Phenotypic Switching of Adipose Tissue Macrophages With Obesity Is Generated by Spatiotemporal Differences in Macrophage Subtypes

作者：Carey N. Lumeng, Jennifer B. DelProposto, Daniel J. Westcott, Alan R. Saltiel · 发表于：Diabetes · 年份：2008 · DOI：10.2337/db08-0872 · 被引用次数：912 · 研究领域：Adipokines, Inflammation, and Metabolic Diseases、Immune cells in cancer、Adipose Tissue and Metabolism

OBJECTIVE: To establish the mechanism of the phenotypic switch of adipose tissue macrophages (ATMs) from an alternatively activated (M2a) to a classically activated (M1) phenotype with obesity. RESEARCH DESIGN AND METHODS: ATMs from lean and obese (high-fat diet-fed) C57Bl/6 mice were analyzed by a combination of flow cytometry, immunofluorescence, and expression analysis for M2a and M1 genes. Pulse labeling of ATMs with PKH26 assessed the recruitment rate of ATMs to spatially distinct regions. RESULTS: Resident ATMs in lean mice express the M2a marker macrophage galactose N-acetyl-galactosamine specific lectin 1 (MGL1) and localize to interstitial spaces between adipocytes independent of CCR2 and CCL2. With diet-induced obesity, MGL1(+) ATMs remain in interstitial spaces, whereas a population of MGL1(-)CCR2(+) ATMs with high M1 and low M2a gene expression is recruited to clusters surrounding necrotic adipocytes. Pulse labeling showed that the rate of recruitment of new macrophages to MGL1(-) ATM clusters is significantly faster than that of interstitial MGL1(+) ATMs. This recruitment is attenuated in Ccr2(-/-) mice. M2a- and M1-polarized macrophages produced different effects on adipogenesis and adipocyte insulin sensitivity in vitro. CONCLUSIONS: The shift in the M2a/M1 ATM balance is generated by spatial and temporal differences in the recruitment of distinct ATM subtypes. The obesity-induced switch in ATM activation state is coupled to the localized recruitment of an infl...