BMP4-mediated brown fat-like changes in white adipose tissue alter glucose and energy homeostasis

Expression of bone morphogenetic protein 4 (BMP4) in adipocytes of white adipose tissue (WAT) produces “white adipocytes” with characteristics of brown fat and leads to a reduction of adiposity and its metabolic complications. Although BMP4 is known to induce commitment of pluripotent stem cells to the adipocyte lineage by producing cells that possess the characteristics of preadipocytes, its effects on the mature white adipocyte phenotype and function were unknown. Forced expression of a BMP4 transgene in white adipocytes of mice gives rise to reduced WAT mass and white adipocyte size along with an increased number of a white adipocyte cell types with brown adipocyte characteristics comparable to those of beige or brite adipocytes. These changes correlate closely with increased energy expenditure, improved insulin sensitivity, and protection against diet-induced obesity and diabetes. Conversely, BMP4-deficient mice exhibit enlarged white adipocyte morphology and impaired insulin sensitivity. We identify peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC1α) as the target of BMP signaling required for these brown fat-like changes in WAT. This effect of BMP4 on WAT appears to extend to human adipose tissue, because the level of expression of BMP4 in WAT correlates inversely with body mass index. These findings provide a genetic and metabolic basis for BMP4’s role in altering insulin sensitivity by affecting WAT development.     

Emerging Role of AMPK in Brown and Beige Adipose Tissue (BAT): Implications for Obesity,Insulin Resistance,and Type 2 Diabetes

Purpose of Review

The global prevalence of type 2 diabetes (T2D) is escalating at alarming rates, demanding the development of additional classes of therapeutics to further reduce the burden of disease. Recent studies have indicated that increasing the metabolic activity of brown and beige adipose tissue may represent a novel means to reduce circulating glucose and lipids in people with T2D. The AMP-activated protein kinase (AMPK) is a cellular energy sensor that has recently been demonstrated to be important in potentially regulating the metabolic activity of brown and beige adipose tissue. The goal of this review is to summarize recent work describing the role of AMPK in brown and beige adipose tissue, focusing on its role in adipogenesis and non-shivering thermogenesis.

Recent Findings

Ablation of AMPK in mouse adipocytes results in cold intolerance, a reduction in non-shivering thermogenesis in brown adipose tissue (BAT), and the development of non-alcoholic fatty liver disease (NAFLD) and insulin resistance; effects associated with a defect in mitochondrial specific autophagy (mitophagy) within BAT. The effects of a β3-adrenergic agonist on the induction of BAT thermogenesis and the browning of white adipose tissue (WAT) are also blunted in mice lacking adipose tissue AMPK. A specific AMPK activator, A-769662, also results in the activation of BAT and the browning of WAT, effects which may involve demethylation of the PR domain containing 16 (Prdm16) promoter region, which is important for BAT development.

Summary

AMPK plays an important role in the development and maintenance of brown and beige adipose tissue. Adipose tissue AMPK is reduced in people with insulin resistance, consistent with findings that mice lacking adipocyte AMPK develop greater NAFLD and insulin resistance. These data suggest that pharmacologically targeting adipose tissue AMPK may represent a promising strategy to enhance energy expenditure and reduce circulating glucose and lipids, which may be effective for the treatment of NAFLD and T2D.

     

