A high-fat diet and sedentary lifestyle could accelerate aging and hypothalamic inflammation. In order to explore the regulatory mechanisms of lifestyle in the hypothalamus, swimming exercise and diet control were applied in the high-fat diet ApoE-/- mice in our study. 20-week-old ApoE-/- mice fed with 12-week high-fat diet were treated by high-fat diet, diet control and swimming exercise. The results showed that hypothalamic inflammation, glial cells activation and cognition decline were induced by high-fat diet. Compared with the diet control, hypothalamic inflammation, glial cells activation and learning and memory impairment were effectively alleviated by swimming exercise plus diet control, which was related to the increasing expression of SIRT1, inhibiting the expression of NF-κB and raising secretion of GnRH in the hypothalamus. These findings supported the hypothesis that hypothalamic inflammation was susceptible to exercise and diet, which was strongly associated with SIRT1-NF-κB-GnRH expression in the hypothalamus.