Properties and functions of adipose tissue macrophages in obesity

Abstract

The expansion of adipose tissue (AT) in obesity is accompanied by the accumulation of immune cells that contribute to a state of low-grade, chronic inflammation and dysregulated metabolism. Adipose tissue macrophages (ATMs) represent the most abundant class of leukocytes in AT and are involved in the regulation of several regulatory physiological processes, such as tissue remodeling and insulin sensitivity. With progressive obesity, ATMs are key mediators of meta-inflammation, insulin resistance and impairment of adipocyte function. While macrophage recruitment from blood monocytes is a critical component of the generation of AT inflammation, new studies have revealed a role for ATM proliferation in the early stages of obesity and in sustaining AT inflammation. In addition, studies have revealed a more complex range of macrophage activation states than the previous M1/M2 model, and the existence of different macrophage profiles between human and animal models. This review will summarize the current understanding of the regulatory mechanisms of ATM function in relation to obesity, type 2 diabetes, depot of origin, and to other leukocytes such as AT dendritic cells, with hopes of emphasizing the regulatory nodes that can potentially be targeted to prevent and treat obesity-related metabolic disorders.

Keywords: MMe; adipose tissue; inflammation; insulin resistance; macrophages; obesity.

Figure 1

Adipose tissue macrophages (ATMs) classification. ‘M0’ macrophages originate from bone marrow‐derived monocytes or yolk‐sac progenitors. Depending on the stimuli, studies in mice have demonstrated that ‘M0’ macrophages differentiate into several subsets. Based on in vitro experiments, ‘M1’ or ‘classical activated’ macrophages (CAMs) originate from the stimulation with lipopolysaccharide (LPS), interferon (IFN)‐γ or tumor necrosis factor α (TNF‐α). These macrophages are characterized by an IL‐12^high, IL‐23^high and IL‐10^low phenotype, display the surface marker CD11c in addition to F4/80 and CD11b, and produce pro‐inflammatory mediators like TNF‐α, IL‐6, IL‐1β and nitric oxide (NO). ‘M2’ or ‘alternatively activated’ macrophages (AAMs) are macrophages with an anti‐inflammatory phenotype derived from IL‐4, IL‐10, IL‐13 and glucocorticoids stimulation. M2 macrophages exhibit an IL‐10^high, IL‐12^low and IL‐23^low phenotype, express the cell‐surface markers CD11b, F4/80, CD301 and CD206, and secrete IL‐4, IL‐10 and IL‐1 receptor antagonist (IL‐1Ra). ‘M2’ macrophages are further divided into three major variants: ‘M2a’, elicited by type II cytokines IL‐4 or IL‐13; ‘M2b’, obtained by triggering of Fc gamma receptors in the presence of a Toll receptor stimulus; and ‘M2c’, elicited by glucocortocoids, IL‐10 or TGF‐β. In obese setting, metabolic cues (e.g. free fatty acids, high insulin, high glucose, oxidized phospholipids, oxidized LDL) give rise to a population of metabolic activated (MMe) or oxidized (Mox) macrophages associated to an insulin‐resistant state. For instance, saturated fatty acids, which are released from hypertrophied adipocytes during the course of obesity, can act as a danger signal to MMe macrophages via the TLR4 complex. MMe macrophages exhibit a phenotype strikingly different from the typical M1/M2. Cell‐surface proteins specifically overexpressed by MMe macrophages include ABCA1, CD36 and PLIN2, while conventional M1/M2 markers are suppressed. Mox macrophages are characterized by high expression of heme oxygenase‐1 (HO‐1), sulforedoxin‐1 (Srnx‐1), thioredoxin‐1 reductase (Txnrd‐1), all redox‐regulatory genes under the control of the Nrf2 transcription factor, IL‐10 and VEGF.

Figure 2

Obesity‐driven changes in adipose tissue‐associated macrophages (ATMs). In lean adipose tissue (AT), eosinophils and type 2 innate lymphoid cells (ILC2s) constitutively produce Th2 cytokines interleukin‐4 (Il‐4) and interleukin‐13 (Il‐13), respectively, which promote anti‐inflammatory polarization of macrophages. As adiposity increases, obese AT manifests adipocyte hypertrophy, which leads to hypoxia, endoplasmic reticulum stress and lipotoxicity resulting in excessive leptin, cytokine and chemokine secretion. Among others, monocyte chemotactic protein‐1 (Mcp‐1) induces Ly6C⁺ monocytes recruitment giving rise to tissue macrophages. Recruited macrophages, increased in number due to augmented infiltration and local proliferation, undergo a drastic change in distribution, forming crown‐like structures (CLSs) around dead adipocytes. Additionally, they adopt a differential spectrum of functional properties and transcriptomic programming more prone to inflammation and metabolic dysregulation. This includes increased production of pro‐inflammatory cytokines and other secretory products.