Abstract
Adipose tissue macrophages (ATMs) regulate homeostasis and contribute to the metabolically harmful chronic inflammation in obese individuals. While evident heterogeneity of resident ATMs has been described previously, their phenotype, developmental origin, and functionality remain inconsistent. We analyzed white adipose tissue (WAT) during homeostasis and diet interventions using comprehensive and unbiased single-cell mass cytometry and genetic lineage tracking models. We now provide a uniform definition of individual subsets of resident ATMs. We show that in lean mice, WAT co-harbors eight kinetically evolving CD206+ macrophage subpopulations (defined by TIM4, CD163, and MHC II) and two CD206– macrophage subpopulations. TIM4–CD163+, TIM4–CD163– and CD206– macrophage populations are largely bone marrow-derived, while the proliferating TIM4+CD163+ subpopulation is of embryonic origin. All macrophage subtypes are active in phagocytosis, endocytosis, and antigen processing in vitro, whereas TIM4+CD163+ cells are superior in scavenging in vivo. A high-fat diet induces massive infiltration of CD206– macrophages and selective down-regulation of MHC II on TIM4+ macrophages. These changes are reversed by dietary intervention. Thus, the developmental origin and environment jointly regulate the functional malleability of resident ATMs.
Highlights
Obesity and impaired metabolic health are escalating worldwide, and obesity is a significant risk factor for metabolic disorders, including type II diabetes, non-alcoholic fatty liver disease, atherosclerosis, and ischemic cardiovascular disease [1, 2]
We carried out comprehensive profiling of epididymal white adipose tissue immune cell composition in 2, 5, 8, 12, 16, and 23 weeks old wild type (WT) male mice on a standard diet
TIM4 and CD163 were identified as dichotomic markers for separating the four major CD206 positive macrophage populations
Summary
Obesity and impaired metabolic health are escalating worldwide, and obesity is a significant risk factor for metabolic disorders, including type II diabetes, non-alcoholic fatty liver disease, atherosclerosis, and ischemic cardiovascular disease [1, 2]. The tissue most strongly associated with the pathogenesis of obesity is white adipose tissue (WAT). Adipose tissue macrophages (ATMs), the most abundant immune cell type in WAT, have been associated with the development. Inhibition of the accumulation of pro-inflammatory macrophages in WAT results in amelioration of obese conditions and improved metabolic status [18, 23,24,25,26,27,28]. Further studies are needed to unravel the function and diversity of resident macrophages, especially in steady state lean adipose tissue, to provide knowledge that would shift intervention approaches away from targeting the inflammatory ATMs towards targeting their metabolic reprogramming in order to maintain adipose tissue homeostasis
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