Glucose-induced insulinomimetic peptide (GIP) is a gut hormone produced by enteroendocrine K-cells in the intestinal mucosa in response to fat, glucose, and also protein. GIP releases insulin from the β cells of the pancreatic islets of Langerhans and therefore is an incretin hormone. GIP acts on a G-protein-coupled receptor that is widely distributed in the body including adipose tissue, stomach, brain, and others. Deletion of the GIP receptor (GIPR) renders mice resistant to weight gain induced by a high fat diet.We observed that weight gain induced by ovarectomy in female mice is prevented by GIPR deletion that is linked to reduced food intake and reduced hypothalamic expression of orectic neurotransmitters. Moreover, old male GIPR(-/-) mice placed on a high glycemic index diet maintained a high insulin sensitivity and were much more active than controls, which was not seen in young animals. Thus, GIP elicits central effects in response to nutrients that protect against obesity and insulin resistance. We then investigated the acute responses of humans to treatment with GIP over 4h in a dose mimicking postprandial plasma levels of about 100pmol/L. At basal glucose, GIP does not elicit insulin release. Fat biopsies taken before and after 4h of GIP treatment were analyzed for transcriptomic responses using Agilent whole human genome assays. There was a highly significant upregulation of an inflammatory expression pattern in a pathway analysis.