Previous studies supported a role of hypothalamic inflammation in fine ambient particulate matter (PM2.5) exposure-mediated diabetes development. We therefore investigated the effects of PM2.5 exposure on insulin resistance and the disorders of hepatic glucose and lipid metabolism via hypothalamic inflammation. KKAy mice, a genetically susceptible model of type II diabetes mellitus, were administered intra-cerebroventricularly with IKK2 inhibitor (IMD-0354) and were exposed to either concentrated PM2.5 or filtered air (FA) for 4 weeks simultaneously via a versatile aerosol concentration exposure system. At the end of the exposure, fasting blood glucose and serum insulin were evaluated before epididymal adipose tissue and liver were collected, flow cytometry, quantitative PCR and Western blot were performed at euthanasia. We observed that intracerebroventricular administration of IMD-0354 attenuated insulin resistance, inhibited macrophage polarization to M1 phenotype in epididymal adipose tissue in response to PM2.5 exposure. Although the treatment did not affect hepatic inflammation or endoplasmic reticulum stress, it inhibited the expression of the enzymes for gluconeogenesis and lipogenesis in the liver. Therefore, our current finding indicates an important role of hypothalamic inflammation in PM2.5 exposure-mediated hepatic glucose and lipid metabolism disorder.