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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 Article has an altmetric score of 68

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

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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 3

Sel1L deficiency in POMC neurons is not associated with elevated inflammation and cell death in ARC.

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Sel1L deficiency in POMC neurons is not associated with elevated inflamm...
(A) Reverse transcriptase PCR (RT-PCR) analysis of Xbp1 mRNA splicing (u, unspliced; s, spliced) in ARC with quantitation shown on the right (n = 2–3 each group). Liver samples from mice injected with thapsigargin (Tg) were included as positive controls. (B) Western blot analysis of unphosphorylated and phosphorylated JNK (p-JNK) in the hypothalamus of 10-week-old mice on LFD with quantitation on the right (n = 3 each group, experiment was performed in duplicate). (C) Representative images of TUNEL analysis in the ARC of 8-week-old mice on LFD (n = approximately 4–5 each group). Quantitation of TUNEL-positive cells in ARC is shown in Supplemental Figure 5G. (D) Representative immunofluorescent images of GFP-positive POMC neurons in the ARC of 8-week-old Sel1LPOMC;POMC-eGFP and control Sel1LPOMC/+;POMC-eGFP mice on LFD with quantitation of the numbers of GFP-positive neurons in central ARC (bregma, –1.58/–1.94 mm) shown in E (n = 3–4 each group). Values are shown as mean ± SEM. Student’s t test was used.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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