Growth hormone promotes hepatic gluconeogenesis by enhancing BTG2\u2013YY1 signaling pathway

Jeong-Rang Jo,Yong Deuk Kim,Swati Ghosh,Balachandar Nedumaran,Seungwon An

doi:10.1038/s41598-021-98537-0

Abstract

Growth hormone (GH) is one of the critical factors in maintaining glucose metabolism. B-cell translocation gene 2 (BTG2) and yin yang 1 (YY1) are key regulators of diverse metabolic processes. In this study, we investigated the link between GH and BTG2–YY1 signaling pathway in glucose metabolism. GH treatment elevated the expression of hepatic Btg2 and Yy1 in primary mouse hepatocytes and mouse livers. Glucose production in primary mouse hepatocytes and serum blood glucose levels were increased during GH exposure. Overexpression of hepatic Btg2 and Yy1 induced key gluconeogenic enzymes phosphoenolpyruvate carboxykinase 1 (PCK1) and glucose-6 phosphatase (G6PC) as well as glucose production in primary mouse hepatocytes, whereas this phenomenon was markedly diminished by knockdown of Btg2 and Yy1. Here, we identified the YY1-binding site on the Pck1 and G6pc gene promoters using reporter assays and point mutation analysis. The regulation of hepatic gluconeogenic genes induced by GH treatment was clearly linked with YY1 recruitment on gluconeogenic gene promoters. Overall, this study demonstrates that BTG2 and YY1 are novel regulators of GH-dependent regulation of hepatic gluconeogenic genes and glucose production. BTG2 and YY1 may be crucial therapeutic targets to intervene in metabolic dysfunction in response to the GH-dependent signaling pathway.

Highlights

Growth hormone (GH) is produced by somatotropic cells of the anterior pituitary gland
Our previous report demonstrated that GH increased hepatic gluconeogenesis, but this phenomenon was abolished by metformin-ataxia telangiectasia mutated (ATM)-AMP-activated protein kinase (AMPK)-small heterodimer partner (SHP) signaling pathway[26]
GH treatment significantly increased the levels of Pck[1] and G6pc along with the increased expression of Btg[2] and Yy1 (Fig. 1a) in primary mouse hepatocytes

Summary

Introduction

Growth hormone (GH) is produced by somatotropic cells of the anterior pituitary gland. Hepatic gluconeogenesis is generally associated with the transcriptional regulation of rate-limiting key enzymes, such as phosphoenolpyruvate carboxykinase 1 (PCK1) and glucose-6 phosphatase (G6PC). These hepatic gluconeogenic genes are regulated by numbers of transcription factors, nuclear receptors, and coregulators, including cAMP-response element-binding protein (CREB), forkhead box protein O1 (FOXO1), CCAAT/enhancing-binding protein alpha (C/EBPα), estrogen-related receptor gamma (ERRγ), peroxisome proliferators-activated receptor γ coativator-1α (PGC-1α), CREB-regulated transcription coactivator 2 (CRTC2)[8,9,10,11,12,13,14]. Yin Yang 1 (YY1) is a member of the polycomb protein family and functions as a transcription factor It is predominantly expressed in diverse tissues and involved in the regulation of multiple target genes via chromatin modification[21,22,23]. BTG2 and YY1 may be novel potential therapeutic targets to combat metabolic dysfunction in response to the GH-dependent signaling pathway

Methods

Results

Conclusion