Hypothalamic ER–associated degradation regulates POMC maturation, feeding, and age-associated obesity
Geun Hyang Kim, … , Martin G. Myers Jr., Ling Qi
Geun Hyang Kim, … , Martin G. Myers Jr., Ling Qi
Published February 19, 2018
Citation Information: J Clin Invest. 2018;128(3):1125-1140. https://doi.org/10.1172/JCI96420.
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Research Article Cell biology Metabolism

Hypothalamic ER–associated degradation regulates POMC maturation, feeding, and age-associated obesity

Abstract

Pro-opiomelanocortin (POMC) neurons function as key regulators of metabolism and physiology by releasing prohormone-derived neuropeptides with distinct biological activities. However, our understanding of early events in prohormone maturation in the ER remains incomplete. Highlighting the significance of this gap in knowledge, a single POMC cysteine-to-phenylalanine mutation at position 28 (POMC-C28F) is defective for ER processing and causes early onset obesity in a dominant-negative manner in humans through an unclear mechanism. Here, we report a pathologically important role of Sel1L-Hrd1, the protein complex of ER-associated degradation (ERAD), within POMC neurons. Mice with POMC neuron–specific Sel1L deficiency developed age-associated obesity due, at least in part, to the ER retention of POMC that led to hyperphagia. The Sel1L-Hrd1 complex targets a fraction of nascent POMC molecules for ubiquitination and proteasomal degradation, preventing accumulation of misfolded and aggregated POMC, thereby ensuring that another fraction of POMC can undergo normal posttranslational processing and trafficking for secretion. Moreover, we found that the disease-associated POMC-C28F mutant evades ERAD and becomes aggregated due to the presence of a highly reactive unpaired cysteine thiol at position 50. Thus, this study not only identifies ERAD as an important mechanism regulating POMC maturation within the ER, but also provides insights into the pathogenesis of monogenic obesity associated with defective prohormone folding.

Authors

Geun Hyang Kim, Guojun Shi, Diane R.M. Somlo, Leena Haataja, Soobin Song, Qiaoming Long, Eduardo A. Nillni, Malcolm J. Low, Peter Arvan, Martin G. Myers Jr., Ling Qi

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Figure 1

POMC neuron–specific Sel1LPOMC mice develop age-associated obesity and hyperleptinemia.

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POMC neuron–specific Sel1LPOMC mice develop age-associated obesity and h...
(A) Representative images of immunohistochemical staining of Hrd1 in the brains of 7-week-old C57BL/6J mice on LFD (n = 2 each group). Zoomed-in images of ARC and thalamus are shown on the right. 3V, third ventricle. Representative images of negative control IgG are shown in Supplemental Figure 1A. (B) Representative images of Hrd1 staining in the ARC of 7-week-old POMC-eGFP reporter mice after an overnight fast with or without 6-hour refeeding. Quantitation of Hrd1 signals in POMC neurons (green arrows) and non-POMC neurons (white arrows) shown on the right (n = 2 mice each group, 70 neurons each mouse). (C) Representative images of Hrd1 staining in the ARC of 8-week-old Sel1LPOMC;POMC-eGFP and control Sel1LPOMC/+;POMC-eGFP mice on LFD (n = 3–4 each group). Green arrows point to POMC neurons; white arrows point to non-POMC neurons. (D) Quantitation of Hrd1 level shown in C in POMC and non-POMC neurons in the ARC (n = 70 and n = 100 neurons per mouse, n = 3–4 mice each). (E and F) Growth curve of Sel1Lfl/fl (n = 5), heterozygous Sel1LPOMC/+ (Sel1Lfl/+;Pomc-Cre, n = 3), and Sel1LPOMC mice (n = 7) on LFD. In E, a green dotted line marks the age at which Sel1LPOMC mice became significantly more obese. (G) Body weight of 10- and 40-week-old mice on LFD. (H) Representative image of 40-week-old mice on LFD. (I) Body composition of 10-week-old (n = 3 each) and 40-week-old (n = 6–7 each) male mice on LFD. (J and K) Representative images of peripheral tissues (J) and H&E images of peripheral tissues (K) from 40-week-old mice (n = 3 each group). gWAT, gonadal WAT. (L and M) Serum leptin (L) and insulin (M) levels of 8- and 40-week-old mice of both sexes fed ad libitum LFD (n = approximately 4–6 each group). Values are shown as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001, 2-way ANOVA.