Repositori URV

Identificador: imarina:9295186

Handle: https://hdl.handle.net/20.500.11797/imarina9295186

Autors:
Villanueva-Carmona, TCedó, LMadeira, ACeperuelo-Mallafré, VRodríguez-Peña, MMNúñez-Roa, CMaymó-Masip, ERepollés-de-Dalmau, MBadia, JKeiran, NMirasierra, MPimenta-Lopes, CSabadell-Basallote, JBosch, RCaubet, LEscolà-Gil, JCFernández-Real, JMVilarrasa, NVentura, FVallejo, MVendrell, JFernández-Veledo, S

Resum:
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.Copyright © 2023 Elsevier Inc. All rights reserved.