Novel Function of Osteoprotegerin in the Modulation of Glucose Metabolism in the Liver via mTORC1

Osteoprotegerin (OPG) has emerged as a pivotal factor in metabolic disease pathology; however, its role in hepatic glucose metabolism remains poorly understood. We demonstrated a pronounced reduction in hepatic OPG expression in obese mice, attributable to DNA hypermethylation mediated by DNMT3α. Opg overexpression in the liver reduced the basal metabolic rate and exacerbated glucose metabolism disorders in mice with high-fat diet–induced obesity, whereas Opg knockout yielded opposite effects. Furthermore, mammalian target of rapamycin complex 1 (mTORC1; Raptor)/S6K1/IRS1/AKT signaling was found to be required for the regulation of hepatic glucose metabolism. Mechanistic investigations revealed that OPG interacts with Raptor within the mTORC1 complex, facilitating its phosphorylation at Ser863 and Ser877, influencing the mTORC1 (Raptor)/S6K1/IRS1/AKT signaling pathway, and thereby affecting glucose metabolism and insulin sensitivity. These findings underscore the integral role of OPG in glucose homeostasis and suggest it as a novel therapeutic target in type 2 diabetes.Article HighlightsMethylation of the Opg promoter inhibits hepatic OPG expression in obese mice.Hepatic OPG regulates glucose metabolism and insulin sensitivity in obese mice.OPG regulates glucose metabolism through interaction with mammalian target of rapamycin complex 1 (Raptor).Opg deficiency in mice reduces age-related metabolic dysfunction.