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

Authors: KANEKO, KENTARO - Children'S Nutrition Research Center (CNRC); FU, YUKIKO - Children'S Nutrition Research Center (CNRC); LIN, HSIAO - Children'S Nutrition Research Center (CNRC); CORDONIER, ELIZABETH - Children'S Nutrition Research Center (CNRC); MO, QIANXING - Baylor College Of Medicine; GAO, YONG - University Of Texas Southwestern Medical Center; YAN, TING - University Of Texas Southwestern Medical Center; NAYLOR, JACQUELINE - Astrazeneca Pharmaceuticals; HOWARD, VICTOR - Astrazeneca Pharmaceuticals; SAITO, KENJI - Children'S Nutrition Research Center (CNRC); XU, PINGWEN - Children'S Nutrition Research Center (CNRC); CHEN, SIYU - Children'S Nutrition Research Center (CNRC); XU, YONG - Children'S Nutrition Research Center (CNRC); WILLIAMS, KEVIN - University Of Texas Southwestern Medical Center; RAVN, PETER - Astrazeneca Pharmaceuticals; FUKUDA, MAKOTO - Children'S Nutrition Research Center (CNRC)

Submitted to: Journal of Clinical Investigation
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/11/2019
Publication Date: 8/12/2019
Citation: Kaneko, K., Fu, Y., Lin, H.Y., Cordonier, E.L., Mo, Q., Gao, Y., Yan, T., Naylor, J., Howard, V., Saito, K., Xu, P., Chen, S.S., Xu, Y., Williams, K.W., Ravn, P., Fukuda, M. 2019. Gut-derived GIP activates central Rap1 to impair neural leptin sensitivity during overnutrition. Journal of Clinical Investigation. https://doi.org/10.1172/JCI126107.
DOI: https://doi.org/10.1172/JCI126107

Interpretive Summary: Leptin is a critical hormone that controls body weight and appetite. Leptin significantly suppresses food intake and reduces body weight when given to healthy lean animals and humans. Due to its remarkable weight-lowering effect, leptin was once thought to be a "magic bullet" for the treatment of obesity. Shortly after the discovery of leptin, however, researchers determined that leptin doesn't work properly in obese animals and humans, which is called "leptin resistance". This observation immediately generated one of the fundamental questions in the field of human obesity, specifically what is the root cause of leptin resistance. In this study, we found that the gut-derived incretin hormone gastric inhibitory polypeptid (GIP) is a physiological signal that arises from excess caloric intake and causes neural leptin resistance. We show that mice lacking the gene of GIP receptor were protected against diet-induced neural leptin resistance. Furthermore, a centrally administered monoclonal antibody that inhibits the GIP receptor had remarkable anti-obesity effects in obese mice. In contrast, centrally administered GIP induces leptin resistance. Finally, we also uncovered a unique mechanism that mediates the brain actions of GIP. Our results identify the GIP receptor signaling in the brain as a molecular pathway linking overnutrition to the control of neural leptin actions.

Technical Abstract: 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.