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Obesity increases the risk of mortality because of metabolic sequelae such as type 2 diabetes and cardiovascular disease1. Thermogenesis by adipocytes can counteract obesity and metabolic diseases2,3. In thermogenic fat, creatine liberates a molar excess of mitochondrial ADP-purportedly via a phosphorylation cycle4-to drive thermogenic respiration. However, the proteins that control this futile creatine cycle are unknown. Here we show that creatine kinase B (CKB) is indispensable for thermogenesis resulting from the futile creatine cycle, during which it traffics to mitochondria using an internal mitochondrial targeting sequence. CKB is powerfully induced by thermogenic stimuli in both mouse and human adipocytes. Adipocyte-selective inactivation of Ckb in mice diminishes thermogenic capacity, increases predisposition to obesity, and disrupts glucose homeostasis. CKB is therefore a key effector of the futile creatine cycle.

Adaptive thermogenesis has attracted much attention because of its ability to increase systemic energy expenditure and to counter obesity and diabetes.sup.1-3. Recent data have indicated that thermogenic fat cells use creatine to stimulate futile substrate cycling, dissipating chemical energy as heat.sup.4,5. This model was based on the super-stoichiometric relationship between the amount of creatine added to mitochondria and the quantity of oxygen consumed. Here we provide direct evidence for the molecular basis of this futile creatine cycling activity in mice. Thermogenic fat cells have robust phosphocreatine phosphatase activity, which is attributed to tissue-nonspecific alkaline phosphatase (TNAP). TNAP hydrolyses phosphocreatine to initiate a futile cycle of creatine dephosphorylation and phosphorylation. Unlike in other cells, TNAP in thermogenic fat cells is localized to the mitochondria, where futile creatine cycling occurs. TNAP expression is powerfully induced when mice are exposed to cold conditions, and its inhibition in isolated mitochondria leads to a loss of futile creatine cycling. In addition, genetic ablation of TNAP in adipocytes reduces whole-body energy expenditure and leads to rapid-onset obesity in mice, with no change in movement or feeding behaviour. These data illustrate the critical role of TNAP as a phosphocreatine phosphatase in the futile creatine cycle. Tissue nonspecific alkaline phosphatase (TNAP) within mitochondria hydrolyses phosphocreatine to initiate a futile cycle of creatine dephosphorylation and phosphorylation in thermogenic fat cells., Author(s): Yizhi Sun [sup.1] [sup.2] , Janane F. Rahbani [sup.3] [sup.4] , Mark P. Jedrychowski [sup.1] [sup.2] , Christopher L. Riley [sup.1] [sup.2] , Sara Vidoni [sup.1] [sup.2] , Dina [...]

The sympathetic nervous system innervates peripheral organs to regulate their function and maintain homeostasis, whereas target cells also produce neurotrophic factors to promote sympathetic innervation.sup.1,2. The molecular basis of this bi-directional communication remains to be fully determined. Here we use thermogenic adipose tissue from mice as a model system to show that T cells, specifically [gamma][delta] T cells, have a crucial role in promoting sympathetic innervation, at least in part by driving the expression of TGF[beta]1 in parenchymal cells via the IL-17 receptor C (IL-17RC). Ablation of IL-17RC specifically in adipose tissue reduces expression of TGF[beta]1 in adipocytes, impairs local sympathetic innervation and causes obesity and other metabolic phenotypes that are consistent with defective thermogenesis; innervation can be fully rescued by restoring TGF[beta]1 expression. Ablating [gamma][delta] [TAU] cells and the IL-17RC signalling pathway also impairs sympathetic innervation in other tissues such as salivary glands. These findings demonstrate coordination between T cells and parenchymal cells to regulate sympathetic innervation. V[gamma]6.sup.+ V[delta]1.sup.+ [gamma][delta] T cells control tolerance to cold by activating adipocyte IL-17RC and promoting sympathetic innervation of thermogenic adipose tissue in mice., Author(s): Bo Hu [sup.1] [sup.2] , Chengcheng Jin [sup.3] [sup.6] , Xing Zeng [sup.1] [sup.2] , Jon M. Resch [sup.4] , Mark P. Jedrychowski [sup.1] [sup.2] , Zongfang Yang [sup.4] [...]

