Accumulation of succinate controls activation of adipose tissue thermogenesis

Evanna L. Mills, Kerry A. Pierce, Mark P. Jedrychowski, Ryan Garrity, Sally Winther, Sara Vidoni, Takeshi Yoneshiro, Jessica B. Spinelli, Gina Z. Lu, Lawrence Kazak, Alexander S. Banks, Marcia C. Haigis, Shingo Kajimura, Michael P. Murphy, Steven P. Gygi, Clary B. Clish and Edward T. Chouchani ()
Additional contact information
Evanna L. Mills: Dana–Farber Cancer Institute
Kerry A. Pierce: Broad Institute of Harvard and MIT
Mark P. Jedrychowski: Dana–Farber Cancer Institute
Ryan Garrity: Dana–Farber Cancer Institute
Sally Winther: Dana–Farber Cancer Institute
Sara Vidoni: Dana–Farber Cancer Institute
Takeshi Yoneshiro: University of California, San Francisco
Jessica B. Spinelli: Harvard Medical School
Gina Z. Lu: Dana–Farber Cancer Institute
Lawrence Kazak: McGill University, Montreal
Alexander S. Banks: Diabetes, and Hypertension, Brigham and Women’s Hospital and Harvard Medical School
Marcia C. Haigis: Harvard Medical School
Shingo Kajimura: University of California, San Francisco
Michael P. Murphy: University of Cambridge, Cambridge Biomedical Campus
Steven P. Gygi: Harvard Medical School
Clary B. Clish: Broad Institute of Harvard and MIT
Edward T. Chouchani: Dana–Farber Cancer Institute

Nature, 2018, vol. 560, issue 7716, 102-106

Abstract: Abstract Thermogenesis by brown and beige adipose tissue, which requires activation by external stimuli, can counter metabolic disease1. Thermogenic respiration is initiated by adipocyte lipolysis through cyclic AMP–protein kinase A signalling; this pathway has been subject to longstanding clinical investigation2–4. 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.

Date: 2018
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DOI: 10.1038/s41586-018-0353-2

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