SUCNR1 signaling in adipocytes controls energy metabolism by modulating circadian clock and leptin expression

Adipose tissue modulates energy homeostasis by secreting leptin, but little is known about the factors governing leptin production. We show that succinate, long perceived as a mediator of immune response and lipolysis, controls leptin expression via its receptor SUCNR1. Adipocyte-specific deletion of Sucnr1 influences metabolic health according to nutritional status. Adipocyte Sucnr1 deficiency impairs leptin response to feeding, whereas oral succinate mimics nutrient-related leptin dynamics via SUCNR1. SUCNR1 activation controls leptin expression via the circadian clock in an AMPK/JNK-C/EBPα-dependent manner. Although the anti-lipolytic role of SUCNR1 prevails in obesity, its function as a regulator of leptin signaling contributes to the metabolically favorable phenotype in adipocyte-specific Sucnr1 knockout mice under standard dietary conditions. Obesity-associated hyperleptinemia in humans is linked to SUCNR1 overexpression in adipocytes, which emerges as the major predictor of adipose tissue leptin expression. Our study establishes the succinate/SUCNR1 axis as a metabolite-sensing pathway mediating nutrient-related leptin dynamics to control whole-body homeostasis. [Display omitted] •Extracellular succinate in adipocytes controls circadian clock and leptin via SUCNR1•SUCNR1 modulates leptin via AMPK/JNK-BMAL1-C/EBPα-dependent signaling•The metabolic impact of SUCNR1 deficiency in adipocytes is dependent on nutritional status•Hyperleptinemia in human obesity is related to overactive succinate/SUCNR1 signaling Villanueva-Carmona et al. describe a new function for the succinate/SUCNR1 axis in controlling leptin expression in adipocytes via a mechanism involving the circadian clock. This system is overactivated in obesity, which might contribute to obesity-related hyperleptinemia.