Neuronal Rap1 Regulates Energy Balance, Glucose Homeostasis, and Leptin Actions

• Published in: Cell reports (Cambridge) Vol. 16; no. 11; pp. 3003 - 3015
• Main Authors: Kaneko, Kentaro, Xu, Pingwen, Cordonier, Elizabeth L., Chen, Siyu S., Ng, Amy, Xu, Yong, Morozov, Alexei, Fukuda, Makoto
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 13.09.2016; Elsevier
• Subjects: Animals; Benzene Derivatives - pharmacology; Central Nervous System - drug effects; Central Nervous System - metabolism; Central Nervous System - pathology; Diet, High-Fat; Endoplasmic Reticulum Stress - drug effects; Energy Metabolism - drug effects; Female; Glucose - metabolism; Homeostasis - drug effects; Insulin Resistance; Leptin - metabolism; Mice, Inbred C57BL; Neurons - drug effects; Neurons - metabolism; Obesity - metabolism; Obesity - pathology; Overnutrition - metabolism; Overnutrition - pathology; rap1 GTP-Binding Proteins - deficiency; rap1 GTP-Binding Proteins - metabolism; Reproducibility of Results; Sulfones - pharmacology
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2016.08.039

The 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. [Display omitted] •The small GTPase Rap1 in the brain is activated in high-fat-diet-induced obesity•Loss of neuronal Rap1 protects against diet-induced obesity and glucose imbalance•Rap1 controls neural leptin sensitivity•Brain Rap1 interacts with ER stress pathways in leptin resistance and obesity The brain is involved in diet-induced obesity and its associated metabolic disturbances. Using mice with neuron-specific deletion of the small GTPase Rap1, Kaneko et al. demonstrate that brain Rap1 plays a central role in dietary obesity, glucose imbalance, peripheral insulin resistance, and central leptin resistance.