Adipose tissue macrophages: Unique polarization and bioenergetics in obesity

Abstract

Macrophages comprise a majority of the resident immune cells in adipose tissue (AT) and regulate both tissue homeostasis in the lean state and metabolic dysregulation in obesity. Since the AT environment rapidly changes based upon systemic energy status, AT macrophages (ATMs) must adapt phenotypically and metabolically. There is a distinct dichotomy in the polarization and bioenergetics of in vitro models, with M2 macrophages utilizing oxidative phosphorylation (OX PHOS) and M1 macrophages utilizing glycolysis. Early studies suggested differential polarization of ATMs, with M2‐like macrophages predominant in lean AT and M1‐like macrophages in obese AT. However, recent studies show that the phenotypic plasticity of ATMs is far more complicated, which is also reflected in their bioenergetics. Multiple ATM populations exist along the M2 to M1 continuum and appear to utilize both glycolysis and OX PHOS in obesity. The significance of the dual fuel bioenergetics is unclear and may be related to an intermediate polarization, their buffering capacity, or the result of a mixed population of distinct polarized ATMs. Recent evidence also suggests that ATMs of lean mice serve as a substrate buffer or reservoir to modulate lipid, catecholamine, and iron availability. Furthermore, recent models of weight loss and weight cycling reveal additional roles for ATMs in systemic metabolism. Evaluating ATM phenotype and intracellular metabolism together may more accurately illuminate the consequences of ATM accumulation in obese AT, lending further insight into obesity‐related comorbidities in humans.

Immunometabolism: From basic mechanisms to translation

“…Since back‐to‐back reports of adipose tissue infiltration by macrophages in 2003, 63‐65 the field has shown the importance of essentially every immune cell in adipose tissue with unique depot specific differences. Caslin et al 66 review the contribution of the predominant immune cell in fat tissue and adipose tissue macrophages (ATM) where extrinsic effects on local and systemic immunometabolism, as well as intrinsic immunometabolism and effects on phenotype, are discussed. From the first report of differences in ATM characteristics between lean and obese, 67 the evolution of the ATM phenotype has varied.…”

Single‐cell RNA sequencing reveals the induction of novel myeloid and myeloid‐associated cell populations in visceral fat with long‐term obesity

“…Historically, AT macrophages have been classified as M1 (pro‐inflammatory, or “classically” activated), or M2 (anti‐inflammatory, or “alternatively” activated) based on a restricted number of markers 11 . However, growing evidence suggests that rather than the presence of a dichotomous nature, macrophages exist in a spectrum of phenotypes and cellular identities, which appear to depend on multiple factors such as genetics, microenvironmental cues, age, or disease state 12 …”

Exercise and Adipose Tissue Immunity: Outrunning Inflammation

“…Single‐cell transcriptomics has shed light into global changes in hematopoietic (CD45+) immune populations within AT from lean and obese mice across several stages of obesity (i.e., duration of obesogenic diets) and has subsequently highlighted unique immune populations, reviewed elsewhere (31). Briefly, a novel macrophage population enriched in obese animals has been uncovered with high expression of genes associated with lipid metabolism, termed “lipid‐associated macrophages” (LAMs).…”