A Correction to this paper has been published: https://doi.org/10.1038/s41586-020-03161-z., Author(s): Xing Zeng [sup.1] [sup.2], Mengchen Ye [sup.3], Jon M. Resch [sup.4], Mark P. Jedrychowski [sup.1] [sup.2], Bo Hu [sup.1] [sup.2], Bradford B. Lowell [sup.4] [sup.5], David D. Ginty [sup.3], [...]

Thermogenesis by brown and beige adipose tissue, which requires activation by external stimuli, can counter metabolic disease.sup.1. Thermogenic respiration is initiated by adipocyte lipolysis through cyclic AMP-protein kinase A signalling; this pathway has been subject to longstanding clinical investigation.sup.2-4. Here we apply a comparative metabolomics approach and identify an independent metabolic pathway that controls acute activation of adipose tissue thermogenesis in vivo. We show that substantial and selective accumulation of the tricarboxylic acid cycle intermediate succinate is a metabolic signature of adipose tissue thermogenesis upon activation by exposure to cold. Succinate accumulation occurs independently of adrenergic signalling, and is sufficient to elevate thermogenic respiration in brown adipocytes. Selective accumulation of succinate may be driven by a capacity of brown adipocytes to sequester elevated circulating succinate. Furthermore, brown adipose tissue thermogenesis can be initiated by systemic administration of succinate in mice. Succinate from the extracellular milieu is rapidly metabolized by brown adipocytes, and its oxidation by succinate dehydrogenase is required for activation of thermogenesis. We identify a mechanism whereby succinate dehydrogenase-mediated oxidation of succinate initiates production of reactive oxygen species, and drives thermogenic respiration, whereas inhibition of succinate dehydrogenase supresses thermogenesis. Finally, we show that pharmacological elevation of circulating succinate drives UCP1-dependent thermogenesis by brown adipose tissue in vivo, which stimulates robust protection against diet-induced obesity and improves glucose tolerance. These findings reveal an unexpected mechanism for control of thermogenesis, using succinate as a systemically-derived thermogenic molecule.A comparative metabolomics approach is used to identify succinate as a key activator of thermogenesis in brown adipose tissue., Author(s): Evanna L. Mills [sup.1] [sup.2] , Kerry A. Pierce [sup.3] , Mark P. Jedrychowski [sup.1] [sup.2] , Ryan Garrity [sup.1] , Sally Winther [sup.1] [sup.2] , Sara Vidoni [sup.1] [...]

Brown and beige adipose tissues can dissipate chemical energy as heat through thermogenic respiration, which requires uncoupling protein 1 (UCP1) (1,2). Thermogenesis from these adipocytes can combat obesity and diabetes (3), encouraging investigation of factors that control UCP1-dependent respiration in vivo. Here we show that acutely activated thermogenesis in brown adipose tissue is defined by a substantial increase in levels of mitochondrial reactive oxygen species (ROS). Remarkably, this process supports in vivo thermogenesis, as pharmacological depletion of mitochondrial ROS results in hypothermia upon cold exposure, and inhibits UCP1-dependent increases in whole-body energy expenditure. We further establish that thermogenic ROS alter the redox status of cysteine thiols in brown adipose tissue to drive increased respiration, and that Cys253 of UCP1 is a key target. UCP1 Cys253 is sulfenylated during thermogenesis, while mutation of this site desensitizes the purine-nucleotide-inhibited state of the carrier to adrenergic activation and uncoupling. These studies identify mitochondrial ROS induction in brown adipose tissue as a mechanism that supports UCP1-dependent thermogenesis and whole-body energy expenditure, which opens the way to improved therapeutic strategies for combating metabolic disorders., The specialized capacity for thermogenic respiration in brown adipose tissue (BAT) and beige fat (4) relies on UCP1. This mitochondrial inner membrane carrier dissipates protonmotive force (Δp) and increases the [...]

