Adenosine/A2B receptor signaling ameliorates the effects of ageing and counteracts obesity

The combination of aging populations with the obesity pandemic results in an alarming rise in non-communicable diseases. Here, we show that the enigmatic adenosine A2B receptor (A2B) is abundantly expressed in skeletal muscle (SKM) as well as brown adipose tissue (BAT) and might be targeted to counteract age-related muscle atrophy (sarcopenia) as well as obesity. Mice with SKM-specific deletion of A2B exhibited sarcopenia, diminished muscle strength, and reduced energy expenditure (EE), whereas pharmacological A2B activation counteracted these processes. Adipose tissue-specific ablation of A2B exacerbated age-related processes and reduced BAT EE, whereas A2B stimulation ameliorated obesity. In humans, A2B expression correlated with EE in SKM, BAT activity, and abundance of thermogenic adipocytes in white fat. Moreover, A2B agonist treatment increased EE from human adipocytes, myocytes, and muscle explants. Mechanistically, A2B forms heterodimers required for adenosine signaling. Overall, adenosine/A2B signaling links muscle and BAT and has both anti-aging and anti-obesity potential

Lipolysis drives expression of the constitutively active receptor GPR3 to induce adipose thermogenesis

Thermogenic adipocytes possess a therapeutically appealing, energy-expending capacity, which is canonically cold-induced by ligand-dependent activation of β-adrenergic G protein-coupled receptors (GPCRs). Here, we uncover an alternate paradigm of GPCR-mediated adipose thermogenesis through the constitutively active receptor, GPR3. We show that the N terminus of GPR3 confers intrinsic signaling activity, resulting in continuous Gs-coupling and cAMP production without an exogenous ligand. Thus, transcriptional induction of Gpr3 represents the regulatory parallel to ligand-binding of conventional GPCRs. Consequently, increasing Gpr3 expression in thermogenic adipocytes is alone sufficient to drive energy expenditure and counteract metabolic disease in mice. Gpr3 transcription is cold-stimulated by a lipolytic signal, and dietary fat potentiates GPR3-dependent thermogenesis to amplify the response to caloric excess. Moreover, we find GPR3 to be an essential, adrenergic-independent regulator of human brown adipocytes. Taken together, our findings reveal a noncanonical mechanism of GPCR control and thermogenic activation through the lipolysis-induced expression of constitutively active GPR3.ISSN:0092-8674ISSN:1097-417

A classical brown adipose tissue mRNA signature partly overlaps with brite in the supraclavicular region of adult humans

SummaryHuman brown adipose tissue (BAT) has been detected in adults but was recently suggested to be of brite/beige origin. We collected BAT from the supraclavicular region in 21 patients undergoing surgery for suspected cancer in the neck area and assessed the gene expression of established murine markers for brown, brite/beige, and white adipocytes. We demonstrate that a classical brown expression signature, including upregulation of miR-206, miR-133b, LHX8, and ZIC1 and downregulation of HOXC8 and HOXC9, coexists with an upregulation of two newly established brite/beige markers, TBX1 and TMEM26. A similar mRNA expression profile was observed when comparing isolated human adipocytes from BAT and white adipose tissue (WAT) depots, differentiated in vitro. In conclusion, our data suggest that human BAT might consist of both classical brown and recruitable brite adipocytes, an observation important for future considerations on how to induce human BAT

Brown Fat AKT2 Is a Cold-Induced Kinase that Stimulates ChREBP-Mediated De Novo Lipogenesis to Optimize Fuel Storage and Thermogenesis

Brown adipose tissue (BAT) is a therapeutic target for metabolic diseases; thus, understanding its metabolic circuitry is clinically important. Many studies of BAT compare rodents mildly cold to those severely cold. Here, we compared BAT remodeling between thermoneutral and mild-cold-adapted mice, conditions more relevant to humans. Although BAT is renowned for catabolic beta-oxidative capacity, we find paradoxically that the anabolic de novo lipogenesis (DNL) genes encoding ACLY, ACSS2, ACC, and FASN were among the most upregulated by mild cold and that, in humans, DNL correlates with Ucp1 expression. The regulation and function of adipocyte DNL and its association with thermogenesis are not understood. We provide evidence suggesting that AKT2 drives DNL in adipocytes by stimulating ChREBPbeta transcriptional activity and that cold induces the AKT2-ChREBP pathway in BAT to optimize fuel storage and thermogenesis. These data provide insight into adipocyte DNL regulation and function and illustrate the metabolic flexibility of thermogenesis

