Gut-derived GIP activates central Rap1 to impair neural leptin sensitivity during overnutrition
| Autor: | Qianxing Mo, Yong Gao, Makoto Fukuda, Jacqueline Naylor, Kenji Saito, Hsiaoyun Lin, Ting Yao, Kentaro Kaneko, Pingwen Xu, Elizabeth L. Cordonier, Miao Hsueh Chen, Yong Xu, Peter Ravn, Kevin W. Williams, Victor G. Howard, Yukiko Fu, Siyu S. Chen |
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| Rok vydání: | 2019 |
| Předmět: |
Leptin
0301 basic medicine endocrine system medicine.medical_specialty Hypothalamus Biology Incretins Receptors Gastrointestinal Hormone Mice 03 medical and health sciences Overnutrition 0302 clinical medicine Internal medicine medicine Humans Animals Obesity SOCS3 Adiposity G protein-coupled receptor Concise Communication digestive oral and skin physiology rap1 GTP-Binding Proteins General Medicine medicine.disease Metabolism G-protein coupled receptors 030104 developmental biology Endocrinology Suppressor of Cytokine Signaling 3 Protein 030220 oncology & carcinogenesis Rap1 Gastric inhibitory polypeptide receptor Energy Metabolism hormones hormone substitutes and hormone antagonists Neuroscience Signal Transduction Hormone |
| Zdroj: | The Journal of Clinical Investigation |
| ISSN: | 1558-8238 0021-9738 |
| DOI: | 10.1172/jci126107 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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