Background-Obesity is associated with chronic inflammation, which includes increased macrophage accumulation in adipose tissue (AT) and upregulation of chemokines and cytokines. T cells also play important roles in chronic inflammatory diseases such as atherosclerosis but have not been well studied in obesity. Methods and Results-Flow cytometric analysis showed higher numbers of T cells and macrophages in AT of diet-induced obese insulin-resistant male mice than in lean mice and obese females (PϽ0.05). RNase protection assay, ELISA, and flow cytometry indicated gender-dependent upregulation of mRNA and protein levels of regulated on activation, normal T cell expressed and secreted (RANTES) and its receptor CCR5 in AT of obese mice. Adipocytes, stromal/vascular cells from mouse AT, and human and murine adipocytes expressed RANTES. RANTES mRNA levels were negatively correlated with adiponectin in mouse AT. Adiponectin-deficient mice fed high-fat diet showed higher RANTES mRNA levels in AT than wild-type mice. Activated T cells coincubated with preadipocytes in vitro significantly suppressed preadipocyte-to-adipocyte differentiation. Obese humans with metabolic syndrome had higher mRNA levels of RANTES and CCR5 in subcutaneous AT than lean humans. RANTES and CCR5 mRNA levels were significantly higher in visceral than subcutaneous AT of morbidly obese humans. RANTES mRNA levels were positively correlated with CD3 and CD11b in human visceral AT. Conclusions-Obesity is associated with increased accumulation of T cells and macrophages in AT, which may play important roles in obesity-related disease by influencing preadipocyte/adipocyte functions. RANTES is an adipokine that is upregulated in AT by obesity in both mice and humans.

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.

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.

Background-Monocyte activation and migration into the arterial wall are key events in atherogenesis associated with hypercholesterolemia. CD11c/CD18, a ␤ 2 integrin expressed on human monocytes and a subset of mouse monocytes, has been shown to play a distinct role in human monocyte adhesion on endothelial cells, but the regulation of CD11c in hypercholesterolemia and its role in atherogenesis are unknown. Methods and Results-Mice genetically deficient in CD11c were generated and crossbred with apolipoprotein E (apoE) Ϫ/Ϫ mice to generate CD11c Ϫ/Ϫ /apoE Ϫ/Ϫ mice. Using flow cytometry, we examined CD11c on blood leukocytes in apoE Ϫ/Ϫ hypercholesterolemic mice and found that compared with wild-type and apoE Ϫ/Ϫ mice on a normal diet, apoE Ϫ/Ϫ mice on a Western high-fat diet had increased CD11c ϩ monocytes. Circulating CD11c ϩ monocytes from apoE Ϫ/Ϫ mice fed a high-fat diet exhibited cytoplasmic lipid vacuoles and expressed higher levels of CD11b and CD29. Deficiency of CD11c decreased firm arrest of mouse monocytes on vascular cell adhesion molecule-1 and E-selectin in a shear flow assay, reduced monocyte/macrophage accumulation in atherosclerotic lesions, and decreased atherosclerosis development in apoE Ϫ/Ϫ mice on a high-fat diet. Conclusions-CD11c, which increases on blood monocytes during hypercholesterolemia, plays an important role in monocyte recruitment and atherosclerosis development in an apoE Ϫ/Ϫ mouse model of hypercholesterolemia. Key Words: atherosclerosis Ⅲ cell adhesion molecules Ⅲ leukocytes A therosclerosis associated with hypercholesterolemia is a complex inflammatory process, characterized pathologically by recruitment of monocytic leukocytes in the arterial wall and lipid accumulation in monocytic leukocytes. 1 Monocyte recruitment is a multistep process mediated by adhesion molecules, beginning with rolling, which is mediated by short-lived bonds between E-selectin on endothelial cells (ECs) and sialylated ligands such as P-selectin glycoprotein ligand-1 on monocytes, followed by firm arrest facilitated through interactions between activated ␤ 1 and ␤ 2 integrins on monocytes with vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) on ECs. Firmly arrested monocytes subsequently undergo transmigration through other adhesion molecules. 2,3 Therefore, adhesion molecules participating in monocyte-EC interactions play a critical role in atherogenesis. 4 EC activation induced by hypercholesterolemia increases expression of VCAM-1, ICAM-1, and E-selectin, thereby contributing to atherogenesis. 4 -6 However, the effect of hypercholesterolemia on monocyte activation and its contribution to atherogenesis are less defined. Clinical Perspective on p 2717The ␤ 2 integrins, which include CD11a/CD18, CD11b/ CD18, CD11c/CD18, and CD11d/CD18, 7 contribute to atherogenesis as evidenced by a significant reduction in atherosclerosis development in CD18 Ϫ/Ϫ mice, which lack all 4 CD11/CD18 integrins. 4 CD11b has been used as an activation marker for monocytes/macrophages...