Objectives: Exploring the physiological role of the intestinal endocannabinoids in the regulation of appetite upon short-term exposure to high-fat-diet (HFD). Understanding the mechanisms responsible for aberrant gut-brain signaling leading to hyperphagia in mice lacking Napepldin the intestinal epithelial cells (IECs). Methods: We generated a murine model harboring an inducible NAPE-PLD deletion in IECs (Napepld^ΔIEC).After an overnight fasting, we exposed wild type (WT) and Napepld^ΔIEC mice to different forms of lipid challenge (HFD or gavage) and we compared the modification occurring in the hypothalamus, in the vagus nerve and at endocrine level 30 and 60 minutes after the stimulation. Results: Napepld^ΔIEC mice displayed lower hypothalamic levels of N-oleoylethanolamine (OEA) in response to HFD. Lower mRNA expression of anorexigenic Pomc occurred in the hypothalamus of Napepld^ΔIEC mice after lipid challenge. This early hypothalamic alteration was not the consequence of impaired vagal signaling in Napepld^ΔIEC mice. Following lipid administration, WT and Napepld^ΔIEC mice had similar portal level of glucagon-like peptide-1 (GLP-1) and similar rate of GLP-1 inactivation. Administration of Exendin-4, a full agonist of GLP-1 receptor (GLP-1R), prevented the hyperphagia of Napepld^ΔIEC mice upon HFD. Conclusions: In response to lipid, Napepld^ΔIEC mice displayed reduced OEA in brain and intestine, suggesting an impairment of the gut-brain axis in this model. We speculated that decreased level of OEA likely contributes to reduce GLP-1R activation, explaining the observed hyperphagia in this model. Altogether, weelucidated novel physiological mechanism regarding the gut-brain axis by which intestinal NAPE-PLD regulates appetite rapidly after lipid exposure.

中文翻译：

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肠NAPE-PLD通过肠脑轴有助于短期调节食物摄入量。

目的：探讨肠道内大麻素在短期接触高脂饮食（HFD）时在食欲调节中的生理作用。了解负责缺乏Napepld的小鼠的异常肠脑信号传导导致食欲亢进的机制在肠上皮细胞（IEC）中。方法：我们生成的小鼠模型包庇的IEC（Napepld可诱导NAPE-PLD缺失^ΔIEC）。经过一个通宵禁食，我们暴露的野生型（WT）和Napepld ^ΔIEC小鼠不同形式的脂质挑战（HFD或管饲）和我们比较了刺激后30分钟和60分钟在下丘脑，迷走神经和内分泌水平发生的修饰。结果：Napepld ^ΔIEC小鼠响应于HFD显示的N- oleoylethanolamine（OEA）的下丘脑水平。脂质激发后，^NapepldΔIEC小鼠的下丘脑发生了厌食性^Pomc的较低mRNA表达。这种早期的下丘脑改变不是Napepld迷走神经信号受损的结果^ΔIEC小鼠。脂质给药后，WT和NapepldΔIEC小鼠的胰高血糖素样肽1（GLP-1）的门^控水平相似，而GLP-1的失活速率也相似。Exendin-4是GLP-1受体（GLP-1R）的完全激动剂，可预防HFD时^NapepldΔIEC小鼠的食欲亢进。结论：响应脂质，^NapepldΔIEC小鼠大脑和肠中的OEA降低，表明此模型中肠脑轴受损。我们推测降低的OEA水平可能有助于减少GLP-1R激活，从而解释了在该模型中观察到的食欲亢进。总而言之，我们阐明了关于肠脑轴的新生理机制，肠道NAPE-PLD通过这种机制可以在脂质暴露后迅速调节食欲。