Inducible hepatic expression of CREBH mitigates diet-induced obesity, insulin resistance, and hepatic steatosis in mice

Christopher S Krumm,Xu Xu,Curtis J Bare,Corey D Holman,Sander Kersten,Lukas E Dow,Ann-Hwee Lee,David E Cohen

doi:10.1016/j.jbc.2021.100815

Abstract

Cyclic AMP-responsive element-binding protein H (CREBH encoded by Creb3l3) is a transcription factor that regulates the expression of genes that control lipid and glucose metabolism as well as inflammation. CREBH is upregulated in the liver under conditions of overnutrition, and mice globally lacking the gene (CREBH−/−) are highly susceptible to diet-induced obesity, insulin resistance, and hepatic steatosis. The net protective effects of CREBH have been attributed in large part to the activities of fibroblast growth factor (Fgf)-21 (Fgf21), a target gene that promotes weight loss, improves glucose homeostasis, and reduces hepatic lipid accumulation. To explore the possibility that activation of the CREBH–Fgf21 axis could ameliorate established effects of high-fat feeding, we generated an inducible transgenic hepatocyte-specific CREBH overexpression mouse model (Tg-rtTA). Acute overexpression of CREBH in livers of Tg-rtTA mice effectively reversed diet-induced obesity, insulin resistance, and hepatic steatosis. These changes were associated with increased activities of thermogenic brown and beige adipose tissues in Tg-rtTA mice, leading to reductions in fat mass, along with enhanced insulin sensitivity and glucose tolerance. Genetically silencing Fgf21 in Tg-rtTA mice abrogated the CREBH-mediated reductions in body weight loss, but only partially reversed the observed improvements in glucose metabolism. These findings reveal that the protective effects of CREBH activation may be leveraged to mitigate diet-induced obesity and associated metabolic abnormalities in both Fgf21-dependent and Fgf21-independent pathways.

Highlights

Cyclic AMP-responsive element-binding protein H (CREBH, encoded by Creb3l3) encodes an endoplasmic reticulum (ER) intramembrane-anchored precursor form that requires intramembrane proteolysis at the Golgi apparatus to
Whereas activation of the cyclic AMP-responsive element-binding protein H (CREBH)–fibroblast growth factor-21 (Fgf21) axis protects mice from high-fat diet (HFD)-induced obesity, insulin resistance (IR), and hepatic steatosis [6, 7], the current study was designed to explore whether its activation would reverse these disorders once established
At a doxycycline concentration of 1 mg/ml in the drinking water, there was no evidence of hepatotoxicity as evidenced by a lack of elevations in plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities [22], and this concentration was chosen for further studies

Summary

Introduction

Cyclic AMP-responsive element-binding protein H (CREBH, encoded by Creb3l3) encodes an endoplasmic reticulum (ER) intramembrane-anchored precursor form that requires intramembrane proteolysis at the Golgi apparatus to. Plasma insulin levels prior to doxycycline treatment were comparable between genotypes and decreased by 42.1% in Tg-rtTA mice relative to Control mice at 6 weeks (Fig. 2B). Following 6 weeks of doxycycline treatment, Tg-rtTA mice were sensitized to insulin (Fig. 2C) and exhibited increased glucose tolerance compared with Control mice (Fig. 2D).

Results

Conclusion