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

Nat Commun. 2022 Sep 5;13(1):5208. doi: 10.1038/s41467-022-32871-3.


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.

MeSH terms

  • Adipocytes* / immunology
  • Adipose Tissue / immunology
  • Animals
  • Humans
  • Hypoxia-Inducible Factor-Proline Dioxygenases* / genetics
  • Hypoxia-Inducible Factor-Proline Dioxygenases* / immunology
  • Inflammation* / genetics
  • Inflammation* / immunology
  • Inflammation* / pathology
  • Insulin Resistance / genetics
  • Insulin Resistance / immunology
  • Insulin Resistance / physiology
  • L-Lactate Dehydrogenase / genetics
  • L-Lactate Dehydrogenase / immunology
  • Lactate Dehydrogenase 5* / genetics
  • Lactate Dehydrogenase 5* / immunology
  • Lactic Acid* / immunology
  • Macrophages* / immunology
  • Mice
  • Obesity / genetics
  • Obesity / immunology
  • Obesity / pathology
  • Procollagen-Proline Dioxygenase / genetics
  • Procollagen-Proline Dioxygenase / immunology
  • Prolyl Hydroxylases


  • Lactic Acid
  • L-Lactate Dehydrogenase
  • LDHA protein, human
  • Lactate Dehydrogenase 5
  • Prolyl Hydroxylases
  • EGLN1 protein, human
  • Procollagen-Proline Dioxygenase
  • Egln1 protein, mouse
  • Hypoxia-Inducible Factor-Proline Dioxygenases