Adipocyte-derived lactate is a signalling metabolite that potentiates adipose macrophage inflammation via targeting PHD2

作者：Feng, Tianshi; Zhao, Xuemei; Gu, Ping; Yang, Wah; Wang, Cunchuan; Guo, Qingyu; Long, Qiaoyun; Liu, Qing; Cheng, Ying; Li, Jin; Cheung, Cynthia Kwan Yui; Wu, Donghai; Kong, Xinyu; Xu, Yong; Ye, Dewei; Hua, Shuang; Loomes, Kerry; Xu, Aimin^*; Hui, Xiaoyan^*

来源：Nature Communications, 2022, 13(1): 5208.

DOI：10.1038/s41467-022-32871-3

• INSULIN-RESISTANCE
• MONOCARBOXYLATE TRANSPORTERS
• PLASMA LACTATE
• TISSUE
• HYPOXIA
• HIF-1-ALPHA
• EXPRESSION
• OBESITY
• RISK

Adipocyte tissue macrophages (ATM) are recruited and activated in obesity. The authors show that adipocytes release lactate as a signal of inflammation and that this metabolite can enhance obesity associated inflammation through stimulation of ATM by direct binding with PHD2. @@@ 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 1 beta (IL-1 beta). 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 alpha-ketoglutarate and stabilizes hypoxia inducible factor (HIF-1 alpha). Lactate-induced IL-1 beta 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.

• 单位
  南京大学; 1; 广东药学院; 中国科学院