Gut Hormone GIP Induces Inflammation and Insulin Resistance in the Hypothalamus
Gut Hormone GIP Induces Inflammation and Insulin Resistance in the Hypothalamus
复制标题
DOI：
10.1210/endocr/bqaa102
复制
发表时间：
2020-09-01
期刊：
影响因子：
4.8
通讯作者：
Fukuda, Makoto
中科院分区：
文献类型：
--
作者：
Fu, Yukiko;Kaneko, Kentaro;Fukuda, Makoto
下丘脑在控制能量平衡方面起着关键作用。高脂饮食(HFD)喂养可增加下丘脑促炎症介质的基因表达，降低胰岛素的作用。在这里，我们展示了一种肠源性激素，葡萄糖依赖的促胰岛素多肽(GIP)，它的水平在饮食诱导的肥胖过程中升高，促进并介导了高脂诱导的肥胖过程中的下丘脑炎症和胰岛素抵抗。对GIP刺激的下丘脑的无偏核糖核酸测序显示，受脑室内GIP刺激影响最大的下丘脑通路与炎症相关反应有关。随后的分析表明，无论是外周还是中枢给予GIP，都会增加C57BL/6J雄性小鼠下丘脑中的促炎相关因子，如IL-6和SOCS3，但不会增加皮质中的促炎相关因子。脑室注射GIP可诱导下丘脑I kappa B激酶-β炎症信号的激活。此外，下丘脑促炎症细胞因子和SOCS3水平显著降低，GIPR拮抗剂抗体和GIPR缺乏显著降低。此外，中央给药GIP减少了胰岛素在大脑中的厌食作用，并减少了胰岛素诱导的蛋白激酶B和下丘脑中糖原合成酶激酶3β的磷酸化。总而言之，这些发现揭示了大脑GIP信号在饮食诱导的炎症和下丘脑胰岛素抵抗中先前未被认识到的作用。
The hypothalamus plays a critical role in controlling energy balance. High-fat diet (HFD) feeding increases the gene expression of proinflammatory mediators and decreases insulin actions in the hypothalamus. Here, we show that a gut-derived hormone, glucose-dependent insulinotropic polypeptide (GIP), whose levels are elevated during diet-induced obesity, promotes and mediates hypothalamic inflammation and insulin resistance during HFD-induced obesity. Unbiased ribonucleic acid sequencing of GIP-stimulated hypothalami revealed that hypothalamic pathways most affected by intracerebroventricular (ICV) GIP stimulation were related to inflammatory-related responses. Subsequent analysis demonstrated that GIP administered either peripherally or centrally, increased proinflammatory-related factors such as Il-6 and Socs3 in the hypothalamus, but not in the cortex of C57BL/6J male mice. Consistently, hypothalamic activation of I kappa B kinase-beta inflammatory signaling was induced by ICV GIP. Further, hypothalamic levels of proinflammatory cytokines and Socs3 were significantly reduced by an antagonistic GIP receptor (GIPR) antibody and by GIPR deficiency. Additionally, centrally administered GIP reduced anorectic actions of insulin in the brain and diminished insulin-induced phosphorylation of Protein kinase B and Glycogen synthase kinase 3 beta in the hypothalamus. Collectively, these findings reveal a previously unrecognized role for brain GIP signaling in diet-induced inflammation and insulin resistance in the hypothalamus.