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 o...

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Authors: Villanueva-Carmona, Teresa, Cedó, Lídia, Madeira, Ana, Ceperuelo-Mallafré, Victoria, Rodríguez-Peña, M-Mar, Núñez-Roa, Catalina, Maymó-Masip, Elsa, Repollés-de-Dalmau, María, Badía, Joan, Keiran, Noelia, Mirasierra, Mercedes, Pimenta-Lopes, Carolina, Sabadell-Basallote, Joan, Bosch, Ramón, Caubet, Laura, Escolà-Gil, Joan Carles, Vilarrasa, Núria, Ventura, Francesc, Vallejo, Mario, Fernández-Veledo, Sonia
Format: article
Status:Versión aceptada para publicación
Publication Date:2023
Country:España
Institution:Consejo Superior de Investigaciones Científicas (CSIC)
Repository:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/350284
Online Access:http://hdl.handle.net/10261/350284
Access Level:Open access
Keyword:Adipose tissue
Succinate
SUCNR1
Leptin
Circadian clock
Obesity
Adipocyte
Metabolite
Metabolism
GPCR
Description
Summary: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.

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