Role of the Transcription Factor ATF4 in the Anabolic Actions of Insulin and the Anti-anabolic Actions of Glucocorticoids

Christopher M Adams

doi:10.1074/jbc.m610510200

Abstract

In most mammalian cells, insulin and glucocorticoids promote anabolism and catabolism, respectively. Whereas the opposing effects of insulin and glucocorticoids on catabolic gene expression have been explained at the molecular level, comparatively little is known about how these hormones alter anabolic gene expression. These studies identify ATF4 as an anabolic transcription factor that is repressed by glucocorticoids and induced by insulin. Insulin-mediated induction of ATF4 required the mammalian target of rapamycin complex 1, was required for the activation of a genetic program for the cellular uptake of essential amino acids and the synthesis of nonessential amino acids and aminoacyl-tRNAs, and was coupled to the repression of Foxo-dependent genes needed for protein and lipid catabolism. These results suggest that ATF4 plays a central role in hormonal regulation of amino acid and protein anabolism by coupling amino acid uptake and synthesis, as well as the generation of charged tRNAs, to mammalian target of rapamycin complex 1-mediated mRNA translation.

Highlights

Insulin and glucocorticoids induce many of their metabolic effects by altering the expression of key genes needed for anabolic and catabolic processes
The presence of glucocorticoids coupled with lower levels of insulin permits the glucocorticoid receptor (GR)2 and Foxo transcription factors to bind cis-acting DNA regulatory elements present in genes encoding key proteins needed for protein catabolism (atrogin-1 and muscle-specific RING finger protein 1 (MuRF1)), lipid catabolism (pyruvate dehydrogenase kinase-4 (PDK4)), and gluconeogenesis (phosphoenolpyruvate carboxykinase (PEPCK))
In contrast to our current understanding of how catabolic genes are regulated by glucocorticoids and insulin, relatively little is known of how these hormones regulate anabolic gene expression

Summary

Introduction

Insulin and glucocorticoids induce many of their metabolic effects by altering the expression of key genes needed for anabolic and catabolic processes. Mouse L cells were incubated in the absence or presence of Glucocorticoids Repress Expression of ATF4 and mRNAs dexamethasone for 48 h, followed by an additional 6 h of incu- Involved in Amino Acid and Protein Anabolism—Of the 13 bation in the absence or presence of insulin, which was directly class I transcripts involved in amino acid and protein anaboadded to the cell culture medium in the continued presence of lism, 7 are known to be induced through the actions of ATF4 dexamethasone.

Results

Conclusion