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

Cell Rep. 2016 Sep 13;16(11):3003-3015. 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • Reproducibility of Results
  • Sulfones / pharmacology
  • rap1 GTP-Binding Proteins / deficiency
  • rap1 GTP-Binding Proteins / metabolism*


  • Benzene Derivatives
  • ESI-05
  • Leptin
  • Sulfones
  • Rap1 protein, mouse
  • rap1 GTP-Binding Proteins
  • Glucose