GTRAP3‐18 regulates food intake and body weight by interacting with pro‐opiomelanocortin

Pro‐opiomelanocortin (POMC)‐expressing neurons provide α‐melanocyte‐stimulating hormone (α‐MSH), which stimulates melanocortin 4 receptor to induce hypophagia by AMPK inhibition in the hypothalamus. α‐MSH is produced by POMC cleavage in secretory granules and released. However, it is not known yet whether any posttranscriptional regulatory mechanism of POMC signaling exists upstream of the secretory granules in neurons. Here we show that glutamate transporter‐associated protein 3‐18 (GTRAP3‐18), an anchor protein that retains interacting proteins in the endoplasmic reticulum, is a critical regulator of food intake and body weight by interacting with POMC. GTRAP3‐18‐deficient mice showed hypophagia, lean bodies, and lower blood glucose, insulin, and leptin levels with increased serum and brain α‐MSH levels, leading to AMPK inhibition. Intraperitoneal glucose tolerance tests revealed significantly decreased blood glucose levels and areas under the curve in GTRAP3‐18‐deficient mice compared to wild‐type mice. An intracerebroventricular infusion of a selective melanocortin 4 receptor antagonist to GTRAP3‐18‐deficient mice significantly increased their food intake and body weight. A fluorescence resonance energy transfer study showed an interaction between GTRAP3‐18 and POMC in vitro. These findings suggest that activation of the melanocortin pathway by modulating GTRAP3‐18/POMC interaction could be an alternative strategy for obesity and/or type 2 diabetes.—Aoyama, K., Bhadhprasit, W., Watabe, M., Wang, F., Matsumura, N., Nakaki, T. GTRAP3‐18 regulates food intake and body weight by interacting with pro‐opiomelanocortin. FASEB J. 32,330‐341 (2018). www.fasebj.org