title: Targeted disruption of the SUCNR1 metabolic receptor leads to dichotomous effects on obesity.
abstract: A number of metabolites have signaling properties by acting through G-protein-coupled receptors. Succinate, a Krebs cycle intermediate, increases after dysregulated energy metabolism and can bind to its cognate receptor succinate receptor 1 (Sucnr1, or GPR91) to activate 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(-/-) mice were generated, and weight gain was monitored under basal and nutritional stress (high-fat diet [HFD]) conditions. On chow diet, Sucnr1(-/-) mice had increased energy expenditure, were lean with a smaller WAT compartment, and had improved glucose buffering. Lipolysis measurements revealed that Sucnr1(-/-) mice were released 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(-/-) 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 protocols to modulate Sucnr1 might have therapeutic utility in the setting of obesity.
authors.affiliation: Department of Cardiovascular Development and Repair, Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: McCreath
authors.affiliation: Department of Cardiovascular Development and Repair, Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.
authors.forename: Sandra
authors.initials: S
authors.lastname: Espada
authors.affiliation: Department of Cardiovascular Development and Repair, Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.
authors.forename: Beatriz G
authors.initials: BG
authors.lastname: Gálvez
authors.affiliation: Advanced Imaging Unit, Department of Atherothrombosis, Imaging, and Epidemiology, Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain CIBER de Enfermedades Respiratorias, Madrid, Spain.
authors.forename: Marina
authors.initials: M
authors.lastname: Benito
authors.affiliation: Comparative Medicine Unit, Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: de Molina
authors.affiliation: Regenerative Medicine and Heart Transplantation Unit, Instituto de Investigación Sanitaria La Fe, Valencia, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Sepúlveda
authors.affiliation: Department of Cardiovascular Development and Repair, Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain Regenerative Medicine and Heart Transplantation Unit, Instituto de Investigación Sanitaria La Fe, Valencia, Spain acervera@iislafe.es amcerveraz@gmail.com.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Cervera
mesh_terms: D052436:Adipose Tissue, White / Q000378:metabolism; D000818:Animals; D059305:Diet, High-Fat; D004435:Eating / Q000502:physiology*; D004734:Energy Metabolism / Q000502:physiology; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D008066:Lipolysis / Q000502:physiology; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000235:genetics / Q000378:metabolism*; D010179:Pancreas / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D014280:Triglycerides / Q000378:metabolism
chemical_list: C531499:GPR91 protein, mouse; D007328:Insulin; D043562:Receptors, G-Protein-Coupled; D014280:Triglycerides