The past, present, and future of adipose tissue browning and aging: A review combined with bibliometrics and bioinformatics of 2527 documents published over the past four decades.

Phosphodiesterase type 10A (PDE10A) is highly enriched in striatum and is under evaluation as a drug target for several psychiatric/neurodegenerative diseases. Preclinical studies implicate PDE10A in the regulation of energy homeostasis, but the mechanisms remain unclear. By utilizing small‐animal PET/MRI and the novel radioligand [18F]‐AQ28A, we found marked levels of PDE10A in interscapular brown adipose tissue (BAT) of mice. Pharmacological inactivation of PDE10A with the highly selective inhibitor MP‐10 recruited BAT and potentiated thermogenesis in vivo. In diet‐induced obese mice, chronic administration of MP‐10 caused weight loss associated with increased energy expenditure, browning of white adipose tissue, and improved insulin sensitivity. Analysis of human PET data further revealed marked levels of PDE10A in the supraclavicular region where brown/beige adipocytes are clustered in adults. Finally, the inhibition of PDE10A with MP‐10 stimulated thermogenic gene expression in human brown adipocytes and induced browning of human white adipocytes. Collectively, our findings highlight a novel thermoregulatory role for PDE10A in mouse and human adipocytes and promote PDE10A inhibitors as promising candidates for the treatment of obesity and diabetes.

Brown adipose tissue expends energy in the form of heat via the mitochondrial uncoupling protein UCP1. Recent studies showed that brown adipose tissue is present in adult humans and may be exploited for its anti-obesity and anti-diabetes actions. Apelin is an adipocyte-derived hormone that plays important roles in energy metabolism. Here, we report that apelin-APJ signaling promotes brown adipocyte differentiation by increasing the expressions of brown adipogenic and thermogenic transcriptional factors via the PI3K/Akt and AMPK signaling pathways. It is also found that apelin relieves the TNFα inhibition on brown adipogenesis. In addition, apelin increases the basal activity of brown adipocytes, as evidenced by the increased PGC1α and UCP1 expressions, mitochondrial biogenesis, and oxygen consumption. Finally, we provide both in vitro and in vivo evidence that apelin is able to increase the brown-like characteristics in white adipocytes. This study, for the first time, reveals the brown adipogenic and browning effects of apelin and suggests a potential therapeutic route to combat obesity and related metabolic disorders.

The relationship between increased body mass index and risk for diabetes mellitus or cardiovascular disease is well established. Such observations have driven considerable interest into the nature of adipose tissue and what mechanisms might help explain how adipose tissue and specific aspects of adipocyte biology influence cardiometabolic disorders. For example, adipocytes are now recognized as a source of mediators released into the circulation, like the adipokines resistin and adiponectin, which can modulate inflammation, insulin sensitivity, and atherosclerosis. Other molecules released from adipocytes like free fatty acids and reactive oxygen species can also exert both local and distant effects that may be integral to the development of diabetes mellitus, atherosclerosis, and their complications. To an increasing extent, adipose tissue is now understood as an organ playing important physiological and pathological roles. Both the absence of fat, as with certain lipodystrophies, and excess adiposity are associated with diabetes mellitus, with mechanisms that appear to include infiltration of inflammatory cells into adipose tissue and the release of systemic mediators. Article see p 1067 To these and the many other adipocyte actions that continue to be uncovered, recent work has added another critical dimension to our evolving view of fat: the specific location of a given adipose depot. Subcutaneous white fat, visceral white fat, brown fat, epicardial fat, and perivascular fat—including fat around the coronaries, the thoracic aorta, and the abdominal aorta—have all been identified as distinct depots that exert unique local and systemic effects (Table). These issues are of particular interest given studies. suggesting that brown adipose tissue (BAT), which drives thermogenesis, is variably present in humans, associated with decreased adiposity, and may be a therapeutic target. In this issue of Circulation , Chang and colleagues add to this still emerging picture by providing the intriguing observation that a deficiency of peroxisome proliferator-activated …

Adipose-Muscle crosstalk in age-related metabolic disorders: The emerging roles of adipo-myokines.

Adipose Acyl-CoA Synthetase-1 Directs Fatty Acids toward β-Oxidation and Is Required for Cold Thermogenesis

Disruption of circadian glucocorticoid oscillations in Cushing's disease and chronic stress results in obesity and adipocyte hypertrophy, which is believed to be a main source of the harmful effects of obesity. Here, we recapitulate stress due to jet lag or work-life imbalances by flattening glucocorticoid oscillations in mice. Within 3days, mice achieve a metabolic state with persistently high insulin, but surprisingly low glucose and fatty acids in the bloodstream, that precedes a more than 2-fold increase in brown and white adipose tissue mass within 3weeks. Transcriptomic and Cd36-knockout mouse analyses show that hyperinsulinemia-mediated de novo fatty acid synthesis and Cd36-mediated fatty acid uptake drive fat mass increases. Intriguingly, this mechanism by which glucocorticoid flattening causes acute hyperinsulinemia and adipocyte hypertrophy is unexpectedly beneficial in preventing high levels of circulating fatty acids and glucose for weeks, thus serving as a protective response to preserve metabolic health during chronic stress.

