Recruitment Of Brown Adipocytes Research Articles

237-LB: Regulation of Brown Adipose Tissue Neurovasculature by Slit3 Fragments

The ability of brown adipocytes to dissipate chemical energy as heat counteracts weight gain and has gained considerable attention as a target against obesity. Chronic cold exposure increases brown adipose tissue (BAT) mass by de novo recruitment of brown adipocytes, as well as expanding the number of blood vessels and sympathetic nerves in the tissue. This coordinated expansion of the BAT neurovasculature is essential for enhanced thermogenesis. However, how these distinct processes are coordinated remains unclear. We have recently identified Slit guidance ligand 3 (Slit3) as a new niche factor that mediates crosstalk between preadipocytes, sympathetic neurons, and endothelial cells. We showed that Slit3 is essential for cold-induced angiogenesis and sympathetic innervation in BAT and that loss of Slit3 impairs cold-induced BAT thermogenesis in vivo. However, how Slit3 regulates the expansion of angiogenesis and sympathetic innervation is not known. Members of the Slit family are proteolytically cleaved into a large N-terminal fragment and a shorter C-terminal fragment. We observed that Slit3 undergoes proteolytic cleavage in adipocyte progenitors, generating Slit3 N-terminal (Slit3-N) and C-terminal (Slit3-C) fragments. Overexpression of Slit3-N and Slit3-C in BAT revealed distinct and overlapping functions of Slit3 fragments in the regulation of angiogenesis and sympathetic innervation. Collectively, this study provides important mechanistic insights into the role of Slit3 in regulating angiogenesis and sympathetic innervation in BAT. These findings could lead to the development of new approaches to enhance thermogenesis and combat obesity and related metabolic disorders. Disclosure F. M. Neto: None. H. E. Cervantes: None. T. Duarte afonso serdan: None. F. Shamsi: None. Funding National Institutes of Health (K01DK125608)

Adipose Tissue Remodeling in Obesity: An Overview of the Actions of Thyroid Hormones and Their Derivatives.

Metabolic syndrome and obesity have become important health issues of epidemic proportions and are often the cause of related pathologies such as type 2 diabetes (T2DM), hypertension, and cardiovascular disease. Adipose tissues (ATs) are dynamic tissues that play crucial physiological roles in maintaining health and homeostasis. An ample body of evidence indicates that in some pathophysiological conditions, the aberrant remodeling of adipose tissue may provoke dysregulation in the production of various adipocytokines and metabolites, thus leading to disorders in metabolic organs. Thyroid hormones (THs) and some of their derivatives, such as 3,5-diiodo-l-thyronine (T2), exert numerous functions in a variety of tissues, including adipose tissues. It is known that they can improve serum lipid profiles and reduce fat accumulation. The thyroid hormone acts on the brown and/or white adipose tissues to induce uncoupled respiration through the induction of the uncoupling protein 1 (UCP1) to generate heat. Multitudinous investigations suggest that 3,3',5-triiodothyronine (T3) induces the recruitment of brown adipocytes in white adipose depots, causing the activation of a process known as "browning". Moreover, in vivo studies on adipose tissues show that T2, in addition to activating brown adipose tissue (BAT) thermogenesis, may further promote the browning of white adipose tissue (WAT), and affect adipocyte morphology, tissue vascularization, and the adipose inflammatory state in rats receiving a high-fat diet (HFD). In this review, we summarize the mechanism by which THs and thyroid hormone derivatives mediate adipose tissue activity and remodeling, thus providing noteworthy perspectives on their efficacy as therapeutic agents to counteract such morbidities as obesity, hypercholesterolemia, hypertriglyceridemia, and insulin resistance.

Effects of Fatty Acid Metabolites on Adipocytes Britening: Role of Thromboxane A2.

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.

Class-specific responses of brown adipose tissue to steroidal and nonsteroidal mineralocorticoid receptor antagonists.

