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This study was supported by grants from the Spanish Ministry of Science and Innovation (MCIN)/AEI/10.13039/501100011033 (SAF2015-65019-R, RTI2018-093919-B-100, and PID2021-122480OB-I00 to S.F.-V.) and from the Instituto de Salud Carlos III (PI20/00095 to V.C.-M., and PI20/00338 to J.V.), all co-financed by the European Regional Development Fund (ERDF). This research was also supported by PID2020-119030RJ-I00 (to L. Cedo), PID2020-117640RB-I00 (to M.V.), and PID2020-117278GB-I00 (to F.V.) from MCIN/AEI/10.13039/501100011033. The project that gave rise to these results received funding from "La Caixa'' Foundation under the grant agreement LCF/PR/HR20/52400013 (to S.F.-V.). N.V. is the recipient of grants "Ajuts per a projectes de recerca clinicade l'Hospital Universitari de Bellvitge (2011-PR143/11)'' and the projects PI11/01960, PI14/01997, and PI17/01556 funded by the Instituto de Salud Carlos III and co-funded by "ERDF, A way to build Europe.'' T.V.-C. is a recipient of an FPI fellowship (PRE2019-090360), and V.C.-M. acknowledges support from the Ramon y Cajal program (RYC2019-02649-I), both from MCIN/AEI/10.13039/501100011033 and "European Social Fund (ESF) Investing in your future.'' M.R.-D.-D. is recipient of a Marti-Franques Research Grant Programme (2021PMF-PIPF-2) from Universitat Rovirai Virgili. C.P.-L. is recipient of an FPU fellowship from the Spanish Ministry of Education. J.S.-B. is a recipient of a predoctoral contract for training in health research from the Instituto de Salud Carlos III, co-financed by the ESF (PFISFI18/00151). S.F.-V. acknowledges support from the Miguel Servet tenue-track program (CP10/00438 and CPII16/00008) from the Fondo de Investigacion Sanitaria, co-financed by the ERDF. The Spanish Biomedical Research Center in Diabetes and Associated Metabilic Disorders (CIBERDEM)(CB07708/0012) is an initiative or the Instituto de Salud Carlos III. We thankthe Genomics Unit at the CRG for assistance with the sequencing, and the Biostatistics/Bioinformatics facility (IRB, Barcelona, Spain) for assistance with the data analysis. We particularly acknowledge the patients and the BioBank IISPV (PT17/0015/0029) integrated in the Spanish National Biobanks Network (registration number #C.0003609) for their collaboration. We thank G.Sabio (CNIC, Spain) for kindly providing the transgenic mice expressing Cre recombinase driven by the adipocyte-specific Adipoq promoter, and Kristin Mahan (University of Texas, USA) and Shin Yamazaki (UT Southwestern Med-ical Center, USA) for kindly providing the pGL3 BMAL-LUC construct. Wethank Marc Claret (IDIBAPS, Barcelona), Sara Ramirez (IDIBAPS, Barcelona),and Aleix Ribas-Latre (University of Leipzig, Germany) for their scientific advicein some aspects of the research, and Kenneth McCreath for helpful commentson the manuscript.

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

Publicated to:Cell Metabolism. 35 (4): 601-619.e10 - 2023-04-04 35(4), DOI: 10.1016/j.cmet.2023.03.004

Authors: Villanueva-Carmona, Teresa; Cedo, Lidia; Madeira, Ana; Ceperuelo-Mallafre, Victoria; Rodriguez-Pena, M -Mar; Nunez-Roa, Catalina; Maymo-Masip, Elsa; Repolles-de-Dalmau, Maria; Badia, Joan; Keiran, Noelia; Mirasierra, Mercedes; Pimenta-Lopes, Carolina; Sabadell-Basallote, Joan; Bosch, Ramon; Caubet, Laura; Escola-Gil, Joan Carles; Fernandez-Real, Jose-Manuel; Vilarrasa, Nuria; Ventura, Francesc; Vallejo, Mario; Vendrell, Joan; Fernandez-Veledo, Sonia

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Abstract

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.

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