Bombesin receptor subtype-3 (BRS-3), a novel candidate as therapeutic molecular target in obesity and diabetes

Abstract

BRS-3 KO-mice developed obesity and unbalanced glucose metabolism, suggesting an important role of BRS-3 receptor in glucose homeostasis. We explored BRS-3 expression in skeletal muscle from normal, obese or type-2 diabetic (T2D) patients, and the effect of [D-Phe6 , b-Ala11, Phe13,Nle14]bombesin6¿14¿ BRS-3-agonist-peptide (BRS-3-AP) ¿ on glucose-related effects, before or after BRS-3 gene silencing. In muscle tissue and primary cultured myocytes from altered metabolic states, BRS-3 gene/protein expres sions were down-regulated. In normal, obese and T2D cells: A) BRS-3-AP as insulin enhanced BRS-3 and GLUT-4 mRNA/protein levels; improving glucotransporter translocation to plasma membrane, and B) BRS-3-AP caused a concentration-related-stimulation of glucose transport, being obese and T2D myo cytes more sensitive to the ligand than normal. Wortmannin and PD98059, but not rapamycin, abolished the stimulatory action of BRS-3-AP on glucose transport. BRS-3 plays an important role in glucose metab olism, and could be use as a molecular target, and/or its ligand, as a therapeutic agent for obesity and dia betes treatments.