Aldosterone exerts deleterious effects on the cardiovascular system and promotes adipose tissue expansion via mineralocorticoid receptor (MR) activation. We previously demonstrated that administration of steroidal mineralocorticoid receptor antagonists (MRA) in mice fed a moderate high-fat diet is able to reduce white adipose tissue (WAT) expansion, stimulate browning of WAT and activate interscapular brown adipose tissue (iBAT). Here, we aimed to compare the metabolic and adipose tissue-specific effects of the novel non-steroidal MRA finerenone (Fine) and spironolactone (Spiro) in a mouse model of very high-fat diet (HFD)-induced obesity. C57BL/6 J male mice were fed a 60% HFD containing or not Spiro or Fine for 12 weeks. WAT and iBAT morphology and adipose tissue gene expression analysis were assessed. After 12 weeks, both groups of mice showed similar weight gain compared to the HFD group. Histological and molecular analyses of WAT did not show significant differences among all experimental groups; differently, iBAT histological analysis revealed that Fine was able to increase recruitment of brown adipocytes in this depot, whereas mice treated with Spiro failed to elicit any iBAT response, as indicated by no changes in lipid droplets size and iBAT density, compared to HFD. Increased iBAT recruitment could explain, at least in part, the improved insulin resistance observed in mice treated with Fine, as shown by a significant reduction in homeostasis model assessment of insulin resistance (HOMA) index. These findings were confirmed by gene expression analysis of ucp-1, pgc1-α, and beta-3 adrenoreceptor (Adrb3) in iBAT, revealing significantly higher expression of these thermogenic genes in HFD + Fine group compared to HFD, whereas Spiro did not modify their expression. In summary, we demonstrated that, differently from Fine, Spiro did not induce iBAT recruitment. Our current study suggests that Fine, through its direct effects on iBAT, represents a promising pharmacologic tool to treat human metabolic diseases associated with adipose tissue dysfunctions.

Vascular smooth muscle-derived Trpv1+ progenitors are a source of cold-induced thermogenic adipocytes.

Brown adipose tissue (BAT) and beige fat function in energy expenditure in part due to their role in thermoregulation, making these tissues attractive targets for treating obesity and metabolic disorders. While prolonged cold exposure promotes de novo recruitment of brown adipocytes, the exact sources of cold-induced thermogenic adipocytes are not completely understood. Here, we identify Trpv1-positive vascular smooth muscle (VSM) cells as previously unidentified brown adipocyte progenitors. Analysis of single-cell RNA sequencing from interscapular brown adipose depots reveals, in addition to the previously-known Pdgfra-expressing mesenchymal progenitors, a previously-unidentified VSM-derived adipocyte progenitor (APC) population, which expresses the temperature-sensitive cation channel, Trpv1. Using flow cytometry and lineage tracing, we demonstrate that the Trpv1-positive VSM-APCs are distinct from the Pdgfra-positive progenitors, and can give rise to thermogenic adipocytes in response to cold. Together, these findings illustrate the landscape of the thermogenic adipose niche at the single cell resolution and identify a new cellular origin for the development of brown and beige adipocytes.

The genesis of brown fat-a smooth muscle origin story revisited.

Brown adipose tissue acquires increased thermogenic capacity with prolonged cold exposure through de novo recruitment of brown adipocytes. Studies by Shamsi et al. and Angueira et al. identify novel cellular origins of cold-induced brown adipocytes and further elucidate the molecular mechanism regulating the expansion of brown adipose tissue.

The Rosmarinus Bioactive Compound Carnosic Acid Is a Novel PPAR Antagonist That Inhibits the Browning of White Adipocytes.

Thermogenic brown and brite adipocytes convert chemical energy from nutrients into heat. Therapeutics that regulate brown adipocyte recruitment and activity represent interesting strategies to control fat mass such as in obesity or cachexia. The peroxisome proliferator-activated receptor (PPAR) family plays key roles in the maintenance of adipose tissue and in the regulation of thermogenic activity. Activation of these receptors induce browning of white adipocyte. The purpose of this work was to characterize the role of carnosic acid (CA), a compound used in traditional medicine, in the control of brown/brite adipocyte formation and function. We used human multipotent adipose-derived stem (hMADS) cells differentiated into white or brite adipocytes. The expression of key marker genes was determined using RT-qPCR and western blotting. We show here that CA inhibits the browning of white adipocytes and favors decreased gene expression of thermogenic markers. CA treatment does not affect β-adrenergic response. Importantly, the effects of CA are fully reversible. We used transactivation assays to show that CA has a PPARα/γ antagonistic action. Our data pinpoint CA as a drug able to control PPAR activity through an antagonistic effect. These observations shed some light on the development of natural PPAR antagonists and their potential effects on thermogenic response.

