Gut-derived GIP activates central Rap1 to impair neural leptin sensitivity during overnutrition
Kentaro Kaneko, … , Peter Ravn, Makoto Fukuda
Kentaro Kaneko, … , Peter Ravn, Makoto Fukuda
Published August 12, 2019
Citation Information: J Clin Invest. 2019;129(9):3786-3791. https://doi.org/10.1172/JCI126107.
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Concise Communication Metabolism Neuroscience

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.

Authors

Kentaro Kaneko, Yukiko Fu, Hsiao-Yun Lin, Elizabeth L. Cordonier, Qianxing Mo, Yong Gao, Ting Yao, Jacqueline Naylor, Victor Howard, Kenji Saito, Pingwen Xu, Siyu S. Chen, Miao-Hsueh Chen, Yong Xu, Kevin W. Williams, Peter Ravn, Makoto Fukuda

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Figure 2

GIP negatively regulates neural leptin actions.

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GIP negatively regulates neural leptin actions. (A and B) Leptin or vehi...
(A and B) Leptin or vehicle was i.c.v. infused into WT and Gipr-KO mice after 4 weeks of a normal chow diet (A) or a HFD (B) (n = 7–11). Body weight and food intake were measured daily. (C) Normal chow–fed mice (n = 11–12, 16 weeks of age) were i.c.v. administered GIP (30 pmol/day) or vehicle. Leptin (5 μg/day) or vehicle was i.c.v. administered. Body weight and food intake were measured. (D) Mice (n = 3) were i.c.v. administered GIP or vehicle followed by leptin (5 μg) 3 hours later. p-STAT3 immunohistochemistry and quantification. Scale bar: 100 μm. (E) Electrophysiological recordings demonstrated that GIP pretreatment (6 h) occluded the leptin-induced depolarization of POMC neurons. The inhibitory effect of GIP on leptin-induced activation of POMC neurons is summarized in the histogram (n = 8–9). (F) GIP (administered i.c.v.) increased hypothalamic mRNA expression of Socs-3, Ptp1b, and Tcptp. Data are from 3 different experiments (n = 17–18). (G) Mice received once-daily i.p. injections of GIP for 3 days and then i.c.v. injections of leptin (5 μg) 2 hours after the last GIP injection. Body weight and food intake were measured 24 hours after leptin injection. n = 11 for groups without GIP treatment, n = 9 for GIP (30 pmol) treatment, and n = 4 for GIP (300 pmol) treatment. Each data point represents the mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001 compared with control mice, by 2-way ANOVA followed by Sidak’s multiple comparisons test (A–D and G); #P < 0.05, ##P < 0.01, ###P < 0.001, and ####P < 0.0001, compared with control mice on day 6 (A and B) and on day 3 (C), by 1-way ANOVA followed by Tukey’s multiple comparisons test; and *P < 0.05 and ***P < 0.001 compared with control, by t test (E and F). Data represent the mean ± SEM of 2 different experiments.