The integrated stress response (ISR) is a signaling system in which the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) by stress-specific kinases and the subsequent activation of activation transcription factor (ATF) 4 help restore cellular homeostasis following exposure to environmental stresses. ISR activation has been observed in metabolic diseases including hepatic steatosis, steatohepatitis and insulin resistance, but it remains unclear whether ISR contributes to the disease pathogenesis, or represents an innate defense mechanism against metabolic stresses. Constitutive repressor of eIF2α phosphorylation (CReP) is a critical regulatory subunit of the eIF2α phosphatase complex. Here we show that CReP ablation causes constitutive eIF2α phosphorylation in the liver, which leads to activation of the ATF4 transcriptional program including increased Fibroblast growth factor 21 (FGF21) production. Liver-specific CReP knockout (CReP ) mice exhibited marked browning of white adipose tissue, increased energy expenditure and insulin sensitivity in a FGF21-dependent manner. Furthermore, CReP mice were protected from high fat diet (HFD)-induced obesity, hepatic steatosis, and insulin resistance. Acute CReP ablation in the liver of HFD-induced obese mice also reduced adiposity and improved glucose homeostasis.

CONCLUSION: These data suggest that CReP abundance is a critical determinant for eIF2α phosphorylation and ensuing ISR activation in the liver. Constitutive ISR activation in the liver induces FGF21 and confers protection from high-fat diet (HFD)-induced adiposity, insulin resistance and hepatic steatosis in mice. Augmenting hepatic ISR may represent a novel therapeutic approach to treat metabolic disorders. This article is protected by copyright. All rights reserved.