41-OR: Single Cell RNA-Sequencing Reveals the Developmental Heterogeneity of Brown Adipocytes

Brown adipose tissue (BAT) is the major thermogenic organ, which promotes energy expenditure through a process called adaptive thermogenesis. Central to the inherent thermogenic activity of brown adipocytes is uncoupling protein 1(UCP1). Other than mature adipocytes, several other cell types form the adipose niche and play important roles in BAT function and remodeling. Prolonged cold exposure increases BAT mass and activity through de novo recruitment of brown adipocytes as well as coordinated expansion of other cells within the adipose niche to enable maximal thermogenic activity. However, the source of cold-induced brown adipocytes and the molecular mechanism regulating BAT expansion is not known. To determine the cellular composition of BAT and its remodeling in response to ambient temperature, we performed single-cell RNA-sequencing (scRNA-seq) of the stromal vascular fraction of BAT from mice housed at different temperatures. The unsupervised clustering identified 19 major cell types, including several sub-populations of adipose progenitors, endothelial cells, immune cells, vascular smooth muscles, and Schwann cells. The transcriptional profile of each cell type in mice housed at different temperatures revealed the dynamic remodeling of brown adipocyte niche in response to environmental challenges. Among them, we identified a novel population of brown adipose progenitors derived from BAT endothelium. These endothelial-derived adipose progenitors have a distinct gene expression profile, which distinguishes them from the previously known Pdgfra-expressing adipose progenitors. Using an inducible genetic reporter, we validated the induction of UCP1 and other thermogenic gene program in the endothelial-derived adipose progenitors upon cold exposure. In summary, scRNA-seq of BAT provides a high-resolution map of brown adipose niche and suggests the critical contribution of each cell type to BAT functions, homeostasis, and turn-over. Disclosure F. Shamsi: None. M. Piper: None. L. Ho: None. T. Huang: None. Y. Tseng: Consultant; Self; Boehringer Ingelheim International GmbH. Funding American Diabetes Association (1-18-PDF-169 to F.S.); National Institutes of Health (R01DK077097, R01DK102898, P30DK036836); Harvard Stem Cell Institute

Adipogenesis in Primary Cell Culture.

Obesity involves a contrasting expansion of the energy-storing white fat and loss of functionally competent brown fat, an energy-consuming thermogenic adipose. Leveraging our understanding of white and brown adipocyte recruitment and investigating factors that regulate these processes might reveal novel targets for counteracting obesity. In vitro differentiation of primary preadipocytes mimics many of the morphological and transcriptional events occurring during adipogenesis in vivo. Moreover, preadipocytes isolated from a specific depot maintain features of their originating niche. This makes in vitro adipogenesis a valuable model for identifying differential regulation patterns between brown and white adipogenesis. In this chapter, we describe step-by-step how to isolate brown and white preadipocytes from human tissue biopsies and how to culture and differentiate them in vitro. We discuss this process, what to consider, and how this in vitro system can be used to model in vivo adipogenesis.

Comparative Transcriptomic and Epigenomic Analyses Reveal New Regulators of Murine Brown Adipogenesis

Increasing energy expenditure through brown adipocyte recruitment is a promising approach to combat obesity. We report here the comprehensive profiling of the epigenome and transcriptome throughout the lineage commitment and differentiation of C3H10T1/2 mesenchymal stem cell line into brown adipocytes. Through direct comparison to datasets from differentiating white adipocytes, we systematically identify stage- and lineage-specific coding genes, lncRNAs and microRNAs. Utilizing chromatin state maps, we also define stage- and lineage-specific enhancers, including super-enhancers, and their associated transcription factor binding motifs and genes. Through these analyses, we found that in brown adipocytes, brown lineage-specific genes are pre-marked by both H3K4me1 and H3K27me3, and the removal of H3K27me3 at the late stage is necessary but not sufficient to promote brown gene expression, while the pre-deposition of H3K4me1 plays an essential role in poising the brown genes for expression in mature brown cells. Moreover, we identify SOX13 as part of a p38 MAPK dependent transcriptional response mediating early brown cell lineage commitment. We also identify and subsequently validate PIM1, SIX1 and RREB1 as novel regulators promoting brown adipogenesis. Finally, we show that SIX1 binds to adipogenic and brown marker genes and interacts with C/EBPα, C/EBPβ and EBF2, suggesting their functional cooperation during adipogenesis.

