CX3CR1hi macrophages sustain metabolic adaptation by relieving adipose-derived stem cell senescence in visceral adipose tissue

Zixin Zhou; Huiying Zhang; Yan Tao; Haipeng Jie; Jingyuan Zhao; Jinhao Zang; Huijie Li; Yalin Wang; Tianci Wang; Hui Zhao; Yuan Li; Chun Guo; Faliang Zhu; Haiting Mao; Lining Zhang; Fengming Liu; Qun Wang

doi:10.1016/j.celrep.2023.112424

CX3CR1^hi macrophages sustain metabolic adaptation by relieving adipose-derived stem cell senescence in visceral adipose tissue

Cell Rep. 2023 May 30;42(5):112424. doi: 10.1016/j.celrep.2023.112424. Epub 2023 Apr 21.

Authors

Zixin Zhou¹, Huiying Zhang¹, Yan Tao¹, Haipeng Jie², Jingyuan Zhao¹, Jinhao Zang¹, Huijie Li¹, Yalin Wang¹, Tianci Wang¹, Hui Zhao³, Yuan Li², Chun Guo¹, Faliang Zhu¹, Haiting Mao³, Lining Zhang¹, Fengming Liu¹, Qun Wang⁴

Affiliations

¹ Key Laboratory of Infection and Immunity of Shandong Province, Shandong Provincial Clinical Research Center for Immune Diseases and Gout, Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China.
² Key Laboratory of Infection and Immunity of Shandong Province, Shandong Provincial Clinical Research Center for Immune Diseases and Gout, Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China; Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, China.
³ Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250033, China.
⁴ Key Laboratory of Infection and Immunity of Shandong Province, Shandong Provincial Clinical Research Center for Immune Diseases and Gout, Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China. Electronic address: wangqun@sdu.edu.cn.

PMID: 37086405
DOI: 10.1016/j.celrep.2023.112424

Abstract

Adipose-derived stem cells (ASCs) drive healthy visceral adipose tissue (VAT) expansion via adipocyte hyperplasia. Obesity induces ASC senescence that causes VAT dysfunction and metabolic disorders. It is challenging to restrain this process by biological intervention, as mechanisms of controlling VAT ASC senescence remain unclear. We demonstrate that a population of CX3CR1^hi macrophages is maintained in mouse VAT during short-term energy surplus, which sustains ASCs by restraining their senescence, driving adaptive VAT expansion and metabolic health. Long-term overnutrition induces diminishment of CX3CR1^hi macrophages in mouse VAT accompanied by ASC senescence and exhaustion, while transferring CX3CR1^hi macrophages restores ASC reservoir and triggers VAT beiging to alleviate the metabolic maladaptation. Mechanistically, visceral ASCs attract macrophages via MCP-1 and shape their CX3CR1^hi phenotype via exosomes; these macrophages relieve ASC senescence by promoting the arginase1-eIF5A hypusination axis. These findings identify VAT CX3CR1^hi macrophages as ASC supporters and unravel their therapeutic potential for metabolic maladaptation to obesity.

Keywords: CP: Immunology; CP: Metabolism; CX3CR1; adipose-derived stem cell; cellular senescence; macrophage; obesity; visceral adipose tissue.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adipocytes* / metabolism
Adipose Tissue / metabolism
Animals
CX3C Chemokine Receptor 1 / metabolism
Cellular Senescence
Intra-Abdominal Fat* / metabolism
Macrophages / metabolism
Mice
Obesity / metabolism

Substances

Cx3cr1 protein, mouse
CX3C Chemokine Receptor 1