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

TitleAdipocyte-derived lactate is a signalling metabolite that potentiates adipose macrophage inflammation via targeting PHD2
Authors
Issue Date5-Sep-2022
PublisherNature Research
Citation
Nature Communications, 2022, v. 13, n. 1 How to Cite?
Abstract

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.


Persistent Identifierhttp://hdl.handle.net/10722/338251
ISSN
2023 Impact Factor: 14.7
2023 SCImago Journal Rankings: 4.887
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorFeng, TS-
dc.contributor.authorZhao, XM-
dc.contributor.authorGu, P-
dc.contributor.authorYang, W-
dc.contributor.authorWang, CC-
dc.contributor.authorGuo, QY-
dc.contributor.authorLong, QY-
dc.contributor.authorLiu, Q-
dc.contributor.authorCheng, Y-
dc.contributor.authorLi, J-
dc.contributor.authorCheung, CKY-
dc.contributor.authorWu, DH-
dc.contributor.authorKong, XY-
dc.contributor.authorXu, Y-
dc.contributor.authorYe, DW-
dc.contributor.authorHua, S-
dc.contributor.authorLoomes, K-
dc.contributor.authorXu, AM-
dc.contributor.authorHui, XY-
dc.date.accessioned2024-03-11T10:27:25Z-
dc.date.available2024-03-11T10:27:25Z-
dc.date.issued2022-09-05-
dc.identifier.citationNature Communications, 2022, v. 13, n. 1-
dc.identifier.issn2041-1723-
dc.identifier.urihttp://hdl.handle.net/10722/338251-
dc.description.abstract<p>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.</p>-
dc.languageeng-
dc.publisherNature Research-
dc.relation.ispartofNature Communications-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.titleAdipocyte-derived lactate is a signalling metabolite that potentiates adipose macrophage inflammation via targeting PHD2-
dc.typeArticle-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1038/s41467-022-32871-3-
dc.identifier.pmid36064857-
dc.identifier.scopuseid_2-s2.0-85137189091-
dc.identifier.volume13-
dc.identifier.issue1-
dc.identifier.eissn2041-1723-
dc.identifier.isiWOS:000850348400015-
dc.publisher.placeBERLIN-
dc.identifier.issnl2041-1723-

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