@article{ae9fbf3c11c14c029109533d9fb0be7c,
title = "Gut-derived GIP activates central Rap1 to impair neural leptin sensitivity during overnutrition",
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.",
author = "Kentaro Kaneko and Yukiko Fu and Lin, {Hsiao Yun} and Cordonier, {Elizabeth L.} and Qianxing Mo and Yong Gao and Ting Yao and Jacqueline Naylor and Victor Howard and Kenji Saito and Pingwen Xu and Chen, {Siyu S.} and Chen, {Miao Hsueh} and Yong Xu and Williams, {Kevin W.} and Peter Ravn and Makoto Fukuda",
note = "Funding Information: We are grateful to the members of the Children's Nutrition Research Center for valuable suggestions; Firoz Vohra and Marta Fiorotto for comprehensive lab animal monitoring system (CLAMS) analyses; Zainab Mabizari and Amy Ng for technical assistance; and Stephanie Sisley and Qiang Tong for comments on the manuscript. We also thank for Alexei Morozov (Virginia Tech Carilion Research Institute) for providing Rap1-floxed mice. This work was supported by grants from the United States Department of Agriculture (USDA) Current Research Information System (CRIS) (6250-51000-055, to MF); the American Heart Association (AHA) (14BGIA20460080, to MF); the NIH (P30-DK079638 and R01DK104901, to MF); the AHA (15POST22500012, to MF); the Uehara Memorial Foundation (201340214, to KK); the NIH (T32HD071839, to ELC); the AHA (13POST13800000 and 15POST22670017, to PX); the NIH (R01DK100699 and DK119169, to KWW); the China Scholarship Council (201406280111, to TY); the CRIS (6250-51000-059, to MHC); and the NIH (P30-DK079638, to MHC). This project was also supported in part by the Genomic and RNA Profiling Core at Baylor College of Medicine, with funding from a P30 Digestive Disease Center Support Grant (NIDDK-DK56338) and a P30 Cancer Center Support Grant (NCI-CA125123). Funding Information: We are grateful to the members of the Children{\textquoteright}s Nutrition Research Center for valuable suggestions; Firoz Vohra and Marta Fiorotto for comprehensive lab animal monitoring system (CLAMS) analyses; Zainab Mabizari and Amy Ng for technical assistance; and Stephanie Sisley and Qiang Tong for comments on the manuscript. We also thank for Alexei Morozov (Virginia Tech Carilion Research Institute) for providing Rap1-floxed mice. This work was supported by grants from the United States Department of Agriculture (USDA) Current Research Information System (CRIS) (6250-51000-055, to MF); the American Heart Association (AHA) (14BGIA20460080, to MF); the NIH (P30-DK079638 and R01DK104901, to MF); the AHA (15POST22500012, to MF); the Uehara Memorial Foundation (201340214, to KK); the NIH (T32HD071839, to ELC); the AHA (13POST13800000 and 15POST22670017, to PX); the NIH (R01DK100699 and DK119169, to KWW); the China Scholarship Council (201406280111, to TY); the CRIS (6250-51000-059, to MHC); and the NIH (P30-DK079638, to MHC). This project was also supported in part by the Genomic and RNA Profiling Core at Baylor College of Medicine, with funding from a P30 Digestive Disease Center Support Grant (NIDDK-DK56338) and a P30 Cancer Center Support Grant (NCI-CA125123). Publisher Copyright: {\textcopyright} 2019 Kaneko et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.",
year = "2019",
month = sep,
day = "3",
doi = "10.1172/JCI126107",
language = "English (US)",
volume = "129",
pages = "3786--3791",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "9",
}