Metformin Boosts Intestinal Lipid sensing via GIP to Suppress Feeding

An acute rise of lipids in the upper small intestine (USI) of rodents and humans triggers lipid-sensing pathways to lower food intake. However, USI lipid sensing fails to lower feeding in high fat (HF) fed conditions, and the underlying mechanism remains elusive. Here, we first discover that HF feeding in male rats impaired USI lipid infusion to stimulate glucose-dependent insulinotropic polypeptide (GIP) secretion and decrease refeeding, and the defects of USI lipid sensing were restored by metformin. Next, we found that infusion of GIP receptor (GIPR) agonist in the nucleus of the solitary tract (NTS), but not mediobasal hypothalamus or area postrema, decreased refeeding in chow rats. The anorectic effect of NTS GIPR agonist remained intact in HF rats and was inhibited by a genetic knockdown of GIPR. Finally, an inhibition of NTS GIPR also negated the ability of USI lipid sensing with metformin to decrease refeeding despite a rise of plasma GIP levels in HF rats. Thus, USI lipid sensing in HF rats is enhanced by metformin to trigger an endocrine GIP to NTS GIPR axis to lower food intake, thereby unveiling small intestinal lipid sensing pathways as potential targets to enhance GIP action and lower weight in obesity.