Kenneth J. McCreath, 1 Sandra Espada, 1 Beatriz G. Gálvez, 1 Marina Benito, 2,3 Antonio de Molina, 4 Pilar Sepúlveda, 5 and Ana M. Cervera 1,5 Targeted Disruption of the SUCNR1 Metabolic Receptor Leads to Dichotomous Effects on Obesity Diabetes 2015;64:1154–1167 | DOI: 10.2337/db14-0346 A number of metabolites have signaling properties by acting through G-protein–coupled receptors. Succinate, a Krebs cycle intermediate, increases after dysregu- lated energy metabolism and can bind to its cognate receptor succinate receptor 1 (Sucnr1, or GPR91) to ac- tivate downstream signaling pathways. We show that Sucnr1 is highly expressed in the white adipose tissue (WAT) compartment of mice and regulates adipose mass and glucose homeostasis. Sucnr1 2/2 mice were generated, and weight gain was monitored under basal and nutritional stress (high-fat diet [HFD]) conditions. On chow diet, Sucnr1 2/2 mice had increased energy expenditure, were lean with a smaller WAT compart- ment, and had improved glucose buffering. Lipolysis measurements revealed that Sucnr1 2/2 mice were re- leased from succinate-induced inhibition of lipolysis, demonstrating a function of Sucnr1 in adipose tissue. Sucnr1 deletion also protected mice from obesity on HFD, but only during the initial period; at later stages, body weight of HFD-fed Sucnr1 2/2 mice was almost comparable with wild-type (WT) mice, but WAT content was greater. Also, these mice became progressively hyperglycemic and failed to secrete insulin, although pancreas architecture was similar to WT mice. These findings suggest that Sucnr1 is a sensor for dietary energy and raise the interesting possibility that proto- cols to modulate Sucnr1 might have therapeutic utility in the setting of obesity. G-protein–coupled receptors (GPCRs) constitute the major and most diverse group of membrane receptors in eukaryotes (1). Found in the plasma membrane, these receptors are tasked with the recognition and transmis- sion of messages from the external environment. An ever- increasing number of GPCRs are now being identified as receptors for metabolites or energy substrates (2), expanding the repertoire of biological targets to diseases associated with the metabolic syndrome, including hyper- tension and type 2 diabetes (3). Metabolites such as lac- tate (4), ketone bodies (5), and a-ketoglutarate (6), known primarily to serve functions distinct to signaling, have been shown to act as ligands for GPCRs. Represen- tative of this new class of receptor is Gpr91, a receptor for the Krebs cycle intermediate succinate, now termed Sucnr1 for succinate receptor (7). The Krebs, or citric acid, cycle occurs at the junction between glycolysis and oxidative phosphorylation (8) and is a key component of aerobic metabolism by providing reducing equivalents for the electron transport chain. Interestingly, succinate has been known for many years to increase in tissues during hypoxia (9–11) and may act as a surrogate marker for reduced oxygenation. Accordingly, Sucnr1 may be acti- vated in times of hypoxic stress such as ischemic injury in liver (12) or retina (13) or during cardiomyocyte crisis (14). Moreover, dysregulated metabolism, akin to diabetes or the metabolic syndrome, also has the potential to in- crease peripheral blood concentrations of succinate to 1 Department of Cardiovascular Development and Repair, Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain 2 Advanced Imaging Unit, Department of Atherothrombosis, Imaging, and Epidemi- ology, Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain 3 CIBER de Enfermedades Respiratorias, Madrid, Spain 4 Comparative Medicine Unit, Fundación Centro Nacional de Investigaciones Cardio- vasculares Carlos III, Madrid, Spain 5 Regenerative Medicine and Heart Transplantation Unit, Instituto de Investigación Sanitaria La Fe, Valencia, Spain Corresponding author: Ana M. Cervera, acervera@iislafe.es or amcerveraz@ gmail.com. Received 28 February 2014 and accepted 14 October 2014. This article contains Supplementary Data online at http://diabetes .diabetesjournals.org/lookup/suppl/doi:10.2337/db14-0346/-/DC1. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. 1154 Diabetes Volume 64, April 2015 METABOLISM