Gut hormone GIP induces inflammation and insulin resistance in the hypothalamus

Authors: FU, YUKIKO - Children'S Nutrition Research Center (CNRC); KANEKO, KENTARO - Children'S Nutrition Research Center (CNRC); LIN, HSIAO - Children'S Nutrition Research Center (CNRC); MO, QIANXING - Baylor College Of Medicine; XU, YONG - Children'S Nutrition Research Center (CNRC); SUGANAMI, TAKAYOSHI - Nagoya University; RAVN, PETER - Astrazeneca Pharmaceuticals; FUKUDA, MAKOTO - Children'S Nutrition Research Center (CNRC)

Submitted to: Endocrinology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/10/2020
Publication Date: 6/30/2020
Citation: Fu, Y., Kaneko, K., Lin, H.Y., Mo, Q., Xu, Y., Suganami, T., Ravn, P., Fukuda, M. 2020. Gut hormone GIP induces inflammation and insulin resistance in the hypothalamus. Endocrinology. https://doi.org/10.1210/endocr/bqaa102.
DOI: https://doi.org/10.1210/endocr/bqaa102

Interpretive Summary: The hypothalamus is a small but vital area in the center of the brain which plays a crucial role in maintaining our body weight. When we consume high-calorie foods, the hypothalamus develops inflammation, which in turn diminishes hypothalamic action to regulate energy balance. Thus, hypothalamic inflammation has been proposed to mediate obesity. However, exact mechanisms by which high-fat diet feeding induces hypothalamic inflammation remains unclear. Through multidisciplinary approaches using pharmacological, mouse genetics, RNA sequencing studies, we found that the gut-derived incretin hormone called Glucose-dependent insulinotropic polypeptide (GIP) is a mediator that arises from excess caloric intake and causes hypothalamic inflammation. Our study revealed that mice lacking the GIP receptor (GIPR) gene were protected against diet-induced hypothalamic inflammation. Furthermore, a centrally administered monoclonal antibody that inhibits the GIP receptor reduced hypothalamic inflammation in obese mice. In contrast, centrally administered GIP induced hypothalamic inflammation. Finally, we also uncovered the role of hypothalamic GIP signaling in mediating hypothalamic inflammation. Our results identify GIPR signaling in the brain as a molecular mediator linking over-nutrition to hypothalamic inflammation. Our findings will potentially create a new therapeutic modality for obesity by targeting the GIPR in the brain.

Technical Abstract: Hypothalamus plays a critical role in controlling energy balance. High-fat diet (HFD) feeding increases the gene expression of pro-inflammatory mediators and decreases insulin actions in the hypothalamus. Here, we show that a gut-derived hormone GIP, whose levels are elevated during diet-induced obesity, promotes and mediates hypothalamic inflammation and insulin resistance during HFD-induced obesity. Unbiased RNA 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 pro-inflammatory-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 IkB kinase (IKK)-Beta inflammatory signaling was induced by ICV GIP. Further, hypothalamic levels of pro-inflammatory cytokines and Socs3 were significantly reduced by an antagonistic GIPR antibody and by GIPR deficiency. Additionally, centrally administered GIP reduced anorectic actions of insulin in the brain and diminished insulin-induced phosphorylation of AKT and GSK3Beta 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.