Food Perception Primes Hepatic ER Homeostasis via Melanocortin-Dependent Control of mTOR Activation
Food Perception Primes Hepatic ER Homeostasis via Melanocortin-Dependent Control of mTOR Activation
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DOI：
10.1016/j.cell.2018.10.015
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发表时间：
2018-11-15
期刊：
影响因子：
64.5
通讯作者：
Bruening, Jens C.
中科院分区：
文献类型：
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作者：
Brandt, Claus;Nolte, Hendrik;Bruening, Jens C.
肝脏适应餐后状态需要协调调节蛋白质合成和折叠与脂质代谢的变化一致。在这里，我们证明了感官食物感知足以引起肝脏mTOR信号传导，Xbp 1剪接，ER应激基因表达增加和磷脂酰胆碱合成的早期激活，这转化为快速的形态学ER重塑。这些反应与再喂食期间激活的反应重叠，在那里它们在营养供应时保持并不断增加。感觉食物感知激活下丘脑中的POMC神经元，POMC神经元的光遗传学激活激活肝脏mTOR信号传导和Xbp 1剪接，而MC 4 R表达的缺乏减弱了这些对感觉食物感知的反应。化学发生-POMC-神经元激活促进交感神经活性（SNA），从而使肝脏受益，去甲肾上腺素在体外肝细胞和体内肝脏中引起与在感觉食物感知时观察到的相同的反应。总的来说，我们的实验揭示了感官食物知觉通过黑皮质素-SNA-mTOR-Xbp 1 s轴协调启动餐后肝脏ER适应。
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.