Steroidogenic factor 1 protects mice from obesity-induced glucose intolerance via improving glucose-stimulated insulin secretion by beta cells

As a potential druggable nuclear receptor, steroidogenic factor-1 (SF1) regulates obesity and insulin resistance in the ventromedial hypothalamic nucleus. Herein, we sought to demonstrate its expression and functions in islets in the development of obesity-induced diabetes. Barely detected in the beta cells of lean mice, SF1 was highly expressed in those of non-diabetic obese mice, but decreased in those with diabetes. Specific deletion of SF1 in beta cells predisposed diet-induced obese (DIO) mice to glucose intolerance by perturbing glucose-stimulated insulin secretion (GSIS). In contrast, forced expression of SF1 restored favorable glucose homeostasis in DIO and db/db mice by improving GSIS. In isolated islets and MIN6, ectopic expression of SF1 potentiated GSIS, mediated by improvement of mitochondrial ATP production. The underlying mechanisms may involve oxidative phosphorylation and lipid metabolism. Collectively, SF1 preserves GSIS involved in beta-cell adaptation to obesity and hence holds promise as a potential therapeutic target for obesity-induced diabetes.