Role of adipose tissue macrophages in obesity-related disorders

Abstract

The obesity epidemic has led researchers and clinicians to reconsider the etiology of this disease and precisely decipher its molecular mechanisms. The excessive accumulation of fat by cells, most notably adipocytes, which play a key role in this process, has many repercussions in tissue physiology. Herein, we focus on how macrophages, immune cells well known for their tissue gatekeeping functions, assume fundamental, yet ill-defined, roles in the genesis and development of obesity-related metabolic disorders. We first discuss the determinants of the biology of these cells before introducing the specifics of the adipose tissue environment, while highlighting its heterogeneity. Finally, we detail how obesity transforms both adipose tissue and local macrophage populations. Understanding macrophage diversity and their cross talk with the diverse cell types constituting the adipose tissue environment will allow us to frame the therapeutic potential of adipose tissue macrophages in obesity.

Figure 1.

AT macrophage subsets at steady state and obesity. scRNA-seq, phenotypic, and functional studies identified specific subpopulations of ATMs at steady state and obesity. (A) In lean mice, three major populations of ATMs have been described. LYVE1⁺ ATMs are the first to populate the primitive AT. They are closely associated with vasculature and were reported to be of embryonic origin and slowly replaced by monocytes in adults. In addition, studies identified one or two CD63⁺ monocyte-derived ATM subpopulations based on differential expression of MHCII, CD11c, and CX3CR1. CX3CR1^hiMHCII^hi were found predominantly associated with nerve bundles. However, the separation of the two monocyte-derived ATMs is still unclear, and CD11c expression can be attributed to both of them. (B) During obesity it was suggested that LYVE1⁺TIM4⁺ ATMs were implicated in control of lipid storage; however, their precise localization and origin during disease are still uncertain. In addition, the fate of the monocyte-derived ATMs from steady-state condition to obesity is not clear. With our current stage of knowledge, we placed LAMs, characterized with TREM2 and CD9 expression, as a separate population, as it is still under investigation if they are recruited during disease or acquire the LAM profile with obesity.

Figure 2.

eW-ATM subpopulations’ cross talk with their respective niches. eWAT is populated by different subtypes of eW-ATM, with specific function and subtissue localization at steady state and obesity. (A) Crowning and LAMs are located surrounding dead or dying adipocytes, which release lipids and/or damage-associated molecular patterns (DAMPs), which in turn induce inflammation. Recruitment of LAMs also induces inflammation and ECM deposition and remodeling. The adipogenetic microenvironment created by cell death and macrophage recruitment in turn induces proliferation of both eW-ATM and AP, subsequently enhancing an inflammatory environment. (B) Hypoxia and adipocyte hypertrophy increase proinflammatory cytokine secretion in both macrophages and adipocytes through FFA release and DAMPs. These proinflammatory cytokines in turn increase obesity-associated meta-inflammation and monocyte recruitment/differentiation to macrophages. In addition to cytokines, adipocytes secrete adipokines such as Leptin and Adiponectin. Meta-inflammation dysregulation of Leptin and Adiponectin secretion is associated with increased recruitment of monocytes sustaining meta-inflammation. (C) A population of eW-ATMs involved in adipocyte-to-macrophage mitochondria transfer through heparan sulfate expression was identified. At steady state, this axis ensures maintenance of glucose and lipid homeostasis and is dysregulated during obesity in response to inflammation such as induces IFN-I and LPS. (D) Nerve bundles and sympathetic neuron-associated macrophages characterized with high CX3CR1 and MHCII expression are able to regulate lipolysis by capturing and degradation noradrenalin (NA) through monoamine oxidase A (MAOA). (E) LYVE1- and TIM4-expressing, embryonic derived eWAT-ATMs are found in contact with the eWAT vasculature. In response to hypoxia, they are able to produce angiogenic factors such as PDGF, MMP, and VEGF. (E) The supportive ECM-rich septum and fascia are endowed with distinct subpopulations of AP. However, to date it is still not known whether this specific subniche is endowed with specific eW-ATM subtypes controlling AP proliferation, differentiation, and recruitment.

Figure 3.

Potential AT niches. (A) Anatomic location of major ATs in mouse. The dotted line virtually indicates the peritoneal cavity. (B) eWAT was virtually subdivided in two zones, distal and proximal. During obesity, CLSs and adipokines were found enriched in the proximal zone. (C) eWAT is endowed with a well-organized stromal network and plastic architecture. eWAT plasticity is in part due to its organization into lobules, where mature adipocytes reside, and is delimited by bundles of ECM, or septa. Finally, the whole AT mass is surrounded by a capsule (also called the fascia or reticular interstitium [RI]) formed from an uninterrupted sheet of connective tissue that extends throughout the body.