Interaction of POMC with GTRAP3-18 in the brain

Abstract

Pro-opiomelanocortin (POMC)-expressing neurons provide alpha-melanocyte-stimulating hormone (α-MSH), which stimulates melanocortin-4 receptor (MC4R) to induce hypophagia by AMP-activated protein kinase (AMPK) inhibition in the hypothalamus. The POMC precursor protein is synthesized in the endoplasmic reticulum (ER) and subsequently translocates to the Golgi complex to secrete POMC-derived peptides, including α-MSH, from the secretory granules. However, no evidence has been reported in the post-transcriptional regulation of POMC in the ER.

　Glutamate transporter-associated protein 3-18 (GTRAP3-18) is an ER protein interacting with target proteins to retain them in the ER. 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. These results suggest an involvement of GTRAP3-18 in the regulation of POMC, which controls food intake and body weight, as well as blood glucose levels.