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

• Published in: The Journal of clinical investigation Vol. 129; no. 9; pp. 3786 - 3791
• Main Authors: Kaneko, Kentaro, Fu, Yukiko, Lin, Hsiao-Yun, Cordonier, Elizabeth L, Mo, Qianxing, Gao, Yong, Yao, Ting, Naylor, Jacqueline, Howard, Victor, Saito, Kenji, Xu, Pingwen, Chen, Siyu S, Chen, Miao-Hsueh, Xu, Yong, Williams, Kevin W, Ravn, Peter, Fukuda, Makoto
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.09.2019
• Subjects: Adipose tissue; Adiposity - genetics; Alzheimer's disease; Animals; Antibodies; Biomedical research; Body mass index; Body weight; Brain; Concise Communication; Diabetes; Diet; Energy; Energy balance; Food; Guanosine triphosphatases; Hormones; Hypothalamus; Hypothalamus - metabolism; Incretins - genetics; Incretins - metabolism; Insulin resistance; Kinases; Leptin; Leptin - genetics; Leptin - metabolism; Liraglutide; Menopause; Mice; Obesity; Obesity - genetics; Obesity - metabolism; Overnutrition; Pharmaceutical industry; Physiological aspects; Physiology; Polypeptides; Proteins; rap1 GTP-Binding Proteins - genetics; rap1 GTP-Binding Proteins - metabolism; Rap1 protein; Receptors, Gastrointestinal Hormone - genetics; Receptors, Gastrointestinal Hormone - metabolism; Signal Transduction; Suppressor of Cytokine Signaling 3 Protein - genetics; Suppressor of Cytokine Signaling 3 Protein - metabolism; Weight control; United Kingdom; Texas; Obesity; Neuroscience; G-protein coupled receptors; Metabolism; Leptin
• ISSN: 0021-9738; 1558-8238
• 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.