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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

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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 3

Rap1 mediates the effects of centrally administered GIP.

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Rap1 mediates the effects of centrally administered GIP.
(A) Organotypic...
(A) Organotypic brain slices were incubated with GIP (0.5 μM, 6 h) and then stimulated with leptin (120 nM, 60 min). Images show p-STAT3 immunostaining of fixed slices. Scale bar: 100 μm. (B) GIP inhibited leptin-induced p-STAT3 in a dose- and time-dependent manner (n = 3–14). (C and D) Brain slices were incubated with GIP (0.5 μM), with or without 50 μM ESI-05 (C) or 10 μM PKI114–22 (D) for 6 hours and then stimulated with 120 nM leptin for 60 minutes. Representative images and quantification of hypothalamic p-STAT3 (n = 3–5) are shown. Scale bars: 100 μm. (E) Lean mice were i.c.v. administered GIP (3 nmol) for 2 hours. Left: Western blot images of active Rap1, total Rap1, and β-actin (n = 6). Middle: Quantification is shown from 3 independent experiments (n = 17–18). Right: Graph shows Rap1 activity in the brains of lean and obese mice treated with Gipg013 or control IgG (n = 7–10). (F and G) Rap1ΔCNS or control mice (n = 7–9) were i.c.v. injected with GIP (3 nmol/day) or vehicle and then i.c.v. injected with leptin (5 μg/day) 4 hours later. (F) Body weight change was measured daily. (G) Relative mRNA expression of the indicated genes in the hypothalamus of GIP- or vehicle-treated Rap1ΔCNS mice. Each data point represents the mean ± SEM. *P < 0.05, **P < 0.01, and ***P < 0.001, by 1-way ANOVA followed by Tukey’s multiple comparisons test (B–E and G); **P < 0.01, by t test (E); and **P < 0.01, by 2-way ANOVA followed by Sidak’s multiple comparisons test (F). ARC, arcuate nucleus; 3V, third ventricle.

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