Hepatic Gadd45 Beta Promotes Hyperglycemia And Glucose Intolerance Through Dna Demethylation Of Pgc-1 Alpha

Although widely used for their potent anti-inflammatory and immunosuppressive properties, the prescription of glucocorticoid analogues (e.g., dexamethasone) has been associated with deleterious glucose metabolism, compromising their long-term therapeutic use. However, the molecular mechanism remains poorly understood. In the present study, through transcriptomic and epigenomic analysis of two mouse models, we identified a growth arrest and DNA damage-inducible beta (Gadd45 beta)-dependent pathway that stimulates hepatic glucose production (HGP). Functional studies showed that overexpression of Gadd45 beta in vivo or in cultured hepatocytes activates gluconeogenesis and increases HGP. In contrast, liver-specific Gadd45 beta-knockout mice were resistant to high-fat diet- or steroid-induced hyperglycemia. Of pathophysiological significance, hepatic Gadd45 beta expression is up-regulated in several mouse models of obesity and diabetic patients. Mechanistically, Gadd45 beta promotes DNA demethylation of PGC-1 alpha promoter in conjunction with TET1, thereby stimulating PGC-1 alpha expression to promote gluconeogenesis and hyperglycemia. Collectively, these findings unveil an epigenomic signature involving Gadd45 beta/TET1/DNA demethylation in hepatic glucose metabolism, enabling the identification of pathogenic factors in diabetes.