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 2

Sel1LPOMC mice exhibit hyperphagia with impaired leptin sensitivity.

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Sel1LPOMC mice exhibit hyperphagia with impaired leptin sensitivity. (A...
(A) Daily food consumption of 8- and 40-week-old mice on LFD (n = approximately 5–6 each group). (B) Body weight of 30-week-old Sel1LPOMC mice under food restricted for 4 weeks (red line) followed by 1-week ad libitum on LFD (black line) or ad libitum LFD for 5 weeks (black line) (n = 3 each group). Sel1Lfl/fl mice fed ad libitum LFD were included as controls (white circles). For clarity, only statistical analyses comparing restricted feeding to ad libitum for Sel1LPOMC mice are shown. (C and D) Meal number (C) and size (D) of 8-week-old mice on LFD (n = 3–4 each group) as measured using the CLAMS metabolic cages. (E–I) Leptin response analyses in which mice approximately 7 to 9 weeks old were i.p. injected daily with leptin (2 mg/kg body weight) for 3 days and then perfused with fixative 30 minutes after the last injection. (E) Schematic diagram for the experiment. BW, body weight. (F) Cumulative food intake and (G) percentage of body weight change following 3 daily vehicle (saline) and leptin injections of 8-week-old mice (n = approximately 6–8 each group). (H and I) Representative images of immunofluorescent staining of pY705 STAT3 in the ARC of POMC-eGFP mice with or without Sel1L (n = 2 each group). Quantitation of the percentage of pY705 STAT3-positive POMC neurons of total POMC neurons in the ARC are shown in I. Values are shown as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001, 2-way ANOVA (C, D, F, G) or Student’s t test (A, B, I).