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 4

Intracellular retention of POMC in the absence of Sel1L.

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Intracellular retention of POMC in the absence of Sel1L. (A) Schematic d...
(A) Schematic diagram showing specific domains and processing derivatives of POMC recognized by various antibodies. SP, signal peptide; β-endo, β-endorphin. (B–E) Representative immunofluorescence images of (B) POMC as a prohormone (n = 5–6 each) in the ARC of mice approximately 5 to 10 weeks of age, (C) α-MSH in the axons of POMC neurons in the PVN of mice approximately 5 to 10 weeks of age (n = 4 each), (D) β-endorphin (n = 4–5 in each), and (E) ACTH (n = 2-3 each) in the ARC and DMH of mice approximately 5 to 8 weeks of age fed ad libitum LFD. White arrows indicate staining in the cell bodies of POMC neurons. Quantitation of POMC and neuropeptide signal intensity in cell bodies and axons are shown in Supplemental Figure 6, A–B. (F) Pomc mRNA level in the ARC of mice approximately 5 to 8 weeks of age fed ad libitum LFD (n = 4 each). (G) α-MSH levels in the hypothalamus of mice approximately 6 to 7 weeks of age, measured by ELISA (n = 3 each group). (H) Cumulative food intake in 8-week-old mice injected daily i.p. with α-MSH (1 mg/kg body weight) for 3 days (n = approximately 5–7 each group). Vehicle, saline. Values are shown as mean ± SEM. *P < 0.05, Student’s t test (F and G) or 2-way ANOVA (H).