Obesity is a major concern for global health care systems. Systemic low-grade inflammation in obesity is a major risk factor for insulin resistance. Leptin is an adipokine secreted by the adipose tissue that functions by controlling food intake, leading to satiety. Leptin levels are increased in obesity. Here, we show that leptin enhances the effects of LPS in macrophages, intensifying the production of cytokines, glycolytic rates, and morphological and functional changes in the mitochondria through an mTORC2-dependent, mTORC1-independent mechanism. Leptin also boosts the effects of IL-4 in macrophages, leading to increased oxygen consumption, expression of macrophage markers associated with a tissue repair phenotype, and wound healing. In vivo, hyperleptinemia caused by diet-induced obesity increases the inflammatory response by macrophages. Deletion of leptin receptor and subsequently of leptin signaling in myeloid cells (ObR-/-) is sufficient to improve insulin resistance in obese mice and decrease systemic inflammation. Our results indicate that leptin acts as a systemic nutritional checkpoint to regulate macrophage fitness and contributes to obesity-induced inflammation and insulin resistance. Thus, specific interventions aimed at downstream modulators of leptin signaling may represent new therapeutic targets to treat obesity-induced systemic inflammation.

中文翻译：

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巨噬细胞中的瘦素信号抑制可改善肥胖症的免疫代谢结果。

肥胖是全球卫生保健系统的一个主要问题。肥胖的全身性低度炎症是胰岛素抵抗的主要危险因素。瘦素是一种由脂肪组织分泌的脂肪因子，其作用是控制食物摄入，导致饱腹感。瘦素水平在肥胖中增加。在这里，我们表明瘦素通过依赖 mTORC2、不依赖 mTORC1 的机制增强 LPS 在巨噬细胞中的作用，从而增强细胞因子的产生、糖酵解速率以及线粒体中的形态和功能变化。Leptin 还增强 IL-4 在巨噬细胞中的作用，导致耗氧量增加、与组织修复表型相关的巨噬细胞标志物的表达和伤口愈合。在体内，由饮食引起的肥胖引起的高瘦素血症会增加巨噬细胞的炎症反应。骨髓细胞中瘦素受体的缺失和随后的瘦素信号传导 (ObR-/-) 足以改善肥胖小鼠的胰岛素抵抗并减少全身炎症。我们的研究结果表明，瘦素作为一个系统性营养检查点来调节巨噬细胞的适应性，并有助于肥胖引起的炎症和胰岛素抵抗。因此，针对瘦素信号下游调节剂的特定干预措施可能代表治疗肥胖引起的全身炎症的新治疗靶点。我们的研究结果表明，瘦素作为一个系统性营养检查点来调节巨噬细胞的适应性，并有助于肥胖引起的炎症和胰岛素抵抗。因此，针对瘦素信号下游调节剂的特定干预措施可能代表治疗肥胖引起的全身炎症的新治疗靶点。我们的研究结果表明，瘦素作为一个系统性营养检查点来调节巨噬细胞的适应性，并有助于肥胖引起的炎症和胰岛素抵抗。因此，针对瘦素信号下游调节剂的特定干预措施可能代表治疗肥胖引起的全身炎症的新治疗靶点。