Rap1 in the VMH regulates glucose homeostasis

Authors: KANEKO, KENTARO - Kyoto University; LIN, HSIAO - Children'S Nutrition Research Center (CNRC); FU, YUKIKO - Children'S Nutrition Research Center (CNRC); SAHA, PRADIP - Baylor College Of Medicine; DE LA PUENTE-GOMEZ, ANA - Children'S Nutrition Research Center (CNRC); XU, YONG - Children'S Nutrition Research Center (CNRC); OHINATA, KOUSAKU - Kyoto University; CHEN, PETER - Cedars-Sinai Medical Center; MOROZOV, ALEXEI - Virginia Tech; FUKUDA, MAKOTO - Children'S Nutrition Research Center (CNRC)

Submitted to: JCI Insight
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/30/2021
Publication Date: 5/11/2021
Citation: Kaneko, K., Lin, H.Y., Fu, Y., Saha, P.K., De La Puente-Gomez, A.B., Xu, Y., Ohinata, K., Chen, P., Morozov, A., Fukuda, M. 2021. Rap1 in the VMH regulates glucose homeostasis. Journal of Clinical Immunology Insights (JCI Insights). https://doi.org/10.1172/jci.insight.142545.
DOI: https://doi.org/10.1172/jci.insight.142545

Interpretive Summary: Maintaining blood glucose within the normal range is vital for organisms. Elevated blood glucose levels beyond normal lead to serious compilations such as heart attack, stroke, kidney failure, leg amputation, and vision loss. This study uncovers a molecular switch in the brain that determines blood glucose levels. A signaling molecule called Rap1 in the hypothalamus acts as a determinant of blood glucose. When Rap1 is turned on, blood glucose is elevated. More importantly, when it is turned off, blood glucose is decreased and corrects diabetic condition in mice. The next step is to find a chemical(s) that can manipulate Rap1 to control our blood glucose, and novel therapeutic opportunities to improve type 2 diabetes may emerge from such efforts.

Technical Abstract: The hypothalamus is a critical regulator of glucose metabolism and is capable of correcting diabetes conditions independently of an effect on energy balance. The small GTPase Rap1 in the forebrain is implicated in high-fat diet (HFD)-induced obesity and glucose imbalance. Here, we report that increasing Rap1 activity selectively in the medial hypothalamus elevated blood glucose without increasing the body weight of HFD-fed mice. In contrast, decreasing hypothalamic Rap1 activity protected mice from diet-induced hyperglycemia but did not prevent weight gain. The remarkable glycemic effect of Rap1 was reproduced when Rap1 was specifically deleted in SF1-positive neurons in the ventromedial hypothalamic nucleus (VMH) known to regulate glucose metabolism. While having no effect on body weight regardless of sex, diet, and age, Rap1 deficiency in the VMH SF1 neurons markedly lowered blood glucose and insulin levels, improved glucose and insulin tolerance, and protected mice against HFD-induced neural leptin resistance and peripheral insulin resistance at the cellular and whole-body levels. Lastly, acute pharmacological inhibition of brain Epac2, a direct activator of Rap1, corrected glucose imbalance in obese mouse models. Our findings uncover the primary role of VMH Rap1 in glycemic control and implicate Rap1 signaling as a potential target for therapeutic intervention in diabetes.