Sex differences in sympathetic innervation and browning of white adipose tissue of mice

BackgroundThe higher prevalence of obesity-related metabolic disease in males suggests that female sex hormones provide protective mechanisms against the pathogenesis of metabolic syndrome. Because browning of white adipose tissue (WAT) is protective against obesity-related metabolic disease, we examined sex differences in β3-adrenergic remodeling of WAT in mice.MethodsEffects of the β3-adrenergic receptor agonist CL316,243 (CL) on browning of white adipose tissue were investigated in male and female C57BL mice. The role of ovarian hormones in female-specific browning was studied in control female C57BL mice and mice with ovarian failure induced by 4-vinylcyclohexene diepoxide treatment for 15 days.ResultsWe found that treatment with CL-induced upregulation of brown adipocyte markers and mitochondrial respiratory chain proteins in gonadal WAT (gWAT) of female mice, but was without effect in males. In contrast, CL treatment was equally effective in males and females in inducing brown adipocyte phenotypes in inguinal WAT. The tissue- and sex-specific differences in brown adipocyte recruitment were correlated with differences in sympathetic innervation, as determined by tyrosine hydroxylase immunostaining and western blotting. Levels of the neurotrophins NGF and BDNF were significantly higher in gWAT of female mice. CL treatment significantly increased NGF levels in gWAT of female mice but did not affect BDNF expression. In contrast, estradiol treatment doubled BDNF expression in female adipocytes differentiated in vitro. Ovarian failure induced by 4-vinylcyclohexene diepoxide treatment dramatically reduced BDNF and TH expression in gWAT, eliminated induction of UCP1 by CL, and reduced tissue metabolic rate.ConclusionsCollectively, these data demonstrate that female mice are more responsive than males to the recruitment of brown adipocytes in gonadal WAT and this difference corresponds to greater levels of estrogen-dependent sympathetic innervation.Electronic supplementary materialThe online version of this article (doi:10.1186/s13293-016-0121-7) contains supplementary material, which is available to authorized users.

EndoG Knockout Mice Show Increased Brown Adipocyte Recruitment in White Adipose Tissue and Improved Glucose Homeostasis

Brown adipose tissue (BAT) plays a central role in the regulation of whole-body energy and glucose homeostasis owing to its elevated capacity for lipid and glucose oxidation. The BAT thermogenic function, which is essential for the defense of body temperature against exposure to low environmental temperatures, relies on the expression in the inner membrane of brown adipocyte's mitochondria of uncoupling protein-1, a protein that uncouples substrate oxidation from oxidative phosphorylation and leads to the production of heat instead of ATP. BAT thermogenesis depends on proper mitochondrial biogenesis during the differentiation of brown adipocytes. Despite the data that support a role for Endonuclease G (EndoG) in the process of mitochondrial biogenesis, its function in BAT has not been explored. Here, using an EndoG knockout mouse model, we demonstrate that EndoG is not essential for the expression of mitochondrial genes involved in substrate oxidation or for the induction of thermogenic genes in BAT in response to cold exposure. We also show that a lack of EndoG is associated with an increased expression of thermogenic genes (ie, uncoupling protein-1, peroxisome proliferator-activated receptor-γ coactivator-1α) in white adipose tissue (WAT) that correlates with the appearance of brown adipocyte-like cells interspersed among white adipocytes. Interestingly, the increased browning of WAT elicited by the lack of EndoG was associated with a better glucose tolerance and reduced fat mass. Our results suggest that the induction of browning in WAT by means of inhibiting EndoG activity appears as a potential therapeutic strategy to prevent obesity and ameliorate glucose intolerance.

Chronic hyperinsulinemia reduces insulin sensitivity and metabolic functions of brown adipocyte.

