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.

中文翻译：

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高瘦素血症是肥胖患者葡萄糖耐受不良受损的一个促成因素

肥胖已成为导致 2 型糖尿病 (T2D) 发展的胰岛素抵抗的主要危险因素。该病症的特征是脂肪源性激素瘦素的高循环水平和慢性低度炎症状态。下丘脑的促炎信号与中枢瘦素和胰岛素作用的降低有关，导致全身葡萄糖耐量受损。有趣的是，瘦素不仅调节体重和葡萄糖稳态，而且还充当促炎细胞因子。在这里，我们证明了在喂食高脂肪饮食 (HFD) 的小鼠中增加瘦素水平（62.5 µg/kg/d，聚乙二醇化瘦素）会加剧体重增加，并加重下丘脑微和星形胶质细胞增生。相反，给予预定剂量的长效瘦素拮抗剂（100 µg/kg/d，PESLAN) 选择在饮食诱导的肥胖 (DIO) 期间阻断过度的瘦素信号传导，显示出相反的效果，显着改善了葡萄糖耐量，并减少了喂食 HFD 的小鼠下丘脑中小胶质细胞和星形胶质细胞的总数。这些结果表明，高水平的瘦素，如肥胖，会加重 HFD 诱导的微量和星形胶质细胞增生，而 DIO 小鼠中高瘦素血症的部分减少可能具有有益的代谢作用并改善下丘脑胶质增生。