Gut-derived GIP activates central Rap1 to impair neural leptin sensitivity during overnutrition

J Clin Invest. 2019 Aug 12;129(9):3786-3791. doi: 10.1172/JCI126107.


Nutrient excess, a major driver of obesity, diminishes hypothalamic responses to exogenously administered leptin, a critical hormone of energy balance. Here, we aimed to identify a physiological signal that arises from excess caloric intake and negatively controls hypothalamic leptin action. We found that deficiency of the gastric inhibitory polypeptide receptor (Gipr) for the gut-derived incretin hormone GIP protected against diet-induced neural leptin resistance. Furthermore, a centrally administered antibody that neutralizes GIPR had remarkable antiobesity effects in diet-induced obese mice, including reduced body weight and adiposity, and a decreased hypothalamic level of SOCS3, an inhibitor of leptin actions. In contrast, centrally administered GIP diminished hypothalamic sensitivity to leptin and increased hypothalamic levels of Socs3. Finally, we show that GIP increased the active form of the small GTPase Rap1 in the brain and that its activation was required for the central actions of GIP. Altogether, our results identify GIPR/Rap1 signaling in the brain as a molecular pathway linking overnutrition to the control of neural leptin actions.

Keywords: G-protein coupled receptors; Leptin; Metabolism; Neuroscience; Obesity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adiposity / genetics
  • Animals
  • Hypothalamus / metabolism*
  • Incretins / genetics
  • Incretins / metabolism*
  • Leptin / genetics
  • Leptin / metabolism*
  • Mice
  • Obesity / genetics
  • Obesity / metabolism*
  • Receptors, Gastrointestinal Hormone / genetics
  • Receptors, Gastrointestinal Hormone / metabolism
  • Signal Transduction*
  • Suppressor of Cytokine Signaling 3 Protein / genetics
  • Suppressor of Cytokine Signaling 3 Protein / metabolism
  • rap1 GTP-Binding Proteins / genetics
  • rap1 GTP-Binding Proteins / metabolism*


  • Incretins
  • Leptin
  • Receptors, Gastrointestinal Hormone
  • Socs3 protein, mouse
  • Suppressor of Cytokine Signaling 3 Protein
  • gastric inhibitory polypeptide receptor
  • Rap1 protein, mouse
  • rap1 GTP-Binding Proteins