Mechanisms of inflammatory responses in obese adipose tissue

Abstract

The fields of immunology and metabolism are rapidly converging on adipose tissue. During obesity, many immune cells infiltrate or populate in adipose tissue and promote a low-grade chronic inflammation. Studies to date have suggested that perturbation of inflammation is critically linked to nutrient metabolic pathways and to obesity-associated complications such as insulin resistance and type 2 diabetes. Despite these advances, however, many open questions remain including how inflammatory responses are initiated and maintained, how nutrients impact the function of various immune populations, and how inflammatory responses affect systemic insulin sensitivity. Here we review recent studies on the roles of various immune cells at different phases of obesity and discuss molecular mechanisms underlying obesity-associated inflammation. Better understanding of the events occurring in adipose tissue will provide insights into the pathophysiological role of inflammation in obesity and shed light on the pathogenesis of obesity-associated metabolic syndrome.

Figure 1

Key immune populations and cytokines in white adipose tissue (WAT). Immune cells involved in both proand anti-inflammatory responses are present in adipose tissue. Cytokines allow immune cells and adipocytes to communicate with each other, maintain inflammatory homeostasis in WAT, and influence systemic insulin sensitivity. Abbreviations: IL, interleukin; M1, classically activated M1 macrophages; M2, alternatively activated M2 macrophages; MCP-1, monocyte chemotactic protein 1; MDSC, myeloid-derived suppressor cell; T_H1/T_H2, CD4⁺ type 1 or 2 helper T cells; TNFα, tumor necrosis factor alpha; Treg, regulatory T cells.

Figure 2

Relative abundance of various immune cells in adipose tissue of lean and obese mice. Pie charts show the abundance of various immune cells in total CD45⁺ leukocytes present in stromal vascular fraction of epididymal adipose tissue of 14- to 20-week-old mice that have been on either LFD (lean) or HFD for 8 to 12 weeks (obese). The numbers shown in the charts indicate the percentage of each cell type in total CD45⁺ leukocytes. The height of the pies reflects the numbers of total CD45⁺ leukocytes in one epididymal fat pad, which are significantly increased in obese animals compared to age-matched lean mice. The relative abundances for B cells, Treg, eosinophils, MDSCs, and macrophages are from References 102 and 158–161; the others are from our unpublished data. These pie charts are our attempt to provide a glimpse of the relative abundance of each immune population and its dynamics in obesity. It is by no means precise, as data have been collected from different studies where different experimental methods and analysis tools have been employed. “Other” refers to mast cells, γδ T cells, and other unidentified immune cells. Abbreviations: HFD, high-fat diet; LFD, low-fat diet; MDSC, myeloid-derived suppressor cell; NK, natural killer cell; NKT, natural killer T cell; Treg, regulatory T cells.

Figure 3

Hypothetic models of how inflammation is initiated and developed in obesity. Stress signals such as lipids may signal through (a) TLRs or (b) inflammasomes to activate inflammatory pathways, which may be responsible for the downregulation of insulin signaling. (c) Lipids may downregulate inflammation via the activation of transcription factor PPAR. (d ) Stress signals induce adipocyte death, from which cell debris may be phagocytosed by macrophages and influence inflammation. (e) Lipids may promote ER stress and UPR, which may lead to the activation of JNK and NF-κB and consequently induce inflammation and attenuate insulin signaling. ( f ) Gut microbiota may influence inflammatory responses in the host by the release of LPS, SCFAs, and PG, which subsequently activate TLR4, GPR43, and NOD1 receptors, respectively. Lipid antigens derived from microbiota may also alter the activation status of NKT cells. Gut microbiota may influence the secretion of Angptl4 from enterocytes, which inhibits LPL activity and lipid uptake in macrophages. Abbreviations: Angptl4, angiopoietin-like 4; AP1, activator protein 1; ER, endoplasmic reticulum; GPR43, G protein–coupled receptor 43; JNK, c-Jun N-terminal kinases; LPL, lipoprotein lipase; LPS, lipopolysaccharide; NF-κB, nuclear factor-κB; NKT, natural killer T cells; NOD1, nucleotide-binding oligomerization domain-containing 1; PG, peptidoglycan; PPAR, peroxisome proliferator-activated receptor; ROS, reactive oxygen species; SCFAs, short-chain fatty acids; STAT, signal transducer and activator of transcription; TLR, Toll-like receptor; UPR, unfolded protein response.

Figure 4

Activation of NLRP3 inflammasomes. Two signals are required for the maturation of proinflammatory cytokines IL-1β and IL-18: transcriptional induction of pro-IL-1β and IL-18, and the activation of inflammasomes. Upon activation, NLRP3 oligomerizes and recruits PYD-containing adaptor ASC, whose CARD domain in turn recruits procaspase-1. Autocleavage of procaspase-1 leads to the formation of the active caspase-1 p10/p20 tetramers, which in turn splice inactive cytokines such as pro-IL-1β and pro-IL-18 to generate active molecules. Potential activating signals are indicated. Abbreviations: ASC, apoptosis-associated speck-like protein containing a carboxy-terminal CARD; ATP, adenosine triphosphate; IL, interleukin; LPS, lipopolysaccharide; LRR, leucine-rich repeat; NACHT, nucleotide-binding and oligomerization domain; NLRP3, NLR family, pyrin domain–containing 3; PYD, pyrin domain; ROS, reactive oxygen species; TLR, Toll-like receptor.