The sympathetic nervous system drives brown and beige adipocyte thermogenesis through the release of noradrenaline from local axons. However, the molecular basis of higher levels of sympathetic innervation of thermogenic fat, compared to white fat, has remained unknown. Here we show that thermogenic adipocytes express a previously unknown, mammal-specific protein of the endoplasmic reticulum that we term calsyntenin 3[beta]. Genetic loss or gain of expression of calsyntenin 3[beta] in adipocytes reduces or enhances functional sympathetic innervation, respectively, in adipose tissue. Ablation of calsyntenin 3[beta] predisposes mice on a high-fat diet to obesity. Mechanistically, calsyntenin 3[beta] promotes endoplasmic-reticulum localization and secretion of S100b--a protein that lacks a signal peptide--from brown adipocytes. S100b stimulates neurite outgrowth from sympathetic neurons in vitro. A deficiency of S100b phenocopies deficiency of calsyntenin 3[beta], and forced expression of S100b in brown adipocytes rescues the defective sympathetic innervation that is caused by ablation of calsyntenin 3[beta]. Our data reveal a mammal-specific mechanism of communication between thermogenic adipocytes and sympathetic neurons. The newly identified calsyntenin 3[beta] protein has a role in the innervation of thermogenic fat through a mechanism of communication--which is unique to mammals--between thermogenic adipocytes and sympathetic neurons., Author(s): Xing Zeng [sup.1] [sup.2] , Mengchen Ye [sup.3] , Jon M. Resch [sup.4] , Mark P. Jedrychowski [sup.1] [sup.2] , Bo Hu [sup.1] [sup.2] , Bradford B. Lowell [sup.4] [...]

Author(s): Evanna L. Mills [1, 2, 3, 4]; Dylan G. Ryan [1]; Hiran A. Prag [5]; Dina Dikovskaya [6]; Deepthi Menon [1]; Zbigniew Zaslona [1]; Mark P. Jedrychowski [2, 3]; [...]

Exercise benefits a variety of organ systems in mammals, and some of the best-recognized effects of exercise on muscle are mediated by the transcriptional co-activator PPAR-γ co-activator-1α (PGC1-α). Here we show in mouse that PGC1-α expression in muscle stimulates an increase in expression of FNDC5, a membrane protein that is cleaved and secreted as a newly identified hormone, irisin. Irisin acts on white adipose cells in culture and in vivo to stimulate UCP1 expression and a broad program of brown-fat-like development. Irisin is induced with exercise in mice and humans, and mildly increased irisin levels in the blood cause an increase in energy expenditure in mice with no changes in movement or food intake. This results in improvements in obesity and glucose homeostasis. Irisin could be therapeutic for human metabolic disease and other disorders that are improved with exercise., PGC1-α is a transcriptional co-activator that mediates many biological programs related to energy metabolism. Originally described as a co-activator of PPAR-γ that modulated expression of uncoupling protein 1 (UCP1) and [...]

Author(s): Edward T. Chouchani; Lawrence Kazak; Mark P. Jedrychowski; Gina Z. Lu; Brian K. Erickson; John Szpyt; Kerry A. Pierce; Dina Laznik-Bogoslavski; Ramalingam Vetrivelan; Clary B. Clish; Alan J. Robinson; [...]

In Fig. 6a of this Article, the two dots corresponding to Cidea and S100b were erroneously moved to the top left of the volcano plot; this figure has been corrected online. An amendment to this paper has been published and can be accessed via a link at the top of the paper, Author(s): Xing Zeng [sup.1] [sup.2] , Mengchen Ye [sup.3] , Jon M. Resch [sup.4] , Mark P. Jedrychowski [sup.1] [sup.2] , Bo Hu [sup.1] [sup.2] , Bradford B. Lowell [sup.4] [...]

Exercise benefits a variety of organ systems in mammals, and some of the best-recognized effects of exercise on muscle are mediated by the transcriptional co-activator PPAR-? co-activator-1 ? (PGC1-?). Here we show in mouse that PGC1-? expression in muscle stimulates an increase in expression of FNDC5, a membrane protein that is cleaved and secreted as a newly identified hormone, irisin. Irisin acts on white adipose cells in culture and in vivo to stimulate UCP1 expression and a broad program of brown-fat-like development. Irisin is induced with exercise in mice and humans, and mildly increased irisin levels in the blood cause an increase in energy expenditure in mice with no changes in movement or food intake. This results in improvements in obesity and glucose homeostasis. Irisin could be therapeutic for human metabolic disease and other disorders that are improved with exercise. [ABSTRACT FROM AUTHOR]