Attenuated secretion of glucose-dependent insulinotropic polypeptide (GIP) does not alleviate hyperphagic obesity and insulin resistance in ob/ob mice

OBJECTIVE: Glucose-dependent insulinotropic polypeptide (GIP) is released during meals and promotes nutrient uptake and storage. GIP receptor knockout mice are protected from diet induced weight gain and thus GIP antagonists have been proposed as a treatment for obesity. In this study, we assessed the role of GIP in hyperphagia induced obesity and metabolic abnormalities in leptin deficient (Lep(ob/ob)) mice. METHODS: We crossbred GIP-GFP knock-in homozygous mice (GIP(gfp/gfp)) that have complete GIP knockout, and mice heterozygous for the ob mutation (Lep(ob/+)) mice to generate Lep(ob/+)/GIP(+/+), Lep(ob/ob)/GIP(+/+), and Lep(ob/ob)/GIP(gfp/gfp) mice. Male animals were weighed weekly and both oral glucose and insulin tolerance testing were performed to assess glucose homeostasis and circulating profiles of GIP and insulin. Body composition was evaluated by computerized tomography (CT) scan and analyses of indirect calorimetry and locomotor activity were performed. RESULTS: Postprandial GIP levels were markedly elevated in Lep(ob/ob)/GIP(+/+) mice compared to Lep(ob/+)/GIP(+/+) controls and were undetectable in Lep(ob/ob)/GIP(gfp/gfp) mice. Insulin levels were equivalently elevated in both Lep(ob/ob)/GIP(+/+) and Lep(ob/ob)/GIP(gfp/gfp) mice compared to controls at 8 weeks of age but the hyperinsulinemia was marginally reduced in Lep(ob/ob)/GIP(gfp/gfp) by 21 weeks, in association with amelioration of glucose intolerance. Both Lep(ob/ob)/GIP(+/+) and Lep(ob/ob)/GIP(gfp/gfp) mice remained equivalently insulin resistant. Body weight gain and subcutaneous and visceral fat volume of both Lep(ob/ob)/GIP(+/+) and Lep(ob/ob)/GIP(gfp/gfp) mice were significantly higher than that of Lep(ob/+)/GIP(+/+) mice, while no significant differences were seen between Lep(ob/ob)/GIP(+/+) and Lep(ob/ob)/GIP(gfp/gfp) mice. Locomotor activity and energy expenditure were decreased in both Lep(ob/ob)/GIP(+/+) and Lep(ob/ob)/GIP(gfp/gfp) mice compared to control Lep(ob/+)/GIP(+/+) mice, while no significant differences were seen between Lep(ob/ob)/GIP(+/+) and Lep(ob/ob)/GIP(gfp/gfp) mice. There was no significant difference in fat oxidation among the three groups. Fat content in liver was significantly lower in Lep(ob/ob)/GIP(gfp/gfp) compared to Lep(ob/ob)/GIP(+/+) mice, while that of control Lep(ob/+)/GIP(+/+) mice was the lowest. CONCLUSIONS: Our results indicate that GIP knockout does not prevent excess weight gain and metabolic derangement in hyperphagic leptin deficient mice.