Obesity is becoming an epidemic in the United States and worldwide and increases risk for many diseases, particularly insulin resistance, type 2 diabetes mellitus, and cardiovascular disease. The mechanisms linking obesity with these diseases remain incompletely understood. Over the past 2 to 3 decades, it has been recognized that in obesity, inflammation, with increased accumulation and inflammatory polarization of immune cells, takes place in various tissues, including adipose tissue, skeletal muscle, liver, gut, pancreatic islet, and brain and may contribute to obesity-linked metabolic dysfunctions, leading to insulin resistance and type 2 diabetes mellitus. Therapies targeting inflammation have shed light on certain obesity-linked diseases, including type 2 diabetes mellitus and atherosclerotic cardiovascular disease, but remain to be tested further and confirmed in clinical trials. This review focuses on inflammation in adipose tissue and its potential role in insulin resistance associated with obesity.

Obesity is associated with chronic inflammation, which contributes to insulin resistance and type 2 diabetes mellitus. Under normal conditions, skeletal muscle is responsible for the majority of insulin-stimulated whole-body glucose disposal; thus, dysregulation of skeletal muscle metabolism can strongly influence whole-body glucose homeostasis and insulin sensitivity. Increasing evidence suggests that inflammation occurs in skeletal muscle in obesity and is mainly manifested by increased immune cell infiltration and proinflammatory activation in intermyocellular and perimuscular adipose tissue. By secreting proinflammatory molecules, immune cells may induce myocyte inflammation, adversely regulate myocyte metabolism, and contribute to insulin resistance via paracrine effects. Increased influx of fatty acids and inflammatory molecules from other tissues, particularly visceral adipose tissue, can also induce muscle inflammation and negatively regulate myocyte metabolism, leading to insulin resistance.

Adipose tissue performs immunoregulatory functions in addition to fat storage. Various T cells in different fat depots either help maintain metabolic homeostasis under healthy conditions or contribute to metabolic disorders in pathological conditions such as obesity, diabetes, cardiovascular diseases, or even cancer. These T cells play critical roles in immunometabolism, which refers to the intersection of immunity and metabolism. Numerous studies have examined the presence and changes of different T cell subsets, including helper T cells, regulatory T cells, cytotoxic T cells, and natural killer T cells, in adipose depots in health and diseases. In this review, we will discuss the adipose tissue niches that influence the patterns and functions of T cell subsets and in turn the impact of these T cells on cell- or body-based immunometabolism accounting for health and obesity.

Objective—: To examine infiltration of blood foamy monocytes, containing intracellular lipid droplets, into early atherosclerotic lesions and its contribution to development of nascent atherosclerosis. Approach and Results—: In apoE ^–/– mice fed Western high-fat diet (WD), >10% of circulating monocytes became foamy monocytes at 3 days on WD and >20% of monocytes at 1 week. Foamy monocytes also formed early in blood of Ldlr ^–/– Apobec1 ^–/– (LDb) mice on WD. Based on CD11c and CD36, mouse monocytes were categorized as CD11c ^– CD36 ^– , CD11c ^– CD36 ⁺ , and CD11c ⁺ CD36 ⁺ . The majority of foamy monocytes were CD11c ⁺ CD36 ⁺ , whereas most nonfoamy monocytes were CD11c ^– CD36 ^– or CD11c ^– CD36 ⁺ in apoE ^–/– mice on WD. In wild-type mice, CD11c ⁺ CD36 ⁺ and CD11c ^– CD36 ⁺ , but few CD11c ^– CD36 ^– , monocytes took up cholesteryl ester–rich very low-density lipoproteins (CE-VLDLs) isolated from apoE ^–/– mice on WD, and CE-VLDL uptake accelerated CD11c ^– CD36 ⁺ to CD11c ⁺ CD36 ⁺ monocyte differentiation. Ablation of CD36 decreased monocyte uptake of CE-VLDLs. Intravenous injection of DiI-CE-VLDLs in apoE ^–/– mice on WD specifically labeled CD11c ⁺ CD36 ⁺ foamy monocytes, which infiltrated into nascent atherosclerotic lesions and became CD11c ⁺ cells that were selectively localized in atherosclerotic lesions. CD11c deficiency reduced foamy monocyte infiltration into atherosclerotic lesions. Specific and consistent depletion of foamy monocytes (for 3 weeks) by daily intravenous injections of low-dose clodrosome reduced development of nascent atherosclerosis. Conclusions—: Foamy monocytes, which form early in blood of mice with hypercholesterolemia, infiltrate into early atherosclerotic lesions in a CD11c-dependent manner and play crucial roles in nascent atherosclerosis development.

Objective—: T cells, particularly CD8 ⁺ T cells, are major participants in obesity-linked adipose tissue (AT) inflammation. We examined the mechanisms of CD8 ⁺ T-cell accumulation and activation in AT and the role of CD11a, a β2 integrin. Approach and Results—: CD8 ⁺ T cells in AT of obese mice showed activated phenotypes with increased proliferation and interferon-γ expression. In vitro, CD8 ⁺ T cells from mouse AT displayed increased interferon-γ expression and proliferation to stimulation with interleukin-12 and interleukin-18, which were increased in obese AT. CD11a was upregulated in CD8 ⁺ T cells in obese mice. Ablation of CD11a in obese mice dramatically reduced T-cell accumulation, activation, and proliferation in AT. Adoptive transfer showed that CD8 ⁺ T cells from wild-type mice, but not from CD11a-deficient mice, infiltrated into AT of recipient obese wild-type mice. CD11a deficiency also reduced tumor necrosis factor-α–producing and interleukin-12–producing macrophages in AT and improved insulin resistance. Conclusions—: Combined action of cytokines in obese AT induces proliferative response of CD8 ⁺ T cells locally, which, along with increased infiltration, contributes to CD8 ⁺ T-cell accumulation and activation in AT. CD11a plays a crucial role in AT inflammation by participating in T-cell infiltration and activation.

Similar to obesity, aging is associated with visceral adiposity and insulin resistance. Inflammation in adipose tissue, mainly evidenced by increased accumulation and proinflammatory polarization of T cells and macrophages, has been well documented in obesity and may contribute to the associated metabolic dysfunctions including insulin resistance. Studies show that increased inflammation, including inflammation in adipose tissue, also occurs in aging, so-called “inflamm-aging.” Aging-associated inflammation in adipose tissue has some similarities but also differences compared to obesity-related inflammation. In particular, conventional T cells are elevated in adipose tissue in both obesity and aging and have been implicated in metabolic functions in obesity. However, the changes and also possibly functions of regulatory T cells (Treg) in adipose tissue are different in aging and obesity. In this review, we will summarize recent advances in research on the changes of these immune cells in adipose tissue with aging and obesity and discuss their possible contributions to metabolism and the potential of these immune cells as novel therapeutic targets for prevention and treatment of metabolic diseases associated with aging or obesity.