Targeted Disruption of the SUCNR1 Metabolic Receptor Leads to Dichotomous Effects on Obesity
Por:
K. MCCREATH, S. ESPADA, B. GALVEZ, M. BENITO, A. DE MOLINA, P. SEPULVEDA and A. CERVERA
Publicada:
1 abr 2015
Resumen:
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.
Filiaciones:
K. MCCREATH:
Fdn Ctr Nacl Invest Cardiovasc Carlos III, Dept Cardiovasc Dev & Repair, Madrid, Spain
S. ESPADA:
Fdn Ctr Nacl Invest Cardiovasc Carlos III, Dept Cardiovasc Dev & Repair, Madrid, Spain
B. GALVEZ:
Fdn Ctr Nacl Invest Cardiovasc Carlos III, Dept Cardiovasc Dev & Repair, Madrid, Spain
M. BENITO:
Fdn Ctr Nacl Invest Cardiovasc Carlos III, Dept Atherothrombosis Imaging & Epidemiol, Adv Imaging Unit, Madrid, Spain
CIBER Enfermedades Resp, Madrid, Spain
A. DE MOLINA:
Fdn Ctr Nacl Invest Cardiovasc Carlos III, Comparat Med Unit, Madrid, Spain
:
Inst Invest Sanitaria La Fe, Regenerat Med & Heart Transplantat Unit, Valencia, Spain
A. CERVERA:
Fdn Ctr Nacl Invest Cardiovasc Carlos III, Dept Cardiovasc Dev & Repair, Madrid, Spain
Inst Invest Sanitaria La Fe, Regenerat Med & Heart Transplantat Unit, Valencia, Spain
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