Food Perception Primes Hepatic ER Homeostasis via Melanocortin-Dependent Control of mTOR Activation

Claus Brandt, Hendrik Nolte, Sinika Henschke, Linda Engström Ruud, Motoharu Awazawa, Donald A. Morgan, Paula Gabel, Hans Georg Sprenger, Martin E. Hess, Stefan Günther, Thomas Langer, Kamal Rahmouni, Henning Fenselau, Marcus Krüger, Jens C. Brüning

Research output: Contribution to journalArticlepeer-review

73 Scopus citations

Abstract

Adaptation of liver to the postprandial state requires coordinated 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 increased upon nutrient supply. Sensory food perception activates POMC neurons in the hypothalamus, optogenetic activation of POMC neurons activates hepatic mTOR signaling and Xbp1 splicing, whereas 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 in liver in vivo as observed upon sensory food perception. Collectively, our experiments unravel that sensory food perception coordinately primes postprandial liver ER adaption through a melanocortin-SNA-mTOR-Xbp1s axis. Video Abstract: The sight and smell of food are sufficient to induce liver endoplasmic reticulum reprogramming through a hypothalamic circuit, thereby anticipating the metabolic changes required for nutrient intake.

Original languageEnglish
Pages (from-to)1321-1335.e20
JournalCell
Volume175
Issue number5
DOIs
StatePublished - 15 Nov 2018
Externally publishedYes

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