Palmitate‐induced impairment of melanocortin‐4 receptor

Abstract

Obese patients, and diet induced obese rodents, exhibit elevated palmitate in the blood stream and hypothalamus. Elevated palmitate has been found to attenuate hypothalamic insulin signaling, and this effect is thought to be mediated through endoplasmic reticulum (ER) stress. Here we investigated the role of elevated palmitate on melanocortin‐4 receptor (MC4R) expression and signaling. Treatment with 200 μM palmitate (highp‐hysiological) and 400 μM palmitate (supraphysiological) for 24 hours in N42 immortalized hypothalamic neurons lead to a loss of MC4R signaling concurrent with a decrease in cholesterol content. While treatment with 200 μM palmitate did not induce an increase of GRP78/BiP or apoptosis, treatment with 400 μM palmitate did. In Neuro2a cells stably transfected to express the reporter HAMC4R‐ GFP we observed similar effects of palmitate treatment on MC4R signaling and cholesterol. Through the reporter we observed a loss of up to 70% of the MC4R protein, and a decreased rate of internalization which lead to a redistribution of the receptor to the plasma membrane. Repletion of cholesterol reversed the accumulation of MC4R at the plasma membrane, but did not recover MC4R expression. We conclude that elevated palmitate induces a loss MC4R expression and signaling before there is an overt ER stress. This research was supported by National Institutes of Health GrantsR01‐DK080424 (to G. B.)