Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.
Endocrinology. 2020 Sep 1;161(9). doi: 10.1210/endocr/bqaa102.
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 IκB kinase-β 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 3β 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.
下丘脑在控制能量平衡方面起着关键作用。高脂肪饮食（HFD）喂养会增加促炎介质的基因表达，并降低下丘脑的胰岛素作用。在这里，我们表明一种肠道来源的激素，葡萄糖依赖性胰岛素释放肽（GIP），其水平在饮食诱导肥胖期间升高，促进和介导了 HFD 诱导肥胖期间的下丘脑炎症和胰岛素抵抗。对 GIP 刺激下丘脑的无偏核糖核酸测序显示，下丘脑受中枢内注射（ICV）GIP 刺激影响最大的途径与炎症相关反应有关。随后的分析表明，外周或中枢给予 GIP 都会增加下丘脑促炎相关因子，如 Il-6 和 Socs3，但不会增加 C57BL/6J 雄性小鼠的皮质。一致地，ICV GIP 诱导了下丘脑 IκB 激酶-β 炎症信号的激活。此外，通过拮抗 GIP 受体（GIPR）抗体和 GIPR 缺乏，可显著降低下丘脑促炎细胞因子和 Socs3 的水平。此外，中枢给予 GIP 可降低胰岛素在大脑中的厌食作用，并减少胰岛素诱导的蛋白激酶 B 和糖原合成酶激酶 3β在下丘脑的磷酸化。总之，这些发现揭示了脑 GIP 信号在饮食诱导的炎症和胰岛素抵抗中的一个以前未被认识的作用。
