Vagal neuron expression of the microbiota-derived metabolite receptor, free fatty acid receptor (FFAR3), is necessary for normal feeding behavior.
Vagal neuron expression of the microbiota-derived metabolite receptor, free fatty acid receptor (FFAR3), is necessary for normal feeding behavior.
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DOI：
10.1016/j.molmet.2021.101350
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发表时间：
2021-12
影响因子：
8.1
通讯作者：
Mansuy-Aubert V
中科院分区：
文献类型：
--
作者：
Cook TM;Gavini CK;Jesse J;Aubert G;Gornick E;Bonomo R;Gautron L;Layden BT;Mansuy-Aubert V
迷走神经提供肠道和大脑之间的直接通信线路，用于适当调节能量平衡和葡萄糖稳态。膳食纤维经肠道微生物群发酵产生的短链脂肪酸（SCFAs）通过迷走神经调节宿主代谢和摄食行为，但其分子机制尚未阐明。我们试图确定迷走神经元内介导SCFA的生理和治疗益处的G蛋白偶联受体。SCFA，特别是丙酸盐，信号传导通过游离脂肪酸受体3（FFAR 3）发生，我们发现其在支配整个肠道的迷走神经感觉神经元中表达。细胞特异性动物模型的缺乏阻碍了我们对肠/脑通讯的理解;因此，我们产生了一种cre重组酶驱动的Ffar 3缺失的小鼠模型。我们全面表征了对照和迷走神经-FFAR 3敲除（KO）小鼠在各种条件下的摄食行为，包括禁食/再摄食、西方饮食（WD）摄食和丙酸盐补充。我们还利用离体器官型迷走神经培养物来研究丙酸FFAR 3激活的下游信号传导途径。Vagal-FFAR 3 KO导致雄性和雌性动物的进食量增加，以及禁食/再喂养和WD挑战期间的摄食量增加。此外，补充丙酸盐的厌食作用在迷走神经-FFAR 3 KO小鼠中丧失。结合离体和体内实验的测序方法揭示了FFAR 3信号传导与胆囊收缩素（CCK）和瘦素受体途径的串扰导致食物摄入的改变。总之，我们的数据表明，在迷走神经元中表达的FFAR 3调节摄食行为，并介导丙酸盐诱导的摄食减少。迷走神经FFAR 3的缺乏会增加食物摄入。当FFAR 3不存在于迷走神经元时，丙酸盐的厌食作用丧失。FFAR 3信号转导与胆囊收缩素（CCK）和瘦素受体途径交叉对话，以改变食物摄入。
The vagus nerve provides a direct line of communication between the gut and the brain for proper regulation of energy balance and glucose homeostasis. Short-chain fatty acids (SCFAs) produced via gut microbiota fermentation of dietary fiber have been proposed to regulate host metabolism and feeding behavior via the vagus nerve, but the molecular mechanisms have not yet been elucidated. We sought to identify the G-protein-coupled receptors within vagal neurons that mediate the physiological and therapeutic benefits of SCFAs. SCFA, particularly propionate, signaling occurs via free fatty acid receptor 3 (FFAR3), that we found expressed in vagal sensory neurons innervating throughout the gut. The lack of cell-specific animal models has impeded our understanding of gut/brain communication; therefore, we generated a mouse model for cre-recombinase-driven deletion of Ffar3. We comprehensively characterized the feeding behavior of control and vagal-FFAR3 knockout (KO) mice in response to various conditions including fasting/refeeding, western diet (WD) feeding, and propionate supplementation. We also utilized ex vivo organotypic vagal cultures to investigate the signaling pathways downstream of propionate FFAR3 activation. Vagal-FFAR3KO led to increased meal size in males and females, and increased food intake during fasting/refeeding and WD challenges. In addition, the anorectic effect of propionate supplementation was lost in vagal-FFAR3KO mice. Sequencing approaches combining ex vivo and in vivo experiments revealed that the cross-talk of FFAR3 signaling with cholecystokinin (CCK) and leptin receptor pathways leads to alterations in food intake. Altogether, our data demonstrate that FFAR3 expressed in vagal neurons regulates feeding behavior and mediates propionate-induced decrease in food intake. Lack of vagal FFAR3 increases food intake. Anorectic effect of propionate is lost when FFAR3 is absent from vagal neurons. FFAR3 signaling cross-talks with cholecystokinin (CCK) and leptin receptor pathways to alter food intake.
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