Adipose tissue macrophage (ATM) inflammation is involved with meta-inflammation and pathology of metabolic complications. Here we report that in adipocytes, elevated lactate production, previously regarded as the waste product of glycolysis, serves as a danger signal to promote ATM polarization to an inflammatory state in the context of obesity. Adipocyte-selective deletion of lactate dehydrogenase A (Ldha), the enzyme converting pyruvate to lactate, protects mice from obesity-associated glucose intolerance and insulin resistance, accompanied by a lower percentage of inflammatory ATM and reduced production of pro-inflammatory cytokines such as interleukin 1β (IL-1β). Mechanistically, lactate, at its physiological concentration, fosters the activation of inflammatory macrophages by directly binding to the catalytic domain of prolyl hydroxylase domain-containing 2 (PHD2) in a competitive manner with α-ketoglutarate and stabilizes hypoxia inducible factor (HIF-1α). Lactate-induced IL-1β was abolished in PHD2-deficient macrophages. Human adipose lactate level is positively linked with local inflammatory features and insulin resistance index independent of the body mass index (BMI). Our study shows a critical function of adipocyte-derived lactate in promoting the pro-inflammatory microenvironment in adipose and identifies PHD2 as a direct sensor of lactate, which functions to connect chronic inflammation and energy metabolism.

脂肪组织巨噬细胞 (ATM) 炎症与代谢并发症的元炎症和病理学有关。在这里，我们报告在脂肪细胞中，乳酸的产生增加，以前被认为是糖酵解的废物，在肥胖的情况下作为一个危险信号促进 ATM 极化到炎症状态。脂肪细胞选择性缺失乳酸脱氢酶 A ( Ldha)，这种将丙酮酸转化为乳酸的酶可保护小鼠免受肥胖相关的葡萄糖耐受不良和胰岛素抵抗，同时炎症性 ATM 的百分比较低，促炎性细胞因子如白细胞介素 1β (IL-1β) 的产生减少。从机制上讲，乳酸在其生理浓度下，通过以与α-酮戊二酸竞争的方式直接结合含脯氨酰羟化酶结构域 2 (PHD2) 的催化结构域来促进炎症巨噬细胞的活化，并稳定缺氧诱导因子 (HIF-1α) . 乳酸诱导的 IL-1β 在 PHD2 缺陷型巨噬细胞中被消除。人体脂肪乳酸水平与局部炎症特征和胰岛素抵抗指数呈正相关，与体重指数 (BMI) 无关。