Brown adipose tissue transplantation ameliorates polycystic ovary syndrome

Polycystic ovary syndrome (PCOS), which is characterized by anovulation, hyperandrogenism, and polycystic ovaries, is a complex endocrinopathy. Because the cause of PCOS at the molecular level is largely unknown, there is no cure or specific treatment for PCOS. Here, we show that transplantation of brown adipose tissue (BAT) reversed anovulation, hyperandrogenism, and polycystic ovaries in a dehydroepiandrosterone (DHEA)-induced PCOS rat. BAT transplantation into a PCOS rat significantly stabilized menstrual irregularity and improved systemic insulin sensitivity up to a normal level, which was not shown in a sham-operated or muscle-transplanted PCOS rat. Moreover, BAT transplantation, not sham operation or muscle transplantation, surprisingly improved fertility in PCOS rats. Interestingly, BAT transplantation activated endogenous BAT and thereby increased the circulating level of adiponectin, which plays a prominent role in whole-body energy metabolism and ovarian physiology. Consistent with BAT transplantation, administration of adiponectin protein dramatically rescued DHEA-induced PCOS phenotypes. These results highlight that endogenous BAT activity is closely related to the development of PCOS phenotypes and that BAT activation might be a promising therapeutic option for the treatment of PCOS.Polycystic ovary syndrome (PCOS) is now recognized as one of the most common endocrine diseases in women of reproductive age. The prevalence of PCOS ranges from 9% to 18%, depending on the criteria used for its definition and ethnicity (1, 2). The core feature of PCOS includes polycystic ovaries, hyperandrogenism, and chronic anovulation. Furthermore, PCOS is a complex and heterogeneous syndrome because it is associated with a high risk for the development of insulin resistance, type 2 diabetes (T2D), obesity, dyslipidemia, and cardiovascular disease (3–5). There are three different criteria used for the diagnosis of PCOS: androgen excess, irregular menstruation, and polycystic ovary appearance on ultrasound after excluding other causes of hyperandrogenism and anovulation (6). Because a single etiologic factor is not able to fully account for all of the clinical features in PCOS, the pathogenesis of PCOS is largely unknown. Several genetic and environmental factors may contribute to the development of PCOS; however, the underlying cellular mechanism of the induction and progression of PCOS remains to be elucidated.Insulin resistance, which is common among PCOS patients, seems to be a key etiological characteristic, and about 85% of women with PCOS suffer from insulin resistance (7). Compensatory hyperinsulinemia can directly stimulate ovarian and adrenal secretion of androgen and decrease hepatic sex hormone binding globulin (SHBG) synthesis, resulting in an increased bioavailability of free testosterone levels (8, 9). Thus, insulin resistance and hyperandrogenism contribute to the key clinical presentation of PCOS. Because the clinical features are complex and vary among PCOS patients, it is hard to provide the first-line treatment of PCOS. Most treatment guidelines recommend that patients change lifestyles, including exercise and dietary modification. Patients can take oral contraceptive pills (OCPs) to control symptoms of hyperandrogenism or take insulin-sensitizing medicines such as metformin or pioglitazone when they have impaired glucose tolerance or features of a metabolic syndrome (10). However, there is a lack of effective treatment for PCOS at present.It has been reported that the functional abnormality of adipose tissue in PCOS patients is primarily linked to insulin resistance, even in the absence of obesity (11, 12). In humans and other mammals, there are mainly two types of adipose tissue with opposing functions: white adipose tissue (WAT) and brown adipose tissue (BAT). The main function of WAT is to store excess energy in WAT as a form of triglycerides whereas BAT contains large numbers of mitochondria that uncouple large amounts of fuel for heat generation and the maintenance of body temperature (13). Recent studies using positron emission tomography (PET) have demonstrated that human adults also possess metabolically active BAT (14, 15) and that BAT activation inversely correlates with age and body mass index (BMI) (16). Therefore, increasing BAT mass and/or function is a promising strategy to treat obesity and metabolic diseases. Indeed, studies by our group and others have shown that BAT transplantation reverses metabolic disorders in various obese mouse models (17–19).Given the several common features between PCOS and a metabolic syndrome, we aimed to investigate whether BAT possibly plays an important role in the development of PCOS phenotypes and the treatment of PCOS. In the current study, we show that BAT activity was dramatically reduced in a dehydroepiandrosterone (DHEA) (a precursor of androgen)-induced PCOS rat compared with a normal control rat. Notably, the key features of PCOS, such as insulin resistance, irregular estrous cycle, and low birth rate, were significantly improved after BAT transplantation in PCOS rats. Interestingly, transplanted BAT in PCOS rats enhanced endogenous BAT activity and thereby increased the circulating adiponectin level, which was lower in both PCOS patients and PCOS rats. In parallel, exogenous adiponectin protein administration in a PCOS rat recapitulated the effects that were seen in a BAT-transplanted PCOS rat. Taken together, these data suggest that BAT is one of the important organs regulating the features of PCOS and that the increase of BAT mass or its activity might provide a new therapeutic strategy for the treatment of PCOS.     

