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

Tianshi Feng, Xuemei Zhao, Ping Gu, Wah Yang, Cunchuan Wang, Qingyu Guo, Qiaoyun Long, Qing Liu, Ying Cheng, Jin Li, Cynthia Kwan Yui Cheung, Donghai Wu, Xinyu Kong, Yong Xu, Dewei Ye, Shuang Hua, Kerry Loomes, Aimin Xu () and Xiaoyan Hui ()
Additional contact information
Tianshi Feng: The University of Hong Kong
Xuemei Zhao: The Chinese University of Hong Kong
Ping Gu: School of Medicine, Nanjing University
Wah Yang: The University of Hong Kong
Cunchuan Wang: The First Affiliated Hospital of Jinan University
Qingyu Guo: School of Medicine, Nanjing University
Qiaoyun Long: The Chinese University of Hong Kong
Qing Liu: The University of Hong Kong
Ying Cheng: The University of Hong Kong
Jin Li: The University of Hong Kong
Cynthia Kwan Yui Cheung: The University of Hong Kong
Donghai Wu: Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
Xinyu Kong: Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
Yong Xu: Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
Dewei Ye: Guangdong Pharmaceutical University
Shuang Hua: Guangdong Pharmaceutical University
Kerry Loomes: University of Auckland
Aimin Xu: The University of Hong Kong
Xiaoyan Hui: The University of Hong Kong

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-32871-3

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