期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 129, 期 9, 页码 3786-3791出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI126107
关键词
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资金
- United States Department of Agriculture (USDA) Current Research Information System (CRIS) [6250-51000-055]
- American Heart Association (AHA) [14BGIA20460080]
- NIH [P30-DK079638, R01DK104901, T32HD071839, R01DK100699, DK119169]
- AHA [15POST22500012, 13POST13800000, 15POST22670017]
- Uehara Memorial Foundation [201340214]
- China Scholarship Council [201406280111]
- CRIS [6250-51000-059]
- Genomic and RNA Profiling Core at Baylor College of Medicine
- P30 Digestive Disease Center Support Grant [NIDDK-DK56338]
- P30 Cancer Center Support Grant [NCI-CA125123]
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.
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