Gamma-Aminobutyric Acid Signaling in Brown Adipose Tissue Promotes Systemic Metabolic Derangement in Obesity

Summary: Brown adipose tissue (BAT) is a metabolically active organ that contributes to the maintenance of systemic metabolism. The sympathetic nervous system plays important roles in the homeostasis of BAT and promotes its browning and activation. However, the role of other neurotransmitters in BAT homeostasis remains largely unknown. Our metabolomic analyses reveal that gamma-aminobutyric acid (GABA) levels are increased in the interscapular BAT of mice with dietary obesity. We also found a significant increase in GABA-type B receptor subunit 1 (GABA-BR1) in the cell membranes of brown adipocytes of dietary obese mice. When administered to obese mice, GABA induces BAT dysfunction together with systemic metabolic disorder. Conversely, the genetic inactivation or inhibition of GABA-BR1 leads to the re-browning of BAT under conditions of metabolic stress and ameliorated systemic glucose intolerance. These results indicate that the constitutive activation of GABA/GABA-BR1 signaling in obesity promotes BAT dysfunction and systemic metabolic derangement. : Brown adipose tissue (BAT) is a metabolically active organ important for systemic metabolism. Here, Ikegami et al. identify a role for gamma-aminobutyric acid (GABA) in metabolic and BAT dysfunction in obese mice and demonstrate that inhibition of GABA/GABA-BR1-mediated signaling and of mitochondrial calcium overload can restore BAT function in obesity. Keywords: brown adipose tissue, BAT, metabolome, gamma-aminobutyric acid, GABA, obesit

Coagulation factors promote brown adipose tissue dysfunction and abnormal systemic metabolism in obesity

Brown adipose tissue (BAT) has a role in maintaining systemic metabolic health in rodents and humans. Here, we show that metabolic stress induces BAT to produce coagulation factors, which then—together with molecules derived from the circulation—promote BAT dysfunction and systemic glucose intolerance. When mice were fed a high-fat diet (HFD), the levels of tissue factor, coagulation Factor VII (FVII), activated coagulation Factor X (FXa), and protease-activated receptor 1 (PAR1) expression increased significantly in BAT. Genetic or pharmacological suppression of coagulation factor-PAR1 signaling in BAT ameliorated its whitening and improved thermogenic response and systemic glucose intolerance in mice with dietary obesity. Conversely, the activation of coagulation factor-PAR1 signaling in BAT caused mitochondrial dysfunction in brown adipocytes and systemic glucose intolerance in mice fed normal chow. These results indicate that BAT produces endogenous coagulation factors that mediate pleiotropic effects via PAR1 signaling under metabolic stress

Adenosine/A2B Receptor Signaling Ameliorates the Effects of Aging and Counteracts Obesity

The combination of aging populations with the obesity pandemic results in an alarming rise in non-communicable diseases. Here, we show that the enigmatic adenosine A2B receptor (A2B) is abundantly expressed in skeletal muscle (SKM) as well as brown adipose tissue (BAT) and might be targeted to counteract age-related muscle atrophy (sarcopenia) as well as obesity. Mice with SKM-specific deletion of A2B exhibited sarcopenia, diminished muscle strength, and reduced energy expenditure (EE), whereas pharmacological A2B activation counteracted these processes. Adipose tissue-specific ablation of A2B exacerbated age-related processes and reduced BAT EE, whereas A2B stimulation ameliorated obesity. In humans, A2B expression correlated with EE in SKM, BAT activity, and abundance of thermogenic adipocytes in white fat. Moreover, A2B agonist treatment increased EE from human adipocytes, myocytes, and muscle explants. Mechanistically, A2B forms heterodimers required for adenosine signaling. Overall, adenosine/A2B signaling links muscle and BAT and has both anti-aging and anti–obesity potential