棕色脂肪组织的形成及其作用机制

人体内脂肪组织分为棕色脂肪组织(BAT)和白色脂肪组织(WAT).它们在组织形态和生理作用上存在较大差异,BAT主要在寒冷环境或交感神经兴奋下参与产热过程,而WAT主要以甘油三酯的形式储存多余能量.通过对BAT形成和作用机制的研究发现,两种脂肪组织的起源不同,并且揭示出部分细胞因子与BAT形成及活化之间的复杂关系,从而...     

棕色脂肪组织的形成及其作用机制

人体内脂肪组织分为棕色脂肪组织(BAT)和白色脂肪组织(WAT).它们在组织形态和生理作用上存在较大差异,BAT主要在寒冷环境或交感神经兴奋下参与产热过程,而WAT主要以甘油三酯的形式储存多余能量.通过对BAT形成和作用机制的研究发现,两种脂肪组织的起源不同,并且揭示出部分细胞因子与BAT形成及活化之间的复杂关系,从而为肥胖及其相关疾病的防治提供了新的途径.     

Gsα deficiency in adipose tissue improves glucose metabolism and insulin sensitivity without an effect on body weight

G_sα, the G protein that transduces receptor-stimulated cAMP generation, mediates sympathetic nervous system stimulation of brown adipose tissue (BAT) thermogenesis and browning of white adipose tissue (WAT), which are both potential targets for treating obesity, as well as lipolysis. We generated a mouse line with G_sα deficiency in mature BAT and WAT adipocytes (Ad-GsKO). Ad-GsKO mice had impaired BAT function, absent browning of WAT, and reduced lipolysis, and were therefore cold-intolerant. Despite the presence of these abnormalities, Ad-GsKO mice maintained normal energy balance on both standard and high-fat diets, associated with decreases in both lipolysis and lipid synthesis. In addition, Ad-GsKO mice maintained at thermoneutrality on a standard diet also had normal energy balance. Ad-GsKO mice had improved insulin sensitivity and glucose metabolism, possibly secondary to the effects of reduced lipolysis and lower circulating fatty acid binding protein 4 levels. G_sα signaling in adipose tissues may therefore affect whole-body glucose metabolism in the absence of an effect on body weight.The sympathetic nervous system (SNS) regulates energy homeostasis and adiposity through several mechanisms, including activation of nonshivering thermogenesis in brown adipose tissue (BAT), browning (formation of BAT-like “beige” cells) of white adipose tissue (WAT), and stimulation of lipolysis. Although these processes have been shown to be potential targets in treating obesity and diabetes (1–3), ablation of sympathetic nerves (4–6) or their main effectors (norepinephrine and epinephrine) (7) does not result in obesity or insulin resistance. Although mice lacking β adrenergic receptors (β-less mice) do develop obesity (8), it is likely that this effect is not due only to loss of β-adrenergic signaling in adipose tissue.The main mediator of SNS function in adipose tissues is G_sα (9, 10), a ubiquitously expressed G protein α-subunit that in adipose tissue couples adrenergic and other receptors, such as the adenosine A2A receptor (11), to the generation of intracellular cAMP. We have previously generated adipose-specific G_sα knockout mice (FGsKO) using fatty acid binding protein 4 (FABP4) (aP2)-cre and showed these mice to have significant early mortality and a severely lean phenotype (12). However, the usefulness of this model to examine the role of G_sα in mature adipocytes is limited due to both the lack of specificity of FABP4-cre expression in adipose tissue and the presence of a severe defect in adipogenesis due to expression of FABP4, and therefore loss of G_sα, during an early step in adipocyte differentiation.Adiponectin is a mature adipocyte marker expressed late in adipocyte differentiation (13). The more recent availability of adiponectin-cre mouse lines (14, 15) has enabled us to generate adipose-specific G_sα knockout mice (Ad-GsKO) in which G_sα deletion is restricted to mature adipocytes. Despite having loss of BAT function or browning of WAT, Ad-GsKO mice failed to develop obesity on either standard chow or a high-fat diet (HFD). Moreover, Ad-GsKO mice had improved glucose tolerance and insulin sensitivity associated with a significant reduction of circulating FABP4. Our results show that thermogenesis in BAT and in beige adipocytes is not required for normal weight maintenance and that G_sα signaling in adipose tissue has an effect on whole-body glucose metabolism independent of adiposity.     

