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 1

Brain GIPR controls body weight and adiposity in obese mice.

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Brain GIPR controls body weight and adiposity in obese mice. The GIPR mo...
The GIPR monoclonal antibody Gipg013 was centrally infused (1 μg, every other day) into HFD-induced obese mice (A–C, 20 weeks of HFD feeding, n = 11–13), normal chow–fed (lean) mice (D–F, n = 6–7), and ob/ob mice (G–I, n = 8–9). Body weight (A, D, and G) and food intake (B, E, and H) were measured daily. Body composition (C, F, and I) was measured on day 14 of Gipg013 treatment. (J) Relative mRNA expression of the indicated genes in the hypothalamus after 15 days of Gipg013 injection. (K) Western blot quantification of SOCS-3 protein in the hypothalamus of Gipg013-treated mice (n = 7–13). β-Actin was used as a loading control. (L–N) HFD-induced obese mice fed for 49 weeks were i.c.v. infused with Gipg013 or control IgG (1 μg every 4 days, arrows) and in combination with an i.p. injection of liraglutide or saline (0.3 mg/kg once a day) (n = 9–11). (L) Body weight, (M) body weight change, and (N) food intake were measured during the treatment. Each data point represents the mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, by 2-way ANOVA followed by Sidak’s multiple comparisons tests (A–I and L–N); 1-way ANOVA followed by Tukey’s multiple comparisons test (K); and t test (J).