Harnessing the Integrated Stress Response to Counteract Metabolic Disease.

Thermogenesis in brown adipose tissue (BAT) declines with aging, however, the underlying mechanism remains unclear. Here, we show that the expression of Y-box binding protein 1 (YB-1), a critical DNA/RNA binding protein, decreased in the BAT of aged mice due to the reduction of microbial metabolite butyrate. Genetic ablation of YB-1 in the BAT accelerated diet-induced obesity and BAT thermogenic dysfunction. In contrast, overexpression of YB-1 in the BAT of aged mice was sufficient to promote BAT thermogenesis, thus alleviating diet-induced obesity and insulin resistance. Interestingly, YB-1 had no direct effect on adipose UCP1 expression. Instead, YB-1 promoted axon guidance of BAT via regulating the expression of Slit2, thus potentiating sympathetic innervation and thermogenesis. Moreover, we have identified that a natural compound Sciadopitysin, which promotes YB-1 protein stability and nuclear translocation, alleviated BAT aging and metabolic disorders. Together, we reveal a novel fat-sympathetic nerve unit in regulating BAT senescence and provide a promising strategy against age-related metabolic disorders.

Studies on promoting thermogenesis of brown and beige adipose tissue have become a hot topic in various metabolic conditions, which based on the conclusions that brown and beige adipose tissue are able to facilitate weight loss and improve metabolic health. However, recent studies showed that there were several problems for the anti-obesity application via promoting brown/beige adipose tissue thermogenesis. In obese individuals, classical brown adipose tissue presents thermogenesis dysfunction. Moreover, the beige adipose tissue has significantly lower thermogenesis capability compared with brown adipose tissue. On such conditions, excessively excited sympathetic innervation is essential to increase energy consumption in obesity via increasing classic brown adipose thermogenesis and inducing white adipose tissuebrowning. However, excessive excited sympathetic nerve results in cardiovascular side effects. Additionally, excessive induction of white adipose tissuebrowningmight disrupt the white adipose tissue homeostasis and aggravate the intrinsic metabolic disorders. Therefore, solving these practical application problems of brown/beige adipose tissue is a new research area for improving metabolic disorders. (Chin J Endocrinol Metab, 2017, 33: 625-628) Key words: Brown adipose tissue; Beige adipose tissue; White adipose tissue browning; Obesity; Energy metabolism; Application limitations

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. 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. 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.

The complex imprinted Gnas locus encodes several gene products including G(s)alpha, the ubiquitously expressed G protein alpha-subunit required for receptor-stimulated cAMP generation, and the neuroendocrine-specific G(s)alpha isoform XLalphas. XLalphas is only expressed from the paternal allele, whereas G(s)alpha is biallelically expressed in most tissues. XLalphas knock-out mice (Gnasxl(m+/p-)) have poor suckling and perinatal lethality, implicating XLalphas as critical for postnatal feeding. We have now examined the metabolic phenotype of adult Gnasxl(m+/p-) mice. Gnasxl(m+/p-) mice had reduced fat mass and lipid accumulation in adipose tissue, with increased food intake and metabolic rates. Gene expression profiling was consistent with increased lipid metabolism in adipose tissue. These changes likely result from increased sympathetic nervous system activity rather than adipose cell-autonomous effects, as we found that XLalphas is not normally expressed in adult adipose tissue, and Gnasxl(m+/p-) mice had increased urinary norepinephrine levels but not increased metabolic responsiveness to a beta3-adrenergic agonist. Gnasxl(m+/p-) mice were hypolipidemic and had increased glucose tolerance and insulin sensitivity. The similar metabolic profile observed in some prior paternal Gnas knock-out models results from XLalphas deficiency (or deficiency of the related alternative truncated protein XLN1). XLalphas (or XLN1) is a negative regulator of sympathetic nervous system activity in mice.

AMPK (adenosine monophosphate-activated protein kinase), a key regulator of cellular energy metabolism and whole-body energy balance, is present in brown adipose tissue but its role in regulating the acute metabolic state and chronic thermogenic potential of this metabolically unique tissue is unknown. To address this, the AMPK signalling system in brown and white adipose tissue was studied in C57Bl/6 mice under control conditions, during acute and chronic cold exposure, and during chronic adrenergic stimulation. In control mice AMPK activity in brown adipose tissue was higher than in any tissue yet reported (3-fold the level in liver) secondary to a high level of expression of the alpha1 isoform. During the first day of cold, a time of intense non-shivering thermogenesis, AMPK activity remained at basal levels. However, chronic (>7 days) cold caused a progressive increase in brown adipose tissue AMPK activity secondary to increased expression of the alpha1 isoform. To investigate the signalling pathway involved, noradrenaline (norepinephrine) and the beta(3)-adrenergic-specific agonist CL 316, 243 were given for 14 days. This increased uncoupling protein-1 content in brown adipose tissue, but not AMPK activity. In white adipose tissue 15 days of cold increased alpha1 AMPK activity 98 +/- 20%, an effect reproduced by chronic noradrenaline or CL 316 243. We conclude that chronic cold not only increases AMPK activity in brown and white adipose tissue, but that it does so via distinct signalling pathways. Our data are consistent with AMPK acting primarily as a regulator of chronic thermogenic potential in brown adipose tissue, and not in the acute activation of non-shivering thermogenesis.

