The gut microbiota regulates hypothalamic inflammation and leptin sensitivity in Western diet-fed mice via a GLP-1R-dependent mechanism
The gut microbiota regulates hypothalamic inflammation and leptin sensitivity in Western diet-fed mice via a GLP-1R-dependent mechanism
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DOI：
10.1016/j.celrep.2021.109163
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发表时间：
2021-05-25
期刊：
影响因子：
8.8
通讯作者：
Olofsson, Louise E.
中科院分区：
文献类型：
--
作者：
Heiss, Christina N.;Manneras-Holm, Louise;Olofsson, Louise E.
缺乏微生物区系的小鼠可以免受饮食诱导的肥胖。此前的研究表明，以西式饮食喂养会导致下丘脑炎症，进而导致瘦素抵抗和体重增加。在这里，我们展示了肠道微生物区系枯竭的野生型(WT)小鼠，即无菌(GF)和抗生素治疗的小鼠，其胰高血糖素样肽-1(GLP-1)水平升高，对饮食诱导的下丘脑炎症具有保护作用，并在喂养西方饮食时增强了瘦素的敏感性。利用GLP-1受体(GLP-1R)缺陷小鼠和WT小鼠GLP-1R的药物抑制，我们证明完整的GLP-1R信号是预防下丘脑炎症和增强瘦素敏感性所必需的。此外，我们发现星形胶质细胞表达GLP-1R，表达胶质纤维酸性蛋白(GFAP)的细胞中GLP-1R受体的缺失减弱了抗生素诱导的对饮食诱导的下丘脑炎症的保护作用。总而言之，我们的结果表明，肠道微生物区系的枯竭可以减轻饮食诱导的下丘脑炎症，并通过GLP-1R依赖机制增强瘦素的敏感性。
Mice lacking a microbiota are protected from diet-induced obesity. Previous studies have shown that feeding a Western diet causes hypothalamic inflammation, which in turn can lead to leptin resistance and weight gain. Here, we show that wild-type (WT) mice with depleted gut microbiota, i.e., germ-free (GF) and antibiotic-treated mice, have elevated levels of glucagon-like peptide-1 (GLP-1), are protected against diet-induced hypothalamic inflammation, and have enhanced leptin sensitivity when fed a Western diet. Using GLP-1 receptor (GLP-1R)-deficient mice and pharmacological inhibition of the GLP-1R in WT mice, we demonstrate that intact GLP-1R signaling is required for preventing hypothalamic inflammation and enhancing leptin sensitivity. Furthermore, we show that astrocytes express the GLP-1R, and deletion of the receptor in glial fibrillary acidic protein (GFAP)-expressing cells diminished the antibiotic-induced protection against diet-induced hypothalamic inflammation. Collectively, our results suggest that depletion of the gut microbiota attenuates diet-induced hypothalamic inflammation and enhances leptin sensitivity via GLP-1R-dependent mechanisms.