Hepatic Gadd45β promotes hyperglycemia and glucose intolerance through DNA demethylation of PGC-1α

Abstract

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 β (Gadd45β)–dependent pathway that stimulates hepatic glucose production (HGP). Functional studies showed that overexpression of Gadd45β in vivo or in cultured hepatocytes activates gluconeogenesis and increases HGP. In contrast, liver-specific Gadd45β-knockout mice were resistant to high-fat diet– or steroid-induced hyperglycemia. Of pathophysiological significance, hepatic Gadd45β expression is up-regulated in several mouse models of obesity and diabetic patients. Mechanistically, Gadd45β promotes DNA demethylation of PGC-1α promoter in conjunction with TET1, thereby stimulating PGC-1α expression to promote gluconeogenesis and hyperglycemia. Collectively, these findings unveil an epigenomic signature involving Gadd45β/TET1/DNA demethylation in hepatic glucose metabolism, enabling the identification of pathogenic factors in diabetes.

Peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) family in physiological and pathophysiological process and diseases

“…Mechanistic study revealed that Gadd45β, in conjunction with teneleven translocation 1 (TET1), promotes DNA demethylation of the PGC-1α promoter, thereby stimulating PGC-1α expression and promoting gluconeogenesis and hyperglycemia. 72 In type 2 diabetes mellitus (T2DM) patients, the methylation levels of PGC-1α promoter in skeletal muscle, adipose tissue, and pancreatic islet cells are higher compared to normal individuals. 73,74 Additionally, PPARGC1A methylated DNA/unmethylated DNA ratio in the liver has a significant correlation with plasma fasting insulin levels and homeostasis model assessment of insulin resistance.…”

Epigenetic modifications in obesity‐associated diseases

“…In obese individuals, those with T2D have hypermethylation of the insulin receptor substrate 2 (IRS2) promoter CpG sites in the liver, and the reduced expression of IRS2 is closely related to IR 75 . Among patients with T2D, the elevated expression of DNA damage‐inducible β (Gadd45β), in conjunction with TET1, stimulates the DNA demethylation of the PPARG coactivator 1 alpha (PPARGC1A) promoter, resulting in heightened gluconeogenesis and reduced glucose tolerance among patients 76 . DNAm alterations are evident across all three stages of adipogenesis in obese individuals, and these differentially methylated genes may play a role in the development of T2D primarily by impairing the function of mature adipocytes 77 …”

Tet methylcytosine dioxygenase 1 modulates Porphyromonas gingivalis–triggered pyroptosis by regulating glycolysis in cementoblasts

“…TET1 was shown to mediate the effects of synergistic treatment with P. gingivalis lipopolysaccharide (LPS) and interferon‐gamma (IFN‐γ) on M1 macrophage polarization 30 . Moreover, TET1 is involved in various diseases, including developmental defects, cancers, inflammation, and metabolic syndromes 31–36 . Based on the above, it is worth investigating whether TET1 is involved in the inflammatory response and pyroptosis elicited by P. gingivalis .…”

“…30 Moreover, TET1 is involved in various diseases, including developmental defects, cancers, inflammation, and metabolic syndromes. [31][32][33][34][35][36] Based on the above, it is worth investigating whether TET1 is involved in the inflammatory response and pyroptosis elicited by P. gingivalis.…”