced apoptosis. We conclude that micromolar concentrations of α-T-13′-COOH trigger cell death and likely also cell cycle arrest by suppressing the SREBP1-SCD1 axis and depleting cells of monounsaturated fatty acids and PI(18:1/18:1). Full article

Obesity is a complex disease highly related to diet and lifestyle and is associated with low amount of thermogenic adipocytes. Therapeutics that regulate brown adipocyte recruitment and activity represent interesting strategies to fight overweight and associated comorbidities. Recent studies suggest a role for several fatty acids and their metabolites, called lipokines, in the control of thermogenesis. The purpose of this work was to analyze the role of several lipokines in the control of brown/brite adipocyte formation. We used a validated human adipocyte model, human multipotent adipose-derived stem cell model (hMADS). In the absence of rosiglitazone, hMADS cells differentiate into white adipocytes, but convert into brite adipocytes upon rosiglitazone or prostacyclin 2 (PGI2) treatment. Gene expression was quantified using RT-qPCR and protein levels were assessed by Western blotting. We show here that lipokines such as 12,13-diHOME, 12-HEPE, 15dPGJ2 and 15dPGJ3 were not able to induce browning of white hMADS adipocytes. However, both fatty acid esters of hydroxy fatty acids (FAHFAs), 9-PAHPA and 9-PAHSA potentiated brown key marker UCP1 mRNA levels. Interestingly, CTA2, the stable analog of thromboxane A2 (TXA2), but not its inactive metabolite TXB2, inhibited the rosiglitazone and PGI2-induced browning of hMADS adipocytes. These results pinpoint TXA2 as a lipokine inhibiting brown adipocyte formation that is antagonized by PGI2. Our data open new horizons in the development of potential therapies based on the control of thromboxane A2/prostacyclin balance to combat obesity and associated metabolic disorders. Full article

In the last few years, the monounsaturated hexadecenoic fatty acids are being increasingly considered as biomarkers of health with key functions in physiology and pathophysiology. Palmitoleic acid (16:1n-7) and sapienic acid (16:1n-10) are synthesized from palmitic acid by the action of stearoyl-CoA desaturase-1 and fatty acid desaturase 2, respectively. A third positional isomer, hypogeic acid (16:1n-9) is produced from the partial β-oxidation of oleic acid. In this review, we discuss the current knowledge of the effects of palmitoleic acid and, where available, sapienic acid and hypogeic acid, on metabolic diseases such as diabetes, cardiovascular disease, and nonalcoholic fatty liver disease, and cancer. The results have shown diverse effects among studies in cell lines, animal models and humans. Palmitoleic acid was described as a lipokine able to regulate different metabolic processes such as an increase in insulin sensitivity in muscle, β cell proliferation, prevention of endoplasmic reticulum stress and lipogenic activity in white adipocytes. Numerous beneficial effects have been attributed to palmitoleic acid, both in mouse models and in cell lines. However, its role in humans is not fully understood, and is sometimes controversial. Regarding sapienic acid and hypogeic acid, studies on their biological effects are still scarce, but accumulating evidence suggests that they also play important roles in metabolic regulation. The multiplicity of effects reported for palmitoleic acid and the compartmentalized manner in which they often occur, may suggest the overlapping actions of multiple isomers being present at the same or neighboring locations. Full article

