Department of Immunology, Duke University School of Medicine, Durham, North Carolina, United States of America.
Department of Pediatrics, University of North Carolina School of Medicine, Chapel Hill, North Carolina, United States of America.
PLoS One. 2023 Jun 5;18(6):e0286470. doi: 10.1371/journal.pone.0286470. eCollection 2023.
BACKGROUND/OBJECTIVES: Leptin is an adipokine secreted in proportion to adipocyte mass and is therefore increased in obesity. Leptin signaling has been shown to directly promote inflammatory T helper 1 (Th1) and T helper 17 (Th17) cell number and function. Since T cells have a critical role in driving inflammation and systemic glucose intolerance in obesity, we sought to determine the role of leptin signaling in this context.
Male and female T cell-specific leptin receptor knockout mice and littermate controls were placed on low-fat diet or high-fat diet to induce obesity for 18 weeks. Weight gain, serum glucose levels, systemic glucose tolerance, T cell metabolism, and T cell differentiation and cytokine production were examined.
In both male and female mice, T cell-specific leptin receptor deficiency did not reverse impaired glucose tolerance in obesity, although it did prevent impaired fasting glucose levels in obese mice compared to littermate controls, in a sex dependent manner. Despite these minimal effects on systemic metabolism, T cell-specific leptin signaling was required for changes in T cell metabolism, differentiation, and cytokine production observed in mice fed high-fat diet compared to low-fat diet. Specifically, we observed increased T cell oxidative metabolism, increased CD4+ T cell IFN-γ expression, and increased proportion of T regulatory (Treg) cells in control mice fed high-fat diet compared to low-fat diet, which were not observed in the leptin receptor conditional knockout mice, suggesting that leptin receptor signaling is required for some of the inflammatory changes observed in T cells in obesity.
T cell-specific deficiency of leptin signaling alters T cell metabolism and function in obesity but has minimal effects on obesity-associated systemic metabolism. These results suggest a redundancy in cytokine receptor signaling pathways in response to inflammatory signals in obesity.
背景/目的：瘦素是一种脂肪细胞分泌的细胞因子，其分泌量与脂肪细胞的数量成正比，因此在肥胖症中会增加。瘦素信号已被证明可直接促进炎症辅助性 T 细胞 1（Th1）和辅助性 T 细胞 17（Th17）细胞数量和功能。由于 T 细胞在肥胖症中驱动炎症和全身葡萄糖不耐受方面起着关键作用，我们试图确定瘦素信号在这种情况下的作用。
雄性和雌性 T 细胞特异性瘦素受体敲除小鼠及其同窝对照小鼠分别置于低脂饮食或高脂饮食中，以诱导肥胖 18 周。检测体重增加、血清葡萄糖水平、全身葡萄糖耐量、T 细胞代谢以及 T 细胞分化和细胞因子产生。
在雄性和雌性小鼠中，T 细胞特异性瘦素受体缺失都不能逆转肥胖症中的葡萄糖耐量受损，尽管它确实以性别依赖的方式防止了肥胖小鼠的空腹血糖水平受损。尽管对全身代谢的影响很小，但与低脂饮食相比，T 细胞特异性瘦素信号对于高脂饮食喂养的小鼠中观察到的 T 细胞代谢、分化和细胞因子产生的变化是必需的。具体而言，与低脂饮食相比，我们观察到高脂饮食喂养的对照小鼠中 T 细胞氧化代谢增加、CD4+T 细胞 IFN-γ表达增加以及 T 调节（Treg）细胞比例增加，而这些变化在瘦素受体条件性敲除小鼠中并未观察到，这表明瘦素受体信号对于肥胖症中 T 细胞观察到的一些炎症变化是必需的。
T 细胞特异性瘦素信号缺失改变了肥胖症中的 T 细胞代谢和功能，但对肥胖症相关的全身代谢影响很小。这些结果表明在肥胖症中，细胞因子受体信号通路对炎症信号的反应具有冗余性。
