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

Abstract

Edited by Qi-Qun Tang 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 dietinduced 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.

In Vivo Two-Photon Imaging Analysis of Dynamic Degradation of Hepatic Lipid Droplets in MS-275-Treated Mouse Liver

“…The MS-275-treated mouse livers showed increased mRNA levels of FAO-related genes, but decreased mRNA levels of lipogenic genes ( Figure 6 B,C). In addition, several studies have reported that FGF21 overexpression influences weight loss and hepatic steatosis [ 23 , 24 ]. Therefore, we investigated the expression of Fgf21 in the livers of the MS-275-treated mice.…”