ABSTRACT
The recent characterization of functional brown adipose tissue in adult humans has opened new perspectives for regulation of energy expenditure with respect to obesity and diabetes. Furthermore, dietary recommendations have taken into account the insufficient dietary intake of ω3 PUFAs and the concomitant excessive intake of ω6 PUFA associated with the occurrence of overweight/obesity. We aimed to study whether ω3 PUFAs could play a role in the recruitment and function of energy-dissipating brown/brite adipocytes. We show that ω3 PUFA supplementation has a beneficial effect on the thermogenic function of adipocytes. In vivo, a low dietary ω6:ω3 ratio improved the thermogenic response of brown and white adipose tissues to ß3-adrenergic stimulation. This effect was recapitulated in vitro by PUFA treatment of hMADS adipocytes. We pinpointed the ω6-derived eicosanoid prostaglandin (PG)F2α as the molecular origin because the effects were mimicked with a specific PGF2α receptor agonist. PGF2α level in hMADS adipocytes was reduced in response to ω3 PUFA supplementation. The recruitment of thermogenic adipocytes is influenced by the local quantity of individual oxylipins, which is controlled by the ω6:ω3 ratio of available lipids. In human nutrition, energy homeostasis may thus benefit from the implementation of a more balanced dietary ω6:ω3 ratio.
Subject(s)
Adipose Tissue, Brown/drug effects , Adipose Tissue, White/drug effects , Dietary Supplements , Fatty Acids, Omega-3/administration & dosage , Fatty Acids, Omega-3/pharmacology , Adipose Tissue, Brown/metabolism , Adipose Tissue, White/metabolism , Cells, Cultured , Humans , Oxylipins/metabolism , Receptors, Prostaglandin/agonists , Receptors, Prostaglandin/metabolismABSTRACT
Brite adipocytes recently discovered in humans are of considerable importance in energy expenditure by converting energy excess into heat. This property could be useful in the treatment of obesity, and nutritional aspects are relevant to this important issue. Using hMADS cells as a human cell model which undergoes a white to a brite adipocyte conversion, we had shown previously that arachidonic acid, the major metabolite of the essential nutrient Ω6-linoleic acid, plays a major role in this process. Its metabolites PGE2 and PGF2 alpha inhibit this process via a calcium-dependent pathway, whereas in contrast carbaprostacyclin (cPGI2), a stable analog of prostacyclin, activates white to brite adipocyte conversion. Herein, we show that cPGI2 generates via its cognate cell-surface receptor IP-R, a cyclic AMP-signaling pathway involving PKA activity which in turn induces the expression of UCP1. In addition, cPGI2 activates the pathway of nuclear receptors of the PPAR family, i.e. PPARα and PPARγ, which act separately from IP-R to up-regulate the expression of key genes involved in the function of brite adipocytes. Thus dual pathways are playing in concert for the occurrence of a browning process of human white adipocytes. These results make prostacyclin analogs as a new class of interesting molecules to treat obesity and associated diseases.
Subject(s)
Adipocytes, Brown/drug effects , Adipocytes, White/drug effects , Adipogenesis/drug effects , Anti-Obesity Agents/pharmacology , Epoprostenol/analogs & derivatives , PPAR alpha/agonists , PPAR gamma/agonists , Receptors, Prostaglandin/agonists , Adipocytes, Brown/metabolism , Adipocytes, White/metabolism , Cells, Cultured , Cyclic AMP-Dependent Protein Kinases/metabolism , Dose-Response Relationship, Drug , Energy Metabolism/drug effects , Enzyme Activation , Epoprostenol/pharmacology , Humans , Infant , Ion Channels/genetics , Ion Channels/metabolism , Male , Mitochondrial Proteins/genetics , Mitochondrial Proteins/metabolism , PPAR alpha/genetics , PPAR alpha/metabolism , PPAR gamma/metabolism , Phenotype , RNA Interference , Receptors, Epoprostenol , Receptors, Prostaglandin/metabolism , Signal Transduction/drug effects , Thermogenesis/drug effects , Time Factors , Transfection , Uncoupling Protein 1ABSTRACT
Brown adipose tissue (BAT) is essential for adaptive thermogenesis and dissipation of caloric excess through the activity of uncoupling protein (UCP)-1. BAT in humans is of great interest for the treatment of obesity and related diseases. In this study, the expression of Twik-related acid-sensitive K(+) channel (TASK)-1 [a pH-sensitive potassium channel encoded by the potassium channel, 2-pore domain, subfamily K, member 3 (Kcnk3) gene] correlated highly with Ucp1 expression in obese and cold-exposed mice. In addition, Task1-null mice, compared with their controls, became overweight, mainly because of an increase in white adipose tissue mass and BAT whitening. Task1(-/-)-mouse-derived brown adipocytes, compared with wild-type mouse-derived brown adipocytes, displayed an impaired ß3-adrenergic receptor response that was characterized by a decrease in oxygen consumption, Ucp1 expression, and lipolysis. This phenotype was thought to be caused by an exacerbation of mineralocorticoid receptor (MR) signaling, given that it was mimicked by corticoids and reversed by an MR inhibitor. We concluded that the K(+) channel TASK1 controls the thermogenic activity in brown adipocytes through modulation of ß-adrenergic receptor signaling.