In response to cold, norepinephrine (NE)-induced triacylglycerol hydrolysis (lipolysis) in adipocytes of brown adipose tissue (BAT) provides fatty acid substrates to mitochondria for heat generation (adaptive thermogenesis). NE-induced lipolysis is mediated by protein kinase A (PKA)-dependent phosphorylation of perilipin, a lipid droplet-associated protein that is the major regulator of lipolysis. We investigated the role of perilipin PKA phosphorylation in BAT NE-stimulated thermogenesis using a novel mouse model in which a mutant form of perilipin, lacking all six PKA phosphorylation sites, is expressed in adipocytes of perilipin knockout (Peri KO) mice. Here, we show that despite a normal mitochondrial respiratory capacity, NE-induced lipolysis is abrogated in the interscapular brown adipose tissue (IBAT) of these mice. This lipolytic constraint is accompanied by a dramatic blunting ( approximately 70%) of the in vivo thermal response to NE. Thus, in the presence of perilipin, PKA-mediated perilipin phosphorylation is essential for NE-dependent lipolysis and full adaptive thermogenesis in BAT. In IBAT of Peri KO mice, increased basal lipolysis attributable to the absence of perilipin is sufficient to support a rapid NE-stimulated temperature increase ( approximately 3.0 degrees C) comparable to that in wild-type mice. This observation suggests that one or more NE-dependent mechanism downstream of perilipin phosphorylation is required to initiate and/or sustain the IBAT thermal response.

Time-dependent changes in metabolism, mass, composition, and total heat production of brown adipose tissue in cold-exposed rats

Dear Sir, Exercise is known to induce weight loss which is more than expected due to energy expenditure during exercise. Till now the molecular mechanism of this disproportionate loss in weight was not known. A novel myokine, Irisin named after Greek goddess iris, discovered by Bruce M. Spiegelman et al. in 2012 [1] has been found to be the hormone responsible for exercise induced improvement in glucose homeostasis. It is a 112 AA polypeptide secreted from muscle into the bloodstream in response to exercise. There is 100 % homology in structure of Irisin between human and mice suggesting it to be a highly conserved hormone during evolution. It is found to be responsible for browning of subcutaneous adipose tissue and thus it is responsible for antiobesity and antidiabetic effect [1]. Regarding the biochemical nature, Irisin is a cleaved and secreted fragment of FNDC5 (FRCP2 and PeP). FNDC5 is synthesised as a type I membrane protein which undergoes proteolytic cleavage and this results in release of N terminal part of protein into extracellular space. FNDC5 consists of three parts, a signal peptide, two fibronectin domains, hydrophobic domain and a C-terminal peptide. FNDC 5 is a glycoprotein. It is released from muscle in response to exercise [2, 3]. As per the molecular mechanism, exercise is the stimulus for release of PGC1α (PPAR-co-activator-1α) which is a coactivator of PPAR γ (involved in energy metabolism). This in turn stimulates expression of FNDC5 which in turn is proteolytically cleaved to release the active hormone, irisin. Irisin has cell surface receptors. It increases the expression of UCP1 and Cidea mRNA, which causes browning of primarily subcutaneous and also of visceral adipose tissue and thereby inducing thermogenesis [4]. White adipose tissue, which is a storehouse of energy, is converted to brown adipose tissue which dissipates energy as heat. This in turn causes increase in total body energy expenditure. As far as the potential biochemical implication is concerned, Irisin causes browning of adipose tissue and thereby inducing thermogenesis, white adipose tissue is primarily composed of triglycerides and fatty acids (mainly responsible for insulin resistance). Irisin causes white adipose tissue to get converted to brown adipose tissue and thereby reduction of insulin resistance and improvement of glucose homeostasis. It may be useful as anti obesity treatment by weight loss and antidiabetic treatment by virtue of improved glucose homeostasis. To conclude, it may be useful in treatment of obesity, diabetes, and metabolic syndrome. It will be specially useful to people who cannot exercise because of physical limitations. However, it can not act as a substitute for exercise. All its effects are presently seen in mice, because of its 100 % sequence homology, it is being assumed to have same effect in humans for which clinical trials are being conducted (Fig. 1). Fig. 1 Mechanism of exercise induced weight loss by Irisin