Inhibition of Gastric Inhibitory Polypeptide Signaling Prevents Obesity

Nat Med. 2002 Jul;8(7):738-42. doi: 10.1038/nm727. Epub 2002 Jun 17.

Abstract

Secretion of gastric inhibitory polypeptide (GIP), a duodenal hormone, is primarily induced by absorption of ingested fat. Here we describe a novel pathway of obesity promotion via GIP. Wild-type mice fed a high-fat diet exhibited both hypersecretion of GIP and extreme visceral and subcutaneous fat deposition with insulin resistance. In contrast, mice lacking the GIP receptor (Gipr(-/-)) fed a high-fat diet were clearly protected from both the obesity and the insulin resistance. Moreover, double-homozygous mice (Gipr(-/-), Lep(ob)/Lep(ob)) generated by crossbreeding Gipr(-/-) and obese ob/ob (Lep(ob)/Lep(ob)) mice gained less weight and had lower adiposity than Lep(ob)/Lep(ob) mice. The Gipr(-/-) mice had a lower respiratory quotient and used fat as the preferred energy substrate, and were thus resistant to obesity. Therefore, GIP directly links overnutrition to obesity and it is a potential target for anti-obesity drugs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue / anatomy & histology
  • Adipose Tissue / physiology*
  • Animals
  • Body Weight
  • Crosses, Genetic
  • Dietary Fats
  • Gastric Inhibitory Polypeptide / deficiency
  • Gastric Inhibitory Polypeptide / genetics
  • Gastric Inhibitory Polypeptide / physiology*
  • Mice
  • Mice, Knockout
  • Obesity / prevention & control*
  • Receptors, Gastrointestinal Hormone / deficiency
  • Receptors, Gastrointestinal Hormone / genetics
  • Receptors, Gastrointestinal Hormone / physiology*
  • Signal Transduction / physiology*

Substances

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