Subject(s)
Adipocytes, Brown/metabolism , Adipose Tissue, Brown/metabolism , Nerve Tissue Proteins/metabolism , Potassium Channels, Tandem Pore Domain/metabolism , Receptors, Adrenergic, beta-3/metabolism , Receptors, Mineralocorticoid/metabolism , Signal Transduction/physiology , Adipocytes, Brown/cytology , Adipose Tissue, Brown/cytology , Animals , Female , Mice , Mice, Knockout , Nerve Tissue Proteins/genetics , Oxygen Consumption/physiology , Potassium Channels, Tandem Pore Domain/genetics , Receptors, Mineralocorticoid/genetics , Thermogenesis/physiologyABSTRACT
Oxylipins are metabolized from dietary ω3 and ω6 polyunsaturated fatty acids and are involved in an inflammatory response. Adipose tissue inflammatory background is a key factor of metabolic disorders and it is accepted that dietary fatty acids, in terms of quality and quantity, modulate oxylipin synthesis in this tissue. Moreover, it has been reported that diet supplementation in ω3 polyunsaturated fatty acids resolves some inflammatory situations. Thus, it is crucial to assess the influence of dietary polyunsaturated fatty acids on oxylipin synthesis and their impact on adipose tissue inflammation. To this end, mice fed an ω6- or ω3-enriched standard diet (ω6/ω3 ratio of 30 and 3.75, respectively) were analyzed for inflammatory phenotype and adipose tissue oxylipin content. Diet enrichment with an ω3 polyunsaturated fatty acid induced an increase in the oxylipins derived from ω6 linoleic acid, ω3 eicosapentaenoic, and ω3 docosahexaenoic acids in brown and white adipose tissues. Among these, the level of pro-resolving mediator intermediates, as well as anti-inflammatory metabolites, were augmented. Concomitantly, expressions of M2 macrophage markers were increased without affecting inflammatory cytokine contents. In vitro, these metabolites did not activate macrophages but participated in macrophage polarization by inflammatory stimuli. In conclusion, we demonstrated that an ω3-enriched diet, in non-obesogenic non-inflammatory conditions, induced synthesis of oxylipins which were involved in an anti-inflammatory response as well as enhancement of the M2 macrophage molecular signature, without affecting inflammatory cytokine secretion.
Subject(s)
Adipose Tissue/metabolism , Anti-Inflammatory Agents/pharmacology , Dietary Fats, Unsaturated/pharmacology , Dietary Supplements , Oxylipins/metabolism , Animals , Diet/methods , Fatty Acids, Omega-3/pharmacology , Fatty Acids, Omega-6/pharmacology , Male , MiceABSTRACT
OBJECTIVE: Thermogenic adipocytes (i.e. brown or brite/beige adipocytes) are able to burn large amounts of lipids and carbohydrates as a result of highly active mitochondria and enhanced uncoupled respiration, due to UCP1 activity. Although mitochondria are the key organelles for this thermogenic function, limited human data are available. METHODS/RESULTS: We characterized changes in the mitochondrial function of human brite adipocytes, using hMADS cells as a model of white- to brite-adipocyte conversion. We found that profound molecular modifications were associated with morphological changes in mitochondria. The fission process was partly driven by the DRP1 protein, which also promoted mitochondrial uncoupling. CONCLUSION: Our data demonstrate that white-to-brite conversion of human adipocytes relies on molecular, morphological and functional changes in mitochondria, which enable brite/beige cells to carry out thermogenesis.
