1528-P: Hypothalamic SEL1L-HRD1 ER–Associated Degradation Is Indispensable for Leptin Signaling in Diet-Induced Obesity by Degrading Misfolded Leptin Receptor

Abstract

It has been reported that endoplasmic reticulum (ER) stress, also known as unfolded protein response (UPR), is a contributor to the development of diet-induced leptin resistance in central nervous system. However, the evidence for this model remains circumstantial and controversial. Moreover, the importance of ER homeostasis in leptin signaling remains unexplored. Interestingly, our data suggested that neither acute nor chronic HFD feeding triggers any overt UPR in vivo though with the presence of the central and peripheral pathogenesis. Rather, we found that the SEL1L-HRD1 protein complex of ER-associated protein degradation (ERAD) - the principal protein degradation and quality control mechanism - in hypothalamic POMC neurons is indispensable for leptin signaling in diet-induced obesity. We found that SEL1L-HRD1 ERAD, ubiquitously expressed in hypothalamic neurons, can be transiently induced by acute HFD. Notably the deficiency of SEL1L-HRD1 ERAD in POMC neurons leads to striking hypothalamic leptin resistance, concomitant hyperphagia and diet-induced obesity and pathogenesis in mice of both sexes. Mechanistically, our data show that in ER, SEL1L-HRD1 interacts with leptin receptors long isoform (LepRb) and mediates the degradation of LepRb. The lack of SEL1L-HRD1 impairs the clearance of misfolded LepRb that forms high molecular aggregates. Further, the SEL1L-HRD1 deficient cells exhibit significantly less membrane display of lepRb. Hence, we hypothesize that leptin receptor is an endogenous substrate candidate of SEL1L-HRD1 ERAD and that SEL1L-HRD1 ERAD is required for the maturation of nascent leptin receptor in the ER in response to leptin signaling. Overall, this study challenges the current dogma by demonstrating a key role of hypothalamic SEL1L-HRD1 ERAD, not UPR, in the pathogenesis of diet-induced obesity and leptin resistance. Disclosure H.Mao: None. L.Qi: None.