364-OR: Beta-Cell SF1 as a Thermogenic Regulator against Diet-Induced Obesity in Mice—Elucidating Its Role in Islet—Adipose Cross Talk

Context/Objectives: Our previous studies have established the crucial role of steroidogenic factor-1 (SF1) in beta-cell adaptation in obese mice by promoting insulin secretion. Given that deletion of SF1 in beta cells exacerbates diet-induced obesity (DIO), we aims to explore the involvement and mechanisms of SF1 in islet-adipose crosstalk and obesity related disturbance of glycometabolism. Methods: We developed an inducible, beta-cell-specific SF1-knockout mouse model, both heterozygous and homozygous, along with control littermates of both genders. Adeno-associated virus was employed to mediate SF1 overexpression. Glucose tolerance test and insulin tolerance test were performed to evaluate glycometabolism parameters in vivo. Metabolic cages recorded food intake, physical activity and energy expenditure. Immunohistochemistry determined UCP1 and VDAC1 expression in adipocytes in brown adipose tissues (BAT), with metabonomics used to explore underlying mechanisms. Results: The genetic deletion of SF1 in beta cells prediposed mice to obesity, glucose intolerance and insulin resistance upon high-fat diet, while ectopic SF1 expression facilitated weight loss and enhanced glucose tolerance. Notably, energy expenditure was significantly disrupted by SF1 knockout in beta cells, whereas forced expression stimulated thermogenesis. Neither food intake nor physical activity was influenced by beta-cell SF1. UCP1 and VDAC1 expression in BAT was down-regulated with beta-cell SF1 deletion but up-regulated with ectopic SF1 expression. Mechanistic investigations suggest roles for glutathione metabolism, thyroid hormone synthesis, and choline metabolism. Conclusions: Beta-cell SF1 serves as a thermogenic enhancer in islet-adipose crosstalk thereby improving metabolic health in obese mice. Disclosure Y. Guo: None. Y. Cheng: None. Y. Li: Consultant; Sanofi, Novo Nordisk, AstraZeneca. Funding National Natural Science Foundation of China (82200876)