Resident and migratory adipose immune cells control systemic metabolism and thermogenesis

Abstract

Glucose is a vital source of energy for all mammals. The balance between glucose uptake, metabolism and storage determines the energy status of an individual, and perturbations in this balance can lead to metabolic diseases. The maintenance of organismal glucose metabolism is a complex process that involves multiple tissues, including adipose tissue, which is an endocrine and energy storage organ that is critical for the regulation of systemic metabolism. Adipose tissue consists of an array of different cell types, including specialized adipocytes and stromal and endothelial cells. In addition, adipose tissue harbors a wide range of immune cells that play vital roles in adipose tissue homeostasis and function. These cells contribute to the regulation of systemic metabolism by modulating the inflammatory tone of adipose tissue, which is directly linked to insulin sensitivity and signaling. Furthermore, these cells affect the control of thermogenesis. While lean adipose tissue is rich in type 2 and anti-inflammatory cytokines such as IL-10, obesity tips the balance in favor of a proinflammatory milieu, leading to the development of insulin resistance and the dysregulation of systemic metabolism. Notably, anti-inflammatory immune cells, including regulatory T cells and innate lymphocytes, protect against insulin resistance and have the characteristics of tissue-resident cells, while proinflammatory immune cells are recruited from the circulation to obese adipose tissue. Here, we review the key findings that have shaped our understanding of how immune cells regulate adipose tissue homeostasis to control organismal metabolism.

Keywords: adipose tissue; immune cells; metabolism.

Fig. 1. Immune spectrum in lean and obese adipose tissue.

Lean adipose tissue is enriched in anti-inflammatory immune cells and immune cells that contribute to a T_H2-dominant environment, including Treg cells, eosinophils, T_H2 cells, M2 macrophages, ILC2s, NKT cells and γδ T cells, and are critical in preserving insulin sensitivity. Importantly, most of these immune cells migrate to adipose tissue early in life, where they establish tissue residency. Obesity displaces these immune cells by facilitating the recruitment of inflammatory immune cells such as M1 macrophages, T_H1 cells, CD8+ T cells, NK cells, ILC1s and B cells. This effect is mediated at least in part by hypoxic and ER stress signals, as well as chemokines such as MCP-1/CCL2

Fig. 2. Immune-stromal cell crosstalk.

PDGFRa+ mesenchymal stromal cells are the primary sources of IL-33 in adipose tissue. The cytokines TNF and IL-17A produced by γδT cells activate IL-33 production in MSCs. Treg cells and ILC2s rely on MSC-derived IL-33 for differentiation, maintenance, survival and activation. MSCs also express CD73, which catalyzes the production of adenosine, which coordinates with Treg cells to promote immune suppression in adipose tissue. Male sex hormones facilitate the differentiation of IL-33+CD73+MSCs, and obesity impairs this population

Fig. 3. Immune regulation of thermogenesis.

Upon cold exposure, M2 macrophages promote the differentiation of beige adipocytes from PDGFRα+ stromal cells. This process is mediated by IL-4 produced by eosinophils. IL-4 and IL-13 derived from eosinophils and ILC2s also promote the proliferation of PDGFRα+ cells to facilitate beiging. While the mechanism by which M2 macrophages promote beiging is unclear, ILC2s and NKT cells promote the upregulation of UCP-1 and FGF-21 in adipose tissue, respectively. Innervation mediated by γδT cell-derived IL-17F also promotes beiging and thermogenesis. The role of Treg cells in thermogenesis is controversial