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.

Purpose To study the long-term anatomic and physiologic effects of nocturnal normobaric hyperoxia (NNBH) in a patient with treatment-resistant diabetic macular edema (DME). Methods A 64-year-old diabetic man with bilateral DME requiring regular anti-VEGF treatments in both eyes was started on 5 LPM (40% FiO2) NNBH treatment 6-h per night. Visual acuity, OCT measurements of retinal thickness and volume, as well as the number of injections given in each eye were retrospectively examined one year prior and prospectively after initiation of NNBH, as well as before and after a planned 1-month discontinuation of NNBH. Results The patient received 12 anti-VEGF injections in the year prior to beginning NNBH treatment (4 OD; 8 OS) and did not require any injections after commencing NNBH treatment. Visual acuity improved and stabilized to 20/20 and macular edema rapidly resolved in both eyes following initiation of NNBH. After a planned 1-month NNBH vacation, DME recurred but quickly resolved once NNBH treatment was restarted. Conclusion This model case demonstrates that a 6-h NNBH regimen can be successful in treating DME and improving vision, without the need for intravitreal injections. NNBH is a more acceptable treatment regimen compared to 24-h continuous oxygen delivery and may provide a less invasive alternate method for treating DME in patients with diabetes. Further study is warranted.