Background: Brain insulin receptor is considered an important regulatory factor for appetite regulation, white fat mass metabolism, and hepatic glucose output. Disruption of neuronal insulin action leads to obesity, metabolic syndrome and neurodegenerative disorders.Objective: The aim of the present study was to find out the effect of exenatide, a GLP-1 analog, on the hypothalamic insulin receptor (IR) gene expression in high fat diet (HFD) obesity rat model. Method: Rats were fed on HFD for 16 weeks and received exenatide (10μg/kg/d, SC) for one month. The body weight difference, fasting blood glucose, fasting insulin levels, HOMA index, lipid profile, oxidative stress markers and serum TNF-α were measured. Additionally, hypothalamic IR gene expression was analyzed using real time polymerase chain reaction. Results: HFD rats showed significant body weight gain, hyperglycemia, hyperinsulinemia, insulin resistance, dyslipidemia, and increase in the oxidative stress and TNFα together with down-regulation of IR gene expression in the hypothalamus. Exenatide significantly reduced the body weight, fasting blood glucose and insulin levels, insulin resistance, dyslipidemia, the oxidative stress and TNF-α serum level. Also, exenatide caused significant up-regulation of hypothalamic IR gene expression. Conclusion: In conclusion, exenatide may exert hypothalamic insulin-sensitizing effect along with its antiinflammatory and antioxidant effects in HFD obese rats.