Accumulation of succinate controls activation of adipose tissue thermogenesis

Abstract

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

Succinate induces skeletal muscle fiber remodeling via SUCNR1 signaling

“…Succinate has been reported to induce cardiomyocyte hypertrophy [17] and osteoclastogenesis [18]. It also plays an important role in energy [19] and glucose [20] homeostasis by regulating mitochondrial oxygen consumption [21] and heat production from brown adipose tissue (BAT) [22]. Therefore, we hypothesize that succinate regulates skeletal muscle fiber remodeling.…”

Innate lymphoid cells, mediators of tissue homeostasis, adaptation and disease tolerance

“…Succinate drove UCP1‐dependent thermogenesis by brown adipose tissue in vivo, which stimulated robust protection against diet‐induced obesity and improved glucose tolerance. These findings reveal an unexpected mechanism for control of thermogenesis, using succinate as a systemically‐derived thermogenic molecule . It is tempting to speculate that some of the succinate controlled effects may depend on the tuft cell‐ILC2 axis.…”

“…As discussed above, succinates can directly activate the tuft cell‐ILC2 axis. Intriguingly, a recent report showed that succinate is a metabolic signature of adipose tissue thermogenesis upon activation by exposure to cold . Succinate drove UCP1‐dependent thermogenesis by brown adipose tissue in vivo, which stimulated robust protection against diet‐induced obesity and improved glucose tolerance.…”

Inter‐organ communication: a gatekeeper for metabolic health

“…These acylcarnitines are in fine used by BAT for adaptive thermogenesis [163]. In addition, Mills and colleagues demonstrated that succinate accumulates in BAT upon cold exposure and favors thermogenesis in an UCP1-dependent manner [164]. Furthermore, gut microbiota has been described in the past two decades as a very important player in the regulation of whole-body energy homeostasis, in response to diverse stimuli such as cold [165,166], nutrition [167,168], or fasting/feeding cycles [168][169][170], through the production of mediators such as short chain fatty acids (SCFAs) and secondary BAs [167,169].…”