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Title: Neuronal Rap1 regulates energy balance, glucose homeostasis, and leptin actions

Author
item KANEKO, KENTARO - Children'S Nutrition Research Center (CNRC)
item XU, PINGWEN - Children'S Nutrition Research Center (CNRC)
item CORDONIER, ELIZABETH - Children'S Nutrition Research Center (CNRC)
item CHEN, SIYU - Children'S Nutrition Research Center (CNRC)
item NG, AMY - Children'S Nutrition Research Center (CNRC)
item XU, YONG - Children'S Nutrition Research Center (CNRC)
item MOROZOV, ALEXEI - National Institutes Of Health (NIH)
item FUKUDA, MAKOTO - Children'S Nutrition Research Center (CNRC)

Submitted to: Cell Reports
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/11/2016
Publication Date: 9/13/2016
Citation: Kaneko, K., Xu, P., Cordonier, E.L., Chen, S.S., Ng, A., Xu, Y., Morozov, A., Fukuda, M. 2016. Neuronal Rap1 regulates energy balance, glucose homeostasis, and leptin actions. Cell Reports. 16:3003-3015.

Interpretive Summary: Consuming a high-fat diet results in changes in the brain that leads to a decreased sensitivity to leptin,(the 'satiety hormone' produced by fatty tissue that helps regulate body weight by inhibiting appetite) that sets the body on a path to obesity. In this study, we examined the role of a signaling molecule called Rap1 in body weight control and glucose balance in the whole body. One group of mice was genetically engineered to lack the Rap1 gene only in the brain, the other (control) group had a functional Rap1 gene. Both groups of mice were fed a high-fat diet. As expected, the control mice with a working Rap1 gene significantly gained weight, but in comparison, the mice that lacked Rap1 did not gain body fat and kept normal body weight even under high-fat diet feeding. These mice also had lower levels of blood glucose and insulin than the mice in the control group. Furthermore, the mice that lacked Rap1 and ate a high-fat diet did not develop leptin resistance, but were able to respond to leptin, and this was reflected in the lower leptin levels in the blood. This new mechanism involving Rap1 in the brain may represent a potential therapeutic target for treating human obesity in the future.

Technical Abstract: The Central Nervous System (CNS) contributes to obesity and metabolic disease; however, the underlying neurobiological pathways remain to be fully established. Here, we show that the small GTPase Rap1 is expressed in multiple hypothalamic nuclei that control whole-body metabolism and is activated in high-fat diet (HFD)-induced obesity. Genetic ablation of CNS Rap1 protects mice from dietary obesity, glucose imbalance, and insulin resistance in the periphery and from HFD-induced neuropathological changes in the hypothalamus, including diminished cellular leptin sensitivity and increased endoplasmic reticulum (ER) stress and inflammation. Furthermore, pharmacological inhibition of CNS Rap1 signaling normalizes hypothalamic ER stress and inflammation, improves cellular leptin sensitivity, and reduces body weight in mice with dietary obesity. We also demonstrate that Rap1 mediates leptin resistance via interplay with ER stress. Thus, neuronal Rap1 critically regulates leptin sensitivity and mediates HFD-induced obesity and hypothalamic pathology and may represent a potential therapeutic target for obesity treatment.