Adipose tissue (AT) is a remarkably plastic and active organ with functional pleiotropism and high remodeling capacity. Although the expansion of fat mass, by definition, represents the hallmark of obesity, the dysregulation of the adipose organ emerges as the forefront of the link between adiposity and its associated metabolic and cardiovascular complications. The dysfunctional fat displays distinct biological signatures, which include enlarged fat cells, low-grade inflammation, impaired redox homeostasis, and cellular senescence. While these events are orchestrated in a cell-type, context-dependent and temporal manner, the failure of the adipose precursor cells to form new adipocytes appears to be the main instigator of the adipose dysregulation, which, ultimately, poses a deleterious milieu either by promoting ectopic lipid overspill in non-adipose targets (i.e., lipotoxicity) or by inducing an altered secretion of different adipose-derived hormones (i.e., adipokines and lipokines). This “adipocentric view” extends the previous “expandability hypothesis”, which implies a reduced plasticity of the adipose organ at the nexus between unhealthy fat expansion and the development of obesity-associated comorbidities. In this review, we will briefly summarize the potential mechanisms by which adaptive changes to variations of energy balance may impair adipose plasticity and promote fat organ dysfunction. We will also highlight the conundrum with the perturbation of the adipose microenvironment and the development of cardio-metabolic complications by focusing on adipose lipoxidation, inflammation and cellular senescence as a novel triad orchestrating the conspiracy to adipose dysfunction. Finally, we discuss the scientific rationale for proposing adipose organ plasticity as a target to curb/prevent adiposity-linked cardio-metabolic complications. Full article

Palmitoleic acid (C16:1n7) has been identified as a regulator of physiological cardiac hypertrophy. In the present study, we aimed to investigate the molecular pathways involved in C16:1n7 responses in primary murine cardiomyocytes (PCM) and a mouse model of isoproterenol (ISO)-induced cardiac damage. PCMs were stimulated with C16:1n7 or a vehicle. Afterwards, RNA sequencing was performed using an Illumina HiSeq sequencer. Confirmatory analysis was performed in PCMs and HL-1 cardiomyocytes. For an in vivo study, 129 sv mice were orally treated with a vehicle or C16:1n7 for 22 days. After 5 days of pre-treatment, the mice were injected with ISO (25 mg/kg/d s. c.) for 4 consecutive days. Cardiac phenotyping was performed using echocardiography. In total, 129 genes were differentially expressed in PCMs stimulated with C16:1n7, including Angiopoietin-like factor 4 (Angptl4) and Pyruvate Dehydrogenase Kinase 4 (Pdk4). Both Angptl4 and Pdk4 are proxisome proliferator-activated receptor α/δ (PPARα/δ) target genes. Our in vivo results indicated cardioprotective and anti-fibrotic effects of C16:1n7 application in mice. This was associated with the C16:1n7-dependent regulation of the cardiac PPAR-specific signaling pathways. In conclusion, our experiments demonstrated that C16:1n7 might have protective effects on cardiac fibrosis and inflammation. Our study may help to develop future lipid-based therapies for catecholamine-induced cardiac damage. Full article

Positional isomers of hexadecenoic acid are considered as fatty acids with anti-inflammatory properties. The best known of them, palmitoleic acid (cis-9-hexadecenoic acid, 16:1n-7), has been identified as a lipokine with important beneficial actions in metabolic diseases. Hypogeic acid (cis-7-hexadecenoic acid, 16:1n-9) has been regarded as a possible biomarker of foamy cell formation during atherosclerosis. Notwithstanding the importance of these isomers as possible regulators of inflammatory responses, very little is known about the regulation of their levels and distribution and mobilization among the different lipid pools within the cell. In this work, we describe that the bulk of hexadecenoic fatty acids found in mouse peritoneal macrophages is esterified in a unique phosphatidylcholine species, which contains palmitic acid at the sn-1 position, and hexadecenoic acid at the sn-2 position. This species markedly decreases when the macrophages are activated with inflammatory stimuli, in parallel with net mobilization of free hexadecenoic acid. Using pharmacological inhibitors and specific gene-silencing approaches, we demonstrate that hexadecenoic acids are selectively released by calcium-independent group VIA phospholipase A₂ under activation conditions. While most of the released hexadecenoic acid accumulates in free fatty acid form, a significant part is also transferred to other phospholipids to form hexadecenoate-containing inositol phospholipids, which are known to possess growth-factor-like-properties, and are also used to form fatty acid esters of hydroxy fatty acids, compounds with known anti-diabetic and anti-inflammatory properties. Collectively, these data unveil new pathways and mechanisms for the utilization of palmitoleic acid and its isomers during inflammatory conditions, and raise the intriguing possibility that part of the anti-inflammatory activity of these fatty acids may be due to conversion to other lipid mediators. Full article

