Fasting Hormones Synergistically Induce Amino Acid Catabolism Genes to Promote Gluconeogenesis

Noga Korenfeld; Maya Finkel; Nufar Buchshtab; Meirav Bar-Shimon; Meital Charni-Natan; Ido Goldstein

doi:10.1016/j.jcmgh.2021.04.017

Fasting Hormones Synergistically Induce Amino Acid Catabolism Genes to Promote Gluconeogenesis

Cell Mol Gastroenterol Hepatol. 2021;12(3):1021-1036. doi: 10.1016/j.jcmgh.2021.04.017. Epub 2021 May 3.

Authors

Noga Korenfeld¹, Maya Finkel¹, Nufar Buchshtab¹, Meirav Bar-Shimon¹, Meital Charni-Natan¹, Ido Goldstein²

Affiliations

¹ Institute of Biochemistry, Food Science and Nutrition. Robert H. Smith Faculty of Agriculture, Food and EnvironmentThe Hebrew University of Jerusalem, Rehovot, Israel.
² Institute of Biochemistry, Food Science and Nutrition. Robert H. Smith Faculty of Agriculture, Food and EnvironmentThe Hebrew University of Jerusalem, Rehovot, Israel. Electronic address: Ido.goldstein@mail.huji.ac.il.

Abstract

Background & aims: Gluconeogenesis from amino acids (AAs) maintains glucose homeostasis during fasting. Although glucagon is known to regulate AA catabolism, the contribution of other hormones to it and the scope of transcriptional regulation dictating AA catabolism are unknown. We explored the role of the fasting hormones glucagon and glucocorticoids in transcriptional regulation of AA catabolism genes and AA-dependent gluconeogenesis.

Methods: We tested the RNA expression of AA catabolism genes and glucose production in primary mouse hepatocytes treated with fasting hormones (glucagon, corticosterone) and feeding hormones (insulin, fibroblast growth factor 19). We analyzed genomic data of chromatin accessibility and chromatin immunoprecipitation in mice and primary mouse hepatocytes. We performed chromatin immunoprecipitation in livers of fasted mice to show binding of cAMP responsive element binding protein (CREB) and the glucocorticoid receptor (GR).

Results: Fasting induced the expression of 31 genes with various roles in AA catabolism. Of them, 15 were synergistically induced by co-treatment of glucagon and corticosterone. Synergistic gene expression relied on the activity of both CREB and GR and was abolished by treatment with either insulin or fibroblast growth factor 19. Enhancers adjacent to synergistically induced genes became more accessible and were bound by CREB and GR on fasting. Akin to the gene expression pattern, gluconeogenesis from AAs was synergistically induced by glucagon and corticosterone in a CREB- and GR-dependent manner.

Conclusions: Transcriptional regulation of AA catabolism genes during fasting is widespread and is driven by glucagon (via CREB) and corticosterone (via GR). Glucose production in hepatocytes is also synergistically augmented, showing that glucagon alone is insufficient in fully activating gluconeogenesis.

Keywords: Chromatin; Endocrinology; Enhancers; Fasting; Metabolism; Transcription Factors.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acids / metabolism*
Animals
CREB-Binding Protein / metabolism*
Cells, Cultured
Enhancer Elements, Genetic / drug effects
Fasting / metabolism*
Fibroblast Growth Factors / metabolism
Fibroblast Growth Factors / pharmacology
Gene Expression Profiling / methods
Gene Expression Regulation / drug effects
Glucagon / metabolism*
Glucagon / pharmacology
Glucocorticoids / metabolism*
Glucocorticoids / pharmacology
Gluconeogenesis*
Hepatocytes / cytology*
Hepatocytes / drug effects
Hepatocytes / metabolism
Insulin / metabolism
Insulin / pharmacology
Mice
Models, Animal
Primary Cell Culture
Receptors, Glucocorticoid / metabolism*
Sequence Analysis, RNA

Substances

Amino Acids
Glucocorticoids
Insulin
Receptors, Glucocorticoid
fibroblast growth factor 15, mouse
Fibroblast Growth Factors
Glucagon
CREB-Binding Protein
Crebbp protein, mouse

Grants and funding

CIHR/Canada