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.

作为一种潜在的可靶向核受体，类固醇生成因子1（steroidogenic factor-1, SF1）可在腹内侧下丘脑核中调节肥胖与胰岛素抵抗。本研究旨在阐明其在胰岛中对肥胖诱导糖尿病发生的表达模式与调控功能。在瘦型小鼠的胰岛β细胞中几乎检测不到SF1的表达；而在非糖尿病性肥胖小鼠的β细胞中，SF1呈高表达，但在糖尿病小鼠的β细胞中其表达水平显著下降。β细胞中SF1的特异性敲除，会通过扰乱葡萄糖刺激胰岛素分泌（glucose-stimulated insulin secretion, GSIS），使饮食诱导肥胖（diet-induced obese, DIO）小鼠易于出现糖耐量异常。与之相反，在DIO小鼠与db/db小鼠中过表达SF1，可通过改善GSIS恢复正常的葡萄糖稳态。在分离的胰岛及MIN6细胞系中，异位表达SF1可增强GSIS，这一效应由线粒体ATP产生的改善所介导。其潜在机制可能涉及氧化磷酸化与脂质代谢过程。综上，SF1可通过参与β细胞对肥胖的适应性调节维持GSIS，因此有望成为肥胖诱导糖尿病的潜在治疗靶点。