Resistance to obesity by repression of VEGF gene expression through induction of brown-like adipocyte differentiation

Adipose tissues are classified into white adipose tissue (WAT) and brown adipose tissue (BAT). WAT is responsible for energy storage, and malfunction is associated with obesity. BAT, on the contrary, consumes fat to generate heat through uncoupling mitochondrial respiration and is important in body weight control. Vascular endothelial growth factor (VEGF)-A is the founding member of the VEGF family and has been found highly expressed in adipose tissue. A genetic mouse model of an inducible VEGF (VEGF-A) repression system was used to study VEGF-regulated energy metabolism in WAT. VEGF-repressed mice demonstrated lower food efficiency, lower body weight, and resistance to high-fat diet-induced obesity. Repression of VEGF expression caused morphological and molecular changes in adipose tissues. VEGF repression induced brown-like adipocyte development in WAT, up-regulation of BAT-specific genes including PRDM16, GATA-1, BMP-7, CIDEA, and UCP-1 and down-regulation of leptin, a WAT-specific gene. VEGF repression up-regulated expression of VEGF-B and its downstream fatty acid transport proteins. Relative levels of VEGF/VEGF-B may be important switches in energy metabolism and of pharmaceutical significances.     

A synopsis of brown adipose tissue imaging modalities for clinical research

Body weight gain results from a chronic excess of energy intake over energy expenditure. Accentuating endogenous energy expenditure has been accorded considerable attention ever since the presence of brown adipose tissue (BAT) in adult humans was recognized, given that BAT is known to increase energy expenditure via thermogenesis. Besides classic BAT, significant strides in our understanding of inducible brown adipocytes have been made regarding its development and function. While it is ideal to study BAT histologically, its relatively inaccessible anatomical locations and the inherent risks associated with biopsy preclude invasive techniques to evaluate BAT on a routine basis. Thus, there has been a surge in interest to employ non-invasive methods to examine BAT. The gold standard of non-invasive detection of BAT activation is ¹⁸F-fluorodeoxyglucose positron emission tomography (PET) with computed tomography (CT). However, a major limitation of PET/CT as a tool for human BAT studies is the clinically significant doses of ionizing radiation. More recently, several other imaging methods, including single-photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), infrared thermography (IRT)/thermal imaging and contrast ultrasonography (US) have been developed in hopes that they would allow non-invasive, quantitative measures of BAT mass and activity with lower costs. This review focuses on such methods to detect human BAT activation and white adipose tissue (WAT) browning to prompt the establishment of BAT-centric strategies for augmenting energy expenditure and combatting obesity. Clinical validation of these methods will most likely expand the scope and flexibility of future BAT studies.     