Subject(s)
Adipocytes, Beige/metabolism , Mitochondrial Dynamics , Uncoupling Protein 1/metabolism , Adipocytes, Beige/ultrastructure , Cells, Cultured , Dynamins , GTP Phosphohydrolases/metabolism , Humans , Microtubule-Associated Proteins/metabolism , Mitochondrial Proteins/metabolismABSTRACT
The transient activation of inflammatory networks is required for adipose tissue remodeling including the "browning" of white fat in response to stimuli such as ß3-adrenergic receptor activation. In this process, white adipose tissue acquires thermogenic characteristics through the recruitment of so-called beige adipocytes. We investigated the downstream signaling pathways impinging on adipocyte progenitors that promote de novo formation of adipocytes. We showed that the Jak family of kinases controlled TGFß signaling in the adipose tissue microenvironment through Stat3 and thereby adipogenic commitment, a function that was required for beige adipocyte differentiation of murine and human progenitors. Jak/Stat3 inhibited TGFß signaling to the transcription factors Srf and Smad3 by repressing local Tgfb3 and Tgfb1 expression before the core transcriptional adipogenic cascade was activated. This pathway cross-talk was triggered in stromal cells by ATGL-dependent adipocyte lipolysis and a transient wave of IL-6 family cytokines at the onset of adipose tissue remodeling induced by ß3-adrenergic receptor stimulation. Our results provide insight into the activation of adipocyte progenitors and are relevant for the therapeutic targeting of adipose tissue inflammatory pathways.
Subject(s)
Adipocytes, Beige/metabolism , Adipose Tissue/metabolism , Inflammation/genetics , Janus Kinases/genetics , Transforming Growth Factor beta/genetics , Adipocytes, Beige/pathology , Adipogenesis/genetics , Adipose Tissue/pathology , Animals , Cell Differentiation/genetics , Cells, Cultured , Female , Gene Expression Profiling , Humans , Inflammation/metabolism , Janus Kinases/metabolism , Lipase/genetics , Lipase/metabolism , Mice, Inbred C57BL , Mice, Knockout , STAT3 Transcription Factor/genetics , STAT3 Transcription Factor/metabolism , Signal Transduction/genetics , Transforming Growth Factor beta/metabolismABSTRACT
Oxylipins are bioactive metabolites derived from the oxygenation of ω3 and ω6 polyunsaturated fatty acids, triggered essentially by cyclooxygenase and lipoxygenase activities. Oxylipins are involved in the development and function of adipose tissue and their productions are strictly related to diet quality and quantity. Oxylipins signal via cell surface membrane (G Protein-coupled receptors) and nuclear receptors (peroxisome proliferator-activated receptors), two pathways playing a pivotal role in adipocyte biology. In this review, we made an attempt to cover the available knowledge about synthesis and molecular function of oxylipins known to modulate adipogenesis, adipocyte function and phenotype conversion, with a focus on their interaction with peroxisome proliferator-activated nuclear receptor family.
Subject(s)
Adipogenesis/physiology , Oxylipins/metabolism , Peroxisome Proliferator-Activated Receptors/physiology , Receptors, G-Protein-Coupled/physiology , Animals , HumansABSTRACT
In response to cold or ß3-adrenoreceptor stimulation brown adipose tissue (BAT) promotes non-shivering thermogenesis, leading to energy dissipation. BAT has long been thought to be absent or scarce in adult humans. The recent discovery of thermogenic brite/beige adipocytes has opened the way to development of novel innovative strategies to combat overweight/obesity and associated diseases. Thus it is of great interest to identify regulatory factors that govern the brite adipogenic program. Here, we carried out global microRNA (miRNA) expression profiling on human adipocytes to identify miRNAs that are regulated upon the conversion from white to brite adipocytes. Among the miRNAs that were differentially expressed, we found that Let-7i-5p was down regulated in brite adipocytes. A detailed analysis of the Let-7i-5p levels showed an inverse expression of UCP1 in murine and human brite adipocytes both in vivo and in vitro. Functional studies with Let-7i-5p mimic in human brite adipocytes in vitro revealed a decrease in the expression of UCP1 and in the oxygen consumption rate. Moreover, the Let-7i-5p mimic when injected into murine sub-cutaneous white adipose tissue inhibited partially ß3-adrenergic activation of the browning process. These results suggest that the miRNAs Let-7i-5p participates in the recruitment and the function of brite adipocytes.
