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.