The role of estrogen and estrogen receptor-alpha in male adipose tissue

Males and females both express estrogen receptor (ER) in white adipose tissue (WAT), and estrogens appear to play an important role in regulating WAT in females. However, the role of ER in male WAT was unclear. In this review, we describe our work, which used wild type (WT) and ERalpha-knockout (alphaERKO) male and female mice to determine the role of ERalpha in regulating WAT and brown adipose tissue (BAT). There were progressive increases in WAT with advancing age in alphaERKO compared with WT males; weights of various WAT depots in alphaERKO males were increased by more than 100% compared with WT controls during adulthood. Conversely, BAT weight was similar in alphaERKO and WT males at all ages. Adipocyte areas and numbers were also increased in WAT from alphaERKO compared with WT males. Compared with WT controls, alphaERKO females also had increases in WAT. The alphaERKO mice also had insulin resistance and impaired glucose tolerance, similar to humans lacking ERalpha or aromatase. The obesity in alphaERKO males appeared to involve decreased energy expenditure rather than hyperphagia. In summary, ERalpha absence causes adipocyte hyperplasia and hypertrophy in WAT, but not BAT, and is accompanied by insulin resistance and glucose intolerance in both males and females. These results are the first evidence that the estrogen/ERalpha signaling system is critical in female and male WAT deposition, and may have clinical implications.     

长链非编码RNAs与脂肪组织的关系

长链非编码RNAs(lncRNAs)是长度大于200个核苷酸而无蛋白编码能力的功能性RNA分子.近年来研究表明,lncRNAs可通过各种机制调控脂肪组织分化形成、功能结构维持及促进白色脂肪组织(WAT)棕色化,特别是对棕色脂肪组织(BAT)的分化成熟发挥重要作用.同时,lncRNAs与肥胖及代谢性疾病的发生、发展密切联系.     

Response of adipose tissue to early infection with Trypanosoma cruzi (Brazil strain)

Brown adipose tissue (BAT) and white adipose tissue (WAT) and adipocytes are targets of Trypanosoma cruzi infection. Adipose tissue obtained from CD-1 mice 15 days after infection, an early stage of infection revealed a high parasite load. There was a significant increase in macrophages in infected adipose tissue and a reduction in lipid accumulation, adipocyte size, and fat mass and increased expression of lipolytic enzymes. Infection increased levels of Toll-like receptor (TLR) 4 and TLR9 and in the expression of components of the mitogen-activated protein kinase pathway. Protein and messenger RNA (mRNA) levels of peroxisome proliferator-activated receptor γ were increased in WAT, whereas protein and mRNA levels of adiponectin were significantly reduced in BAT and WAT. The mRNA levels of cytokines, chemokines, and their receptors were increased. Nuclear Factor Kappa B levels were increased in BAT, whereas Iκκ-γ levels increased in WAT. Adipose tissue is an early target of T. cruzi infection.     

The role of brown adipose tissue in human obesity

It is widely accepted that newborn humans are provided with brown adipose tissue (BAT) and that adult humans lack, or have only a small amount, of it. Therefore the physiological role of BAT in humans is debated. It is quite clear that BAT in rodents has an important role in the prevention and therapy of obesity and diabetes and specific drugs can induce BAT development in adult animals. New concepts regarding the biology of adipose tissues in mammals have been developed during the last years leading to the hope for the development of BAT in human adults as a new challenge for the treatment of obesity and related diseases. These new concepts are basic to understanding the above-proposed therapeutic strategy and are the concept of the adipose organ and the concept of transdifferentiation. In this paper these new concepts will be explained together with a review of available scientific data on human BAT.     

Brown fat and obesity: the next big thing?

Brown adipose tissue (BAT) is well recognised to have an important role in the maintenance of body temperature in animals and human neonates, its thermogenic action affected by a tissue-specific uncoupling protein; fatty acid oxidation within the numerous brown adipocyte mitochondria is rendered inefficient leading to heat, rather than adenosine triphosphate (ATP), production. BAT was believed to show rapid involution in early childhood, leaving only vestigial amounts in adults. However, recent evidence suggests that its expression in adults is far more common than previously appreciated, with a higher likelihood of detection in women and leaner individuals. It is conceivable that BAT activity might reduce the risk of developing obesity since fat stores are used for thermogenesis, and a directed enhancement of adipocyte metabolism might have value in weight reduction. However, it is as yet unclear how such manipulation of BAT might be achieved; even in animal models, the control of thermogenic activity is incompletely understood. Even so, there is still much to interest the endocrinologist in BAT, with a range of hormones affecting adipocyte activity. This may either contribute to normal physiological function, or the phenotypical presentation of states of pathological hormone excess or deficiency. Thus, the gender differences in BAT distribution may be attributable to the differential effects of male and female sex hormones, whilst BAT expansion may drive the weight loss associated with catecholamine-producing phaeochromocytomas. These observations support an important influence of the endocrine system on BAT activity and offer new potential targets in the treatment of obesity.     

