Absence of GIP secretion alleviates age-related obesity and insulin resistance

Glucose-dependent insulinotropic polypeptide (GIP) is an incretin secreted from enteroendocine K cells after nutrient ingestion. Fat strongly induces GIP secretion, and GIP hypersecretion is involved in high-fat diet-induced obesity and insulin resistance. Aging also induces GIP hypersecretion, but its effect on body weight gain and insulin sensitivity remains unclear. In the present study, we investigated the effect of GIP on age-related body weight gain and insulin resistance using GIP-knockout homozygous (GIP(−/)(−)) and heterozygous (GIP(+/)(−)) mice, which have entirely absent and 50% reduced GIP secretion compared to wild-type (WT) mice, respectively. Under 12% fat-containing normal diet feeding condition, body weight was significantly lower in GIP(−/)(−) mice compared to that in WT and GIP(+/)(−) mice from 38 weeks of age, while there was no significant difference between WT and GIP(+/)(−) mice. Visceral and s.c. fat mass were also significantly lower in GIP(−/)(−) mice compared to those in WT and GIP(+/)(−) mice. During oral glucose tolerance test, blood glucose levels did not differ among the three groups. Insulin levels were significantly lower in GIP(−/)(−) mice than those in WT and GIP(+/)(−) mice. During insulin tolerance test, GIP(−/)(− )mice showed higher insulin sensitivity than that of WT and GIP(+/)(−) mice. Adiponectin mRNA levels were increased and leptin mRNA levels tended to be decreased in adipose tissue of GIP(−/)(−) mice. These results demonstrate that GIP is involved in age-related obesity and insulin resistance and that inhibition of GIP secretion alleviates age-related fat mass gain and insulin resistance under carbohydrate-based diet feeding condition.