Subject(s)
Adipocytes, Beige/metabolism , MicroRNAs/metabolism , Adipocytes, Beige/physiology , Adipocytes, Brown/metabolism , Adipocytes, Brown/physiology , Adipogenesis/physiology , Adipose Tissue, Brown/metabolism , Adipose Tissue, Brown/physiology , Adipose Tissue, White/metabolism , Adipose Tissue, White/physiology , Animals , Down-Regulation/physiology , Humans , Male , Mice , Mice, Inbred C57BL , Obesity/metabolism , Oxygen Consumption/physiology , Receptors, Adrenergic, beta-3/metabolism , Thermogenesis/physiology , Uncoupling Protein 1/metabolismABSTRACT
Human brown adipocytes are able to burn fat and glucose and are now considered as a potential strategy to treat obesity, type 2 diabetes and metabolic disorders. Besides their thermogenic function, brown adipocytes are able to secrete adipokines. One of these is visfatin, a nicotinamide phosphoribosyltransferase involved in nicotinamide dinucleotide synthesis, which is known to participate in the synthesis of insulin by pancreatic ß cells. In a therapeutic context, it is of interest to establish whether a potential correlation exists between brown adipocyte activation and/or brite adipocyte recruitment, and adipokine expression. We analyzed visfatin expression, as a pre-requisite to its secretion, in rodent and human biopsies and cell models of brown/brite adipocytes. We found that visfatin was preferentially expressed in mature adipocytes and that this expression was higher in brown adipose tissue of rodents compared to other fat depots. However, using various rodent models we were unable to find any correlation between visfatin expression and brown or brite adipocyte activation or recruitment. Interestingly, the situation is different in humans where visfatin expression was found to be equivalent between white and brown or brite adipocytes in vivo and in vitro. In conclusion, visfatin can be considered only as a rodent brown adipocyte biomarker, independently of tissue activation.
ABSTRACT
OBJECTIVE: In rodents and humans, besides brown adipose tissue (BAT), islands of thermogenic adipocytes, termed "brite" (brown-in-white) or beige adipocytes, emerge within white adipose tissue (WAT) after cold exposure or ß3-adrenoceptor stimulation, which may protect from obesity and associated diseases. microRNAs are novel modulators of adipose tissue development and function. The purpose of this work was to characterize the role of microRNAs in the control of brite adipocyte formation. METHODS/RESULTS: Using human multipotent adipose derived stem cells, we identified miR-125b-5p as downregulated upon brite adipocyte formation. In humans and rodents, miR-125b-5p expression was lower in BAT than in WAT. In vitro, overexpression and knockdown of miR-125b-5p decreased and increased mitochondrial biogenesis, respectively. In vivo, miR-125b-5p levels were downregulated in subcutaneous WAT and interscapular BAT upon ß3-adrenergic receptor stimulation. Injections of an miR-125b-5p mimic and LNA inhibitor directly into WAT inhibited and increased ß3-adrenoceptor-mediated induction of UCP1, respectively, and mitochondrial brite adipocyte marker expression and mitochondriogenesis. CONCLUSION: Collectively, our results demonstrate that miR-125b-5p plays an important role in the repression of brite adipocyte function by modulating oxygen consumption and mitochondrial gene expression.
ABSTRACT
OBJECTIVE: Brite adipocytes are inducible energy-dissipating cells expressing UCP1 which appear within white adipose tissue of healthy adult individuals. Recruitment of these cells represents a potential strategy to fight obesity and associated diseases. METHODS/RESULTS: Using human Multipotent Adipose-Derived Stem cells, able to convert into brite adipocytes, we show that arachidonic acid strongly inhibits brite adipocyte formation via a cyclooxygenase pathway leading to secretion of PGE2 and PGF2α. Both prostaglandins induce an oscillatory Ca(++) signaling coupled to ERK pathway and trigger a decrease in UCP1 expression and in oxygen consumption without altering mitochondriogenesis. In mice fed a standard diet supplemented with ω6 arachidonic acid, PGF2α and PGE2 amounts are increased in subcutaneous white adipose tissue and associated with a decrease in the recruitment of brite adipocytes. CONCLUSION: Our results suggest that dietary excess of ω6 polyunsaturated fatty acids present in Western diets, may also favor obesity by preventing the "browning" process to take place.