Expression of peroxisome proliferator-activated receptors in lean and obese Zucker rats

OBJECTIVE: Examination of the pattern of expression of peroxisome proliferator-activated receptor (PPAR) isoforms alpha and gamma in a model of obesity. DESIGN: Examination of adipose tissue and primary adipocyte cultures from lean and obese Zucker rats at different ages (28 days and 12 weeks). METHODS: mRNA levels were measured by RNase protection assay.RESULTS: The highest levels of PPARalpha and gamma mRNA were present in brown adipose tissue (BAT), followed by liver and white adipose tissue (WAT) for the alpha and gamma subtypes, respectively, at both ages examined. PPARalpha was expressed 100-fold higher in BAT compared with WAT, and PPARgamma mRNA levels were 2-fold higher in the WAT of obese compared with lean rats. PPARalpha and gamma expression was minimal in m. soleus, although higher levels of PPARgamma were found in the diaphragm. In marked contrast to the findings in vivo, virtually no PPARalpha mRNA could be detected in BAT cultures differentiated in vitro. CONCLUSION: PPARalpha and gamma are most highly expressed in BAT in vivo. However, PPARalpha is undetectable in brown adipose cells in vitro, suggesting that the expression of this receptor is induced by some external stimuli. In addition, the expression of PPARgamma was increased in WAT from young obese animals, compatible with an early adaptive phenomenon. Finally, the presence of PPARgamma mRNA is detectable only in particular muscles, such as the diaphragm, suggesting the possibility of an influence of fiber type on its expression, although exercise did not influence the expression of PPARgamma in other skeletal muscles.     

Depressed expression of adipocyte beta-adrenergic receptors is a common feature of congenital and diet-induced obesity in rodents.

OBJECTIVE: To determine whether the dramatic reduction in expression and functional activity of the beta3-adrenergic receptor (AR) and beta1AR subtypes originally observed in adipose tissue of the C57BL/6J Lep(ob)/Lep(ob) ('obese') mouse are general features of all models of obesity, and whether obesity-related differences in betaAR subtype expression occur between adipose depots. DESIGN: Survey of adipose tissue betaAR expression from four mouse models of congenital obesity: the 'obese' mouse (C57BL/6J Lep(ob)/Lep(ob)), the 'diabetic' mouse (C57BL/KsJ LepRdb/LepRdb), the 'tubby' mouse (C57BL/6J tub/tub) and the 'fat' mouse (C57BL/KsJ Cpe(fat)/Cpe(fat)), and in a model of high-fat diet-induced obesity in C57BL/6J mice. MEASUREMENTS: Expression of the betaAR subtypes was measured by Northern blot hybridization in white and brown adipose depots. RESULTS: In the severely obese Lep(ob) and LepRdb mice, mRNA concentrations of beta3AR and beta1AR in white adipose tissue (WAT) were decreased by > 99% and by > 70%, respectively. More modest effects on beta3AR expression were observed in brown adipose tissue (BAT, decreased by 20 - 30%). In less severe forms of obesity, as found in the tubby and carboxypeptidase (Cpe)fat mice, and in diet-induced obese B6 mice, beta3AR expression was decreased in WAT by up to 90%, with more modest decreases in interscapular BAT (IBAT). Changes in beta1AR mRNA concentrations were more variable. Beta2AR mRNA levels did not differ in most cases, with the exception that there was a 3-5-fold increase in BAT for both Lep(ob) and LepRdb mice. CONCLUSIONS: Impaired expression of adipocyte betaAR subtypes is a general feature of both genetic and dietary obesity in mice. The degree of obesity is correlated with the extent of loss of beta3AR and beta1AR expression in WAT. The distinct endocrine abnormalities associated with these obesity models may be responsible for the degree of impaired adipocyte betaAR expression.     

