Chronic Reduction of GIP Secretion Alleviates Obesity and Insulin Resistance Under High-Fat Diet Conditions

Abstract

Gastric inhibitory polypeptide (GIP) exhibits potent insulinotropic effects on β-cells and anabolic effects on bone formation and fat accumulation. We explored the impact of reduced GIP levels in vivo on glucose homeostasis, bone formation, and fat accumulation in a novel GIP-GFP knock-in (KI) mouse. We generated GIP-GFP KI mice with a truncated prepro-GIP gene. The phenotype was assessed in heterozygous and homozygous states in mice on a control fat diet and a high-fat diet (HFD) in vivo and in vitro. Heterozygous GIP-GFP KI mice (GIP-reduced mice [GIPgfp/+]) exhibited reduced GIP secretion; in the homozygous state (GIP-lacking mice [GIPgfp/gfp]), GIP secretion was undetectable. When fed standard chow, GIPgfp/+ and GIPgfp/gfp mice showed mild glucose intolerance with decreased insulin levels; bone volume was decreased in GIPgfp/gfp mice and preserved in GIPgfp/+ mice. Under an HFD, glucose levels during an oral glucose tolerance test were similar in wild-type, GIPgfp/+, and GIPgfp/gfp mice, while insulin secretion remained lower. GIPgfp/+ and GIPgfp/gfp mice showed reduced obesity and reduced insulin resistance, accompanied by higher fat oxidation and energy expenditure. GIP-reduced mice demonstrate that partial reduction of GIP does not extensively alter glucose tolerance, but it alleviates obesity and lessens the degree of insulin resistance under HFD conditions, suggesting a potential therapeutic value.