<i>Ire1α</i> in <i>Pomc</i> Neurons Is Required for Thermogenesis and Glycemia.

Abstract

Whether neuronal inositol-requiring enzyme 1 (<i>Ire1</i>) is required for the proper regulation of energy balance and glucose homeostasis is unclear. We found that pro-opiomelanocortin (<i>Pomc</i>)-specific deficiency of <i>Ire1α</i> accelerated diet-induced obesity concomitant with a decrease in energy expenditure. This hypometabolic phenotype included deficits in thermogenic responses to diet and cold exposure as well as "beiging" of white adipose tissue. We also demonstrate that loss of <i>Ire1α</i> in <i>Pomc</i> neurons impaired whole-body glucose and insulin tolerance as well as hepatic insulin sensitivity. At the cellular level, deletion of <i>Ire1α</i> in <i>Pomc</i> neurons elevated hypothalamic endoplasmic reticulum (ER) stress and predisposed <i>Pomc</i> neurons to leptin and insulin resistance. Together, the current studies extend and confirm conclusions that <i>Ire1α-Xbp1s</i> and associated molecular targets link ER stress in arcuate <i>Pomc</i> neurons to aspects of normal energy and glucose homeostasis.