Melatonin induces browning of inguinal white adipose tissue in Zucker diabetic fatty rats

Melatonin limits obesity in rodents without affecting food intake and activity, suggesting a thermogenic effect. Identification of brown fat (beige/brite) in white adipose tissue (WAT) prompted us to investigate whether melatonin is a brown‐fat inducer. We used Zücker diabetic fatty (ZDF) rats, a model of obesity‐related type 2 diabetes and a strain in which melatonin reduces obesity and improves their metabolic profiles. At 5 wk of age, ZDF rats and lean littermates (ZL) were subdivided into two groups, each composed of four rats: control and those treated with oral melatonin in the drinking water (10 mg/kg/day) for 6 wk. Melatonin induced browning of inguinal WAT in both ZDF and ZL rats. Hematoxylin–eosin staining showed patches of brown‐like adipocytes in inguinal WAT in ZDF rats and also increased the amounts in ZL animals. Inguinal skin temperature was similar in untreated lean and obese rats. Melatonin increased inguinal temperature by 1.36 ± 0.02°C in ZL and by 0.55 ± 0.04°C in ZDF rats and sensitized the thermogenic effect of acute cold exposure in both groups. Melatonin increased the amounts of thermogenic proteins, uncoupling protein 1 (UCP1) (by ~2‐fold, P < 0.01) and PGC‐1α (by 25%, P < 0.05) in extracts from beige inguinal areas in ZL rats. Melatonin also induced measurable amounts of UCP1 and stimulated by ~2‐fold the levels of PGC‐1α in ZDF animals. Locomotor activity and circulating irisin levels were not affected by melatonin. These results demonstrate that chronic oral melatonin drives WAT into a brown‐fat‐like function in ZDF rats. This may contribute to melatonin′s control of body weight and its metabolic benefits.     

Adipose tissue regulates insulin sensitivity: role of adipogenesis,de novo lipogenesis and novel lipids

Obesity, the major cause of the current global epidemic of type 2 diabetes (T2D), induces insulin resistance in peripheral insulin target tissues. Several mechanisms have been identified related to cross‐talk between adipose tissue, skeletal muscle and liver. These mechanisms involve both increased free fatty acid release and altered secretion of adipokines from adipose tissue. A major determinant of metabolic health is the ability of subcutaneous adipose tissue (SAT) to store excess fat rather than allowing it to accumulate in ectopic depots including liver (i.e. in nonalcoholic fatty liver disease), muscle and heart, or in epicardial/pericardial and visceral fat depots which promote the metabolic complications of obesity. The ability to recruit and differentiate precursor cells into adipose cells (adipogenesis) in SAT is under genetic regulation and is reduced in high‐risk individuals who have first‐degree relatives with T2D. Early recruitment of new adipose cells is dependent on the cross‐talk between canonical WNT and BMP4 signalling; WNT enhances their undifferentiated and proliferative state whereas BMP4 induces their commitment to the adipogenic lineage. Dysregulation of these signalling pathways is associated with impaired adipogenesis and impaired ability to respond to the need to store excess lipids in SAT. This leads to hypertrophic, dysfunctional and insulin‐resistant adipose cells with a reduced content of GLUT4, the major insulin‐regulated glucose transporter, which in turn reduces adipose tissue glucose uptake and de novo lipogenesis. We recently identified that reduced GLUT4 and lipogenesis in adipocytes impairs the synthesis of a novel family of lipids secreted by adipose tissue (and potentially other tissues), branched fatty acid esters of hydroxy fatty acids (FAHFAs). FAHFAs have beneficial metabolic effects, including enhancing insulin‐stimulated glucose transport and glucose‐stimulated GLP1 and insulin secretion, as well as powerful anti‐inflammatory effects. FAHFA levels are reduced in subcutaneous adipose tissue in insulin‐resistant individuals, and this novel family of lipids may become of future therapeutic use.