Glucose-dependent insulinotropic polypeptide is required for moderate high-fat diet- but not high-carbohydrate diet-induced weight gain

Am J Physiol Endocrinol Metab. 2018 Jun 1;314(6):E572-E583. doi: 10.1152/ajpendo.00352.2017. Epub 2018 Feb 6.


Both high-fat (HFD) and high-carbohydrate (ST) diets are known to induce weight gain. Glucose-dependent insulinotropic polypeptide (GIP) is secreted mainly from intestinal K cells upon stimuli by nutrients such as fat and glucose, and it potentiates glucose-induced insulin secretion. GIP is well known to contribute to HFD-induced obesity. In this study, we analyzed the effect of ST feeding on GIP secretion and metabolic parameters to explore the role of GIP in ST-induced weight gain. Both wild-type (WT) and GIP receptor deficient ( GiprKO) mice were fed normal chow (NC), ST, or moderate (m)HFD for 22 wk. Body weight was measured, and then glucose tolerance tests were performed. Insulin secretion from isolated islets also was analyzed. WT mice fed ST or mHFD displayed weight gain concomitant with increased plasma GIP levels compared with WT mice fed NC. WT mice fed mHFD showed improved glucose tolerance due to enhanced insulin secretion during oral glucose tolerance tests compared with WT mice fed NC or ST. GiprKO mice fed mHFD did not display weight gain. On the other hand, GiprKO mice fed ST showed weight gain and did not display obvious glucose intolerance. Glucose-induced insulin secretion was enhanced during intraperitoneal glucose tolerance tests and from isolated islets in both WT and GiprKO mice fed ST compared with those fed NC. In conclusion, enhanced GIP secretion induced by mHFD-feeding contributes to increased insulin secretion and body weight gain, whereas GIP is marginally involved in weight gain induced by ST-feeding.

Keywords: GIP; carbohydrate; fat; insulin; obesity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Diet, High-Fat / adverse effects*
  • Dietary Carbohydrates / adverse effects
  • Dietary Fats / pharmacology*
  • Gastric Inhibitory Polypeptide / physiology*
  • Glucose / metabolism
  • Glucose Intolerance / genetics
  • Glucose Intolerance / metabolism
  • Glucose Tolerance Test / methods
  • Insulin / metabolism
  • Insulin Resistance / genetics
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptors, Gastrointestinal Hormone / genetics
  • Receptors, Gastrointestinal Hormone / metabolism
  • Weight Gain / drug effects*


  • Dietary Carbohydrates
  • Dietary Fats
  • Insulin
  • Receptors, Gastrointestinal Hormone
  • Gastric Inhibitory Polypeptide
  • gastric inhibitory polypeptide receptor
  • Glucose