Sensory Food Perception Rapidly Primes Postprandial ER-Homeostasis through Melanorcortin-Dependent Control of Liver mTOR Activation

Adaptation of liver to the postprandial state requires coordinate regulation of protein synthesis and folding aligned with changes in lipid metabolism. Here we demonstrate that sensory food perception is sufficient to elicit early activation of hepatic mTOR-signaling, Xbp1-splicing, increased expression of ER-stress genes and phosphatidylcholine synthesis, which translate into a rapid morphological ER-remodeling. These responses overlap with those activated during refeeding, where they are maintained and constantly increase upon nutrient supply. Sensory food perception activates POMC-neurons in the hypothalamus, optogenetic activation of POMC-neurons activates hepatic mTOR-signaling and Xbp1-splicing and lack of MC4R-expression attenuates these responses to sensory food perception. Chemogenetic POMC-neuron activation promotes sympathetic nerve activity (SNA) subserving the liver, and norepinephrine evokes the same responses in hepatocytes in vitro and liver in vivo as observed upon sensory food perception. Collectively, our experiments unravel that sensory food perception coordinatly primes postprandrial liver ER adaption through a melanocortin-SNA-mTOR-Xbp1s-axis In total 60 independent samples were analyzed. Three biological replicates were measured. Three conditions: fasted, refed, caged. For refed and caged 4 times (30,60,120,240 min) were analyzed.