In obesity, the dysfunctional adipose tissue (AT) releases increased levels of proinflammatory adipokines such as TNFα, IL-6, and IL-1β and free fatty acids (FFAs), characterizing a chronic, low-grade inflammation. Whilst FFAs and proinflammatory adipokines are known to elicit an inflammatory response within AT, their relative influence upon preadipocytes, the precursors of mature adipocytes, is yet to be determined. Our results demonstrated that the conditioned medium (CM) derived from obese AT was rich in FFAs, which guided us to evaluate the role of TLR4 in the induction of inflammation in preadipocytes. We observed that CM derived from obese AT increased reactive oxygen species (ROS) levels and NF-ĸB nuclear translocation together with IL-6, TNFα, and IL-1β in 3T3-L1 cells in a TLR4-dependent manner. Furthermore, TLR4 signaling was involved in the increased expression of C/EBPα together with the release of leptin, adiponectin, and proinflammatory mediators, in response to the CM derived from obese AT. Our results suggest that obese AT milieu secretes lipokines, which act in a combined paracrine/autocrine manner, inducing inflammation in preadipocytes via TLR4 and ROS, thus creating a paracrine loop that facilitates the differentiation of adipocytes with a proinflammatory profile. Full article

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

Adipose tissue is a highly metabolically-active tissue that senses and secretes hormonal and lipid mediators that facilitate adaptations to metabolic tissues. In recent years, the role of lipokines, which are lipid species predominantly secreted from adipose tissue that act as hormonal regulators in many metabolic tissues, has been an important area of research for obesity and diabetes. Previous studies have identified that these secreted lipids, including palmitoleate, 12,13-diHOME, and fatty acid–hydroxy–fatty acids (FAHFA) species, are important regulators of metabolism. Moreover, environmental factors that directly affect the secretion of lipokines such as diet, exercise, and exposure to cold temperatures constitute attractive therapeutic strategies, but the mechanisms that regulate lipokine stimulation have not been thoroughly reviewed. In this study, we will discuss the chemical characteristics of lipokines that position them as attractive targets for chronic disease treatment and prevention and the emerging roles of lipokines as regulators of inter-tissue communication. We will define the target tissues of lipokines, and explore the ability of lipokines to prevent or delay the onset and development of chronic diseases. Comprehensive understanding of the lipokine synthesis and lipokine-driven regulation of metabolic outcomes is instrumental for developing novel preventative and therapeutic strategies that harness adipose tissue-derived lipokines. Full article

Adipose tissue is critical to whole-body energy metabolism and has become recognized as a bona fide endocrine organ rather than an inert lipid reservoir. As such, adipose tissue is dynamic in its ability to secrete cytokines, free fatty acids, lipokines, hormones and other factors in response to changes in environmental stimuli such as feeding, fasting and exercise. While excess adipose tissue, as in the case of obesity, is associated with metabolic complications, mass itself is not the only culprit in obesity-driven metabolic abnormalities, highlighting the importance of healthy and metabolically adaptable adipose tissue. In this review, we discuss the fundamental cellular processes of adipose tissue that become perturbed in obesity and the impact of exercise on these processes. While both endurance and resistance exercise can promote positive physiological adaptations in adipose tissue, endurance exercise has a more documented role in remodeling adipocytes, increasing adipokine secretion and fatty acid mobilization and oxidation during post-exercise compared with resistance exercise. Exercise is considered a viable therapeutic strategy for the treatment of obesity to optimize body composition, in particular as an adjuvant therapy to bariatric surgery; however, there is a gap in knowledge of the molecular underpinnings of these exercise-induced adaptations, which could provide more insight and opportunity for precision-based treatment strategies. Full article