Journal
NATURE COMMUNICATIONS
Volume 13, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-022-32871-3
Keywords
-
Categories
Funding
- Hong Kong Research Grants Council/ Area of Excellence [AoE/M/707-18]
- Collaborative Research Fund [C7037-17W]
- National Natural Science Foundation of China (NSFC) - Excellent Young Scientists Fund [81922079]
- Health Medical Research Fund [05163426]
- National Natural Science Foundation of China (NSFC) [81774134]
- International Partnership Program of the Chinese Academy of Sciences [154144KYSB20180063]
- China-New Zealand Joint Laboratory on Biomedicine and Health
Ask authors/readers for more resources
Adipocyte tissue macrophages (ATM) are recruited and activated in obesity. Adipocytes release lactate as a signal of inflammation, which can enhance obesity-associated inflammation through direct binding with PHD2. This study reveals the critical role of adipocyte-derived lactate in promoting the pro-inflammatory microenvironment in adipose tissue and identifies PHD2 as a direct sensor of lactate, linking chronic inflammation and energy metabolism.
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available