Based on the evidence discussed above, our aims were to investigate in mice under a normal chow diet: (1) whether short-term (one to five days) exposure to PM2.5 induces hypothalamic inflammation before the development of obesity as occurs in mice fed a HFD; (2) whether long-term (12 weeks) exposure to PM2.5 impairs leptin signaling/action in the hypothalamus, contributing to an increase of food intake and decrease of energy expenditure, and (3) whether inflammatory mediators such as TLR4 and IKKε play a role in impairing leptin signaling and action. The gene discussed is TLR4; the disease is obesity due to melanocortin 4 receptor deficiency.