Obesity has emerged as a major risk factor for insulin resistance leading to the development of type 2 diabetes (T2D). The condition is characterized by high circulating levels of the adipose‐derived hormone leptin and a state of chronic low‐grade inflammation. Pro‐inflammatory signaling in the hypothalamus is associated with a decrease of central leptin‐ and insulin action leading to impaired systemic glucose tolerance. Intriguingly, leptin not only regulates body weight and glucose homeostasis but also acts as a pro‐inflammatory cytokine. Here we demonstrate that increasing leptin levels (62,5 µg/kg/d, PEGylated leptin) in mice fed a high‐fat diet (HFD) exacerbated body weight gain and aggravated hypothalamic micro‐ as well as astrogliosis. In contrast, administration of a predetermined dose of a long‐acting leptin antagonist (100 µg/kg/d, PESLAN) chosen to block excessive leptin signaling during diet‐induced obesity (DIO) showed the opposite effect and significantly improved glucose tolerance as well as decreased the total number of microglia and astrocytes in the hypothalamus of mice fed HFD. These results suggest that high levels of leptin, such as in obesity, worsen HFD‐induced micro‐and astrogliosis, whereas the partial reduction of hyperleptinemia in DIO mice may have beneficial metabolic effects and improves hypothalamic gliosis.