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

• DOI: 10.1016/j.cmet.2023.03.004
• Publication Date: 2023-03-27T14:43:31Z
• Authors: Teresa Villanueva...; Lídia Cedó; Ana Madeira; Victòria Ceperuel...; M.-Mar Rodríguez-...; Catalina Núñez-Roa; Elsa Maymó- Masip; Maria Repollés-de...; Joan Badia; Noelia Keiran; Mercedes Mirasierra; Carolina Pimenta-...; Joan Sabadell-Bas...; Ramón Bosch; Laura Caubet; Joan Carles Escol...; José-Manuel Ferná...; Nuria Vilarrasa; Francesc Ventura; Mario Vallejo; Joan Vendrell; Sonia Fernández-V...
• Keywords: 2. Zero hunger; Leptin; Mice, Knockout; Succinate; Adipocyte; Adipose tissue; Metabolite; Succinates; Circadian clock; Mice; Metabolism; GPCR; SUCNR1; Circadian Clocks; Adipocytes; Animals; Humans; Obesity; Energy Metabolism

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.