PERK in POMC neurons connects celastrol with metabolism.

Zhenyan He,Linh Lieu,Kevin W Williams,Dominic Chau,Yanbin Dong,Anita Kabahizi,Ling Hu,Jennifer Okolo,Briana Wallace,Eun-Sang Hwang,Bo Cheng,Yong Gao,Jianhong Cao,Yiru Huang,Ting Yao,Sadia Afrin

doi:10.1172/jci.insight.145306

Abstract

ER stress and activation of the unfolded protein response in the periphery as well as the central nervous system have been linked to various metabolic abnormalities. Chemically lowering protein kinase R–like ER kinase (PERK) activity within the hypothalamus leads to decreased food intake and body weight. However, the cell populations required in this response remain undefined. In the current study, we investigated the effects of proopiomelanocortin-specific (POMC-specific) PERK deficiency on energy balance and glucose metabolism. Male mice deficient for PERK in POMC neurons exhibited improvements in energy balance on a high-fat diet, showing decreased food intake and body weight, independent of changes in glucose and insulin tolerances. The plant-based inhibitor of PERK, celastrol, increases leptin sensitivity, resulting in decreased food intake and body weight in a murine model of diet-induced obesity (DIO). Our data extend these observations by demonstrating that celastrol-induced improvements in leptin sensitivity and energy balance were attenuated in mice with PERK deficiency in POMC neurons. Altogether, these data suggest that POMC-specific PERK deficiency in male mice confers protection against DIO, possibly providing a new therapeutic target for the treatment of diabetes and metabolic syndrome.

Highlights

ER stress and the unfolded protein response (UPR) have been linked to several physiological and pathological conditions [1,2,3,4,5,6,7,8,9]
Protein kinase R–like ER kinase (PERK) deficiency in humans is associated with Wolcott-Rallison syndrome (WRS), which results in decreased growth and permanent neonatal or early infancy insulin-dependent diabetes [11]
In order to test the requirement of PERK in POMC neurons for regulation of energy balance, we generated mice that were deficient for PERK in POMC neurons (POMC-cre:PERKloxp/loxp mice)

Summary

Introduction

ER stress and the unfolded protein response (UPR) have been linked to several physiological and pathological conditions [1,2,3,4,5,6,7,8,9]. Protein kinase R–like ER kinase (PERK) is part of the ER-anchored receptor signaling network that is involved when the UPR is activated in response to ER stress. Impairment in PERK-dependent phosphorylation of Eif2α in mice leads to decreased body weight, elevated blood glucose levels, and reduced serum insulin [16]. Within the central nervous system, the chemical compound celastrol increases leptin sensitivity, resulting in marked improvements in the body weight of diet-induced obesity (DIO) mice and enhancement of leptin-induced hypophagia by reducing ER stress in the hypothalamus via selectively reducing PERK phosphorylation [17]. While there is growing evidence that PERK/Eif2α signaling regulates proper body weight maintenance and glucose metabolism in various tissues, including the hypothalamus, the neuronal cell type(s) involved in this response remains undefined

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