The growing pandemics of diabetes have become a real threat to world economy. Hyperinsulinemia and insulin resistance are closely associated with the pathophysiology of type 2 diabetes. In pretext of brown adipocytes being considered as the therapeutic strategy for the treatment of obesity and insulin resistance, we have tried to understand the effect of hyperinsulinemia on brown adipocyte function. We here with for the first time report that hyperinsulinemia-induced insulin resistance in brown adipocyte is also accompanied with reduced insulin sensitivity and brown adipocyte characteristics. CI treatment decreased expression of brown adipocyte-specific markers (such as PRDM16, PGC1α, and UCP1) and mitochondrial content as well as activity. CI-treated brown adipocytes showed drastic decrease in oxygen consumption rate (OCR) and spare respiratory capacity. Morphological study indicates increased accumulation of lipid droplets in CI-treated brown adipocytes. We have further validated these findings in vivo in C57BL/6 mice implanted with mini-osmotic insulin pump for 8weeks. CI treatment in mice leads to increased body weight gain, fat mass and impaired glucose intolerance with reduced energy expenditure and insulin sensitivity. CI-treated mice showed decreased BAT characteristics and function. We also observed increased inflammation and ER stress markers in BAT of CI-treated animals. The above results conclude that hyperinsulinemia has deleterious effect on brown adipocyte function, making it susceptible to insulin resistance. Thus, the above findings have greater implication in designing approaches for the treatment of insulin resistance and diabetes via recruitment of brown adipocytes.

CGMP and Brown Adipose Tissue.

The second messenger cyclic guanosine monophosphate (cGMP) is a key mediator in physiological processes such as vascular tone, and its essential involvement in pathways regulating metabolism has been recognized in recent years. Here, we focus on the fundamental role of cGMP in brown adipose tissue (BAT) differentiation and function. In contrast to white adipose tissue (WAT), which stores energy in the form of lipids, BAT consumes energy stored in lipids to generate heat. This so-called non-shivering thermogenesis takes place in BAT mitochondria, which express the specific uncoupling protein 1 (UCP1). The energy combusting properties of BAT render it a promising target in antiobesity strategies in which BAT could burn the surplus energy that has accumulated in obese and overweight individuals. cGMP is generated by guanylyl cyclases upon activation by nitric oxide or natriuretic peptides. It affects several downstream molecules including cGMP-receptor proteins such as cGMP-dependent protein kinase and is degraded by phosphodiesterases. The cGMP pathway contains several signaling molecules that can increase cGMP signaling, resulting in activation and recruitment of brown adipocytes, and hence can enhance the energy combusting features of BAT. In this review we highlight recent results showing the physiological significance of cGMP signaling in BAT, as well as pharmacological options targeting cGMP signaling that bear a high potential to become BAT-centered therapies for the treatment of obesity.

18F-FDG PET/CT monitoring of β3 agonist-stimulated brown adipocyte recruitment in white adipose tissue.

There is rising interest in recruitment of brown adipocytes into white adipose tissue (WAT) as a means to augment energy expenditure for weight reduction. We thus investigated the potential of (18)F-FDG uptake as an imaging biomarker that can monitor the process of WAT browning. C57BL/6 mice were treated daily with the β3 agonist CL316,243 (5-[(2R)-2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-1,3-benzodioxole-2,2-dicarboxylic acid disodium salt), whereas controls received saline. (18)F-FDG small-animal PET/CT was serially performed at 1 h after CL316,243 injection. After sacrifice, interscapular brown adipose tissue (BAT) and WAT depots were extracted, weighed, and measured for (18)F-FDG uptake. Tissues underwent immunostaining, and UCP1 content was quantified by Western blotting. PET/CT showed low (18)F-FDG uptake in both BAT and inguinal WAT at baseline. BAT uptake was substantially increased by a single stimulation with CL316,243. Uptake in inguinal WAT was only modestly elevated by the first stimulation uptake but gradually increased to BAT level by prolonged stimulation. Ex vivo measurements recapitulated the PET findings, and measured (18)F-FDG uptake in other WAT depots was similar to inguinal WAT. WAT browning by prolonged stimulation was confirmed by a substantial increase in uncoupling protein 1 (UCP1), cytochrome-c oxidase 4 (COX4), and PR domain containing 16 (PRDM16) staining as markers of brown adipocytes. UCP1 content, which served as a measure for extent of browning, was low in baseline inguinal WAT but linearly increased over 10 d of CL316,243 injection. Finally, image-based and ex vivo-measured (18)F-FDG uptake in inguinal WAT correlated well with UCP1 content. (18)F-FDG PET/CT has the capacity to monitor brown adipocyte recruitment into WAT depots in vivo and may thus be useful for screening the efficacy of strategies to promote WAT browning.

An Enzymatic Chromatin Switch that Directs Formation of Active Brown Fat

How is the recruitment of brown adipocytes regulated? Ohno et al. (2013) show that the euchromatic histone-lysine N-metyltransferase 1 (EHMT1) is essential for the specification of the brown adipocyte fate, a finding with important implications for the pathophysiology of obesity and obesity-related maladies.

