Gut hormone GIP induces inflammation and insulin resistance in the hypothalamus.

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 IκB kinase (IKK)-β 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 GSK3β 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.