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Review
. 2020 May;295(1):101-113.
doi: 10.1111/imr.12853. Epub 2020 Apr 1.

Adipose tissue macrophages: Unique polarization and bioenergetics in obesity

Heather L Caslin  1 , Monica Bhanot  2 , W Reid Bolus  3 , Alyssa H Hasty  1   4
Affiliations
Review

Adipose tissue macrophages: Unique polarization and bioenergetics in obesity

Heather L Caslin et al. Immunol Rev. 2020 May.

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.

Keywords: bioenergetics; immunometabolism; phenotype; plasticity; polarization.

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Conflict of interest statement

Conflict of Interest

The authors have no conflict of interest to declare.

Figures

Figure 1.
Figure 1.. Obese adipose tissue macrophages (ATMs) display a hypermetabolic phenotype, different from M1 or M2 polarized bone marrow derived macrophages (BMDMs).
A-B) BMDMs from C57BL/6J mice were polarized for 24 hr with 10 ng/mL LPS/IFNy (M1) or IL-4/IL1-3 (M2). A) A mitochondrial stress test was completed on a Seahorse metabolic flux analyser for basal and maximal oxygen consumption rate (OCR) and B) basal extracellular acidication rate (ECAR). C-D) ATMs were isolated from C57BL/6J mice on a low fat diet (LFD) or high fat diet (HFD) for 9 wks and C) OCR and D) ECAR were assessed. *p<0.05, **p<0.01, ***p<0.001, ***p<0.0001 by two-way ANOVA (A and C), one way ANOVA (B), or t-test (C and D) and post-hoc testing where appropriate.
Figure 2:
Figure 2:. Electron microscopy of closly interacting adipocytes and macrophages: invaginated lipid structures budding off adipocytes and many vesicular structures resembling exosomes.
Adipose tissue was collected from lean chow fed C57BL/6J mice, cut into 1 mm pieces, and immediately fixed in 2.5% glutaraldehyde, before being prepared by Vanderbilt Imaging Core for TEM imaging. Images were captured on a Philips/FEI T-12 transmission electron microscope.
Figure 3:
Figure 3:. Obese ATM have a unique hypermetabolic phenotype.
A) Metabolic pathways are well-defined in BMDM polarized to M1 and M2 macrophages in vitro. B) Lean ATMs have low metabolic utilization, and may have multiple populations that handle catecholamines, iron, and lipids. In contrast, obese ATMs are hypermetabolic. Recent single cell RNA-sequencing data suggests that obese ATM also have multiple mixed populations. Future work should define 1) if the hypermetabolic phenotype is a result of pooled populations or if it is present in single populations and 2) how obese ATMs use glycolysis and OX PHOS for energy production, intermediate mediators, and both phagocytic and inflammatory functions.
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