Systemic control of brown fat thermogenesis: integration of peripheral and central signals

Brown adipose tissue (BAT) is of great scientific interest as a potential target to treat obesity. The development of novel strategies to quantify brown fat thermogenesis in adult humans now enables minimally invasive assessment of novel pharmacotherapeutics. Input from the central nervous system via sympathetic efferents is widely regarded as the key controller of BAT-mediated thermogenesis in response to changes in body temperature or nutrient availability. More recently, however, it has become clear that locally secreted signals and endocrine factors originating from multiple organs can control the recruitment of brown adipocytes and, more importantly, induce thermogenesis in brown fat. Thus, they provide an attractive strategy to fine-tune brown fat thermogenesis independent of classical temperature sensing. Here, we summarize recent findings on bone morphogenetic protein signaling as an example of secreted factors in the regulation of brown adipocyte formation and systemic control of energy metabolism. We further highlight endocrine communication routes between the different types of brown adipocytes and other organs that contribute to regulation of thermogenesis. Thus, emerging evidence suggests that the classical mechanisms of central temperature sensing and sympathetic nervous system-driven thermogenesis are complemented by local and endocrine signals to determine systemic energy homeostasis.

Altered White Adipose Tissue Protein Profile in C57BL/6J Mice Displaying Delipidative, Inflammatory, and Browning Characteristics after Bitter Melon Seed Oil Treatment

ObjectiveWe have previously shown that bitter melon seed oil (BMSO), which is rich in cis-9, trans-11, trans-13 conjugated linolenic acid, is more potent than soybean oil in attenuating body fat deposition in high-fat diet-induced obese C57BL/6J mice. The aim of this study was to obtain a comprehensive insight into how white adipose tissue (WAT) is affected by BMSO administration and to explore the underlying mechanisms of the anti-adiposity effect of BMSO.Methods and ResultsA proteomic approach was used to identify proteins differentially expressed in the WAT of mice fed diets with or without BMSO for 11 wks. The WAT was also analyzed histologically for morphological changes. Two-dimensional gel electrophoresis (pH 4–7) revealed 32 spots showing a statistically significant difference (P<0.05) in intensity in BMSO-treated mice and 30 of these were shown to code for 23 proteins (15 increased and 8 decreased expression; >2-fold change). Combined with histological evidence of macrophage infiltration and brown adipocyte recruitment, the proteomic and immunoblotting data showed that the WAT in mice subjected to long-term high dose BMSO administration was characterized by reduced caveolae formation, increased ROS insult, tissue remodeling/repair, mitochondria uncoupling, and stabilization of the actin cytoskeleton, this last change being putatively related to an increased inflammatory response.ConclusionThe anti-adiposity effect of BMSO is associated with WAT delipidation, inflammation, and browning. Some novel proteins participating in these processes were identified. In addition, the BMSO-mediated WAT browning may account for the increased inflammation without causing adverse metabolic effects.

Irisin, Turning Up the Heat

Exercise exerts beneficial effects on systemic metabolism. A recent Nature paper (Boström etal., 2012) identifies irisin as an exercise-induced hormone secreted by skeletal muscle in mice and humans. Irisin promotes brown adipocyte recruitment in white fat and improves systemic metabolism by increasing energy expenditure.

Significance and application of melatonin in the regulation of brown adipose tissue metabolism: relation to human obesity

A worldwide increase in the incidence of obesity indicates the unsuccessful battle against this disorder. Obesity and the associated health problems urgently require effective strategies of treatment. The new discovery that a substantial amount of functional brown adipose tissue (BAT) is retained in adult humans provides a potential target for treatment of human obesity. BAT is active metabolically and disposes of extra energy via generation of heat through uncoupling oxidative phosphorylation in mitochondria. The physiology of BAT is readily regulated by melatonin, which not only increases recruitment of brown adipocytes but also elevates their metabolic activity in mammals. It is speculated that the hypertrophic effect and functional activation of BAT induced by melatonin may likely apply to the human. Thus, melatonin, a naturally occurring substance with no reported toxicity, may serve as a novel approach for treatment of obesity. Conversely, because of the availability of artificial light sources, excessive light exposure after darkness onset in modern societies should be considered a potential contributory factor to human obesity as light at night dramatically reduces endogenous melatonin production. In the current article, the potential associations of melatonin, BAT, obesity and the medical implications are discussed.