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.

Neutrophil emigration in the lung differs substantially from that in systemic vascular beds where extravasation occurs primarily through postcapillary venules. Migration into the alveolus occurs directly from alveolar capillaries and appears to progress through a sequence of steps uniquely influenced by the cellular anatomy and organization of the alveolar wall. The cascade of adhesive and stimulatory events so critical to the extravasation of neutrophils from postcapillary venules in many tissues is not evident in this setting. Compelling evidence exists for unique cascades of biophysical, adhesive, stimulatory, and guidance factors that arrest neutrophils in the alveolar capillary bed and direct their movement through the endothelium, interstitial space, and alveolar epithelium. A prominent path accessible to the neutrophil appears to be determined by the structural interactions of endothelial cells, interstitial fibroblasts, as well as type I and type II alveolar epithelial cells.

Obesity and its associated comorbidities, termed metabolic syndrome, are increasingly prevalent, and they pose a serious threat to the health of individuals and populations. Gene-environment interactions have been scrutinized since the kinetics of the increased prevalence of obesity would argue against a purely genetic etiology. Toll-like receptors (TLRs), widely expressed and highly conserved transmembrane receptors, are at the intersection of diet and metabolism, and may therefore be important determinants of weight gain and its sequellae. We sought specifically to determine the role of Tlr2 in the development of obesity and metabolic syndrome utilizing two dietary models that approximate contemporary diet compositions. Using C57BL/6 Hsd mice (wild type, WT) and mice with a targeted mutation in Tlr2 (Tlr2(-/-)), we showed that mice lacking TLR2 are substantially protected from diet-induced adiposity, insulin resistance, hypercholesterolemia, and hepatic steatosis. In adipose tissue, Tlr2 deletion was associated with attenuation of adipocyte hypertrophy, as well as diminished macrophage infiltration and inflammatory cytokine expression.-Himes, R. W., Smith, C. W. Tlr2 is critical for diet-induced metabolic syndrome in a murine model.

Objective-To examine CD11c, a ␤ 2 -integrin, on adipose tissue (AT) leukocytes and blood monocytes and its role in diet-induced obesity. Methods and Results-High-fat diet-induced obese C57BL/6 mice, CD11c-deficient mice, and obese humans were studied. CD11c, leukocytes, and chemokines/cytokines were examined in AT and/or blood by flow cytometry, RNase protection assay, quantitative polymerase chain reaction, or enzyme-linked immunosorbent assay. Obese C57BL/6 mice had increased CD11c in AT and blood compared with lean controls. CD11c messenger RNA positively correlated with monocyte chemoattractant protein 1 in human visceral AT. Obese humans with metabolic syndrome had a higher CD11c level on blood monocytes compared with lean humans. Low-fat diet-induced weight loss reduced blood monocyte CD11c in obese mice and humans. Mouse and human monocyte CD11c levels and mouse AT CD11c messenger RNA correlated with insulin resistance. CD11c deficiency in mice did not alter weight gain but decreased inflammation, evidenced by a lower T-cell number and reduced levels of major histocompatibility complex class II, C-C chemokine ligand 2 (CCL5), CCL4, and interferon ␥ in AT, and ameliorated insulin resistance and glucose intolerance associated with diet-induced obesity. Conclusions-Diet-induced obesity increased CD11c in both AT and blood in mice and humans. CD11c plays an important role in T-cell accumulation and activation in AT, and contributes to insulin resistance associated with obesity. Key Words: inflammation Ⅲ obesity O besity increases the risk for type 2 diabetes and cardiovascular disease. Chronic inflammation, which occurs in obesity, has been acknowledged as an important link between obesity and the development of diabetes and cardiovascular disease. Adipose tissue (AT) synthesizes and secretes proinflammatory substances, such as cytokines, which are upregulated in obesity and may play important roles in mediating obesity-linked insulin resistance. 1 Chemokines, which contribute to inflammation because of their active properties for leukocyte trafficking and activation, have also been shown to be expressed by AT and increased in obesity. 2,3 Along with the increased levels of chemokines, such as monocyte chemoattractant protein (MCP) 1, or CCL2, and regulated on activation, normal T-cell expressed and secreted (RANTES), or CCL5, leukocytes, including macrophages and T cells, are increased in AT in obesity, and increased leukocytes in AT may contribute to obesity-linked metabolic abnormalities. 2,4 -7 Initial studies used CD11b and/or F4/80 to define total macrophages in AT. 4,5 Using mice fed a high-fat diet (HFD) for 3 weeks, we first reported a significant increase in CD11cϩ cells in AT. 8 Subsequently, other investigators reported an accumulation of F4/80 ϩ CD11c ϩ leukocytes in the AT of obese mice. 9,10 CD11c ϩ leukocytes in the AT of obese mice show proinflammatory characteristics of classically activated macrophages (M1) 9,10 and were demonstrated to play an important role in obesity-linked AT inflam...

. ICAM-1 expression in adipose tissue: effects of diet-induced obesity in mice.

The risk for developing NAFLD was high in the overweight Hispanic children. The proportion of "at risk" children was not influenced by gender, age, or maturation. The risk for elevated ALT was predicted by the severity of obesity, central adiposity, hyperinsulinemia, hypertriglyceridemia, elevated thyroid-stimulating hormone, and systemic inflammation.

Objectives High-fat diet (HFD) feeding in mice is characterized by accumulation of αβ T cells in adipose tissue. However, the contribution of αβ T cells to obesity-induced inflammation of skeletal muscle, a major organ of glucose uptake, is unknown. This study was undertaken to evaluate the effect of αβ T cells on insulin sensitivity and inflammatory state of skeletal muscle and adipose tissue in obesity. Furthermore, we investigated whether CD4+IFNγ+ (TH1) cells are involved in skeletal muscle and adipose tissue metabolic dysfunction that accompanies obesity. Methods Mice lacking αβ T cells (T cell receptor beta chain–deficient [TCRb−/−] mice) were fed HFD for 12 weeks. Obesity-induced skeletal muscle and adipose tissue inflammation was assessed by flow cytometry and quantitative RT-PCR. To investigate the effect of TH1 cells on skeletal muscle and adipose tissue inflammation and metabolic functions, we injected 5×105 TH1 cells or PBS weekly over 12 weeks into HFD-fed TCRb−/− mice. We also cultured C2C12 myofibers and 3T3-L1 adipocytes with TH1-conditioned medium. Results We showed that similar to adipose tissue, skeletal muscle of obese mice have higher αβ T cell content, including TH1 cells. TCRb−/− mice were protected against obesity-induced hyperglycemia and insulin resistance. We also demonstrated suppressed macrophage infiltration and reduced inflammatory cytokine expression in skeletal muscle and adipose tissue of TCRb−/− mice on HFD compared to wild-type obese controls. Adoptive transfer of TH1 cells into HFD-fed TCRb−/− mice resulted in increased skeletal muscle and adipose tissue inflammation and impaired glucose metabolism. TH1 cells directly impaired functions of C2C12 myotubes and 3T3-L1 adipocytes in vitro. Conclusions We conclude that reduced adipose tissue and skeletal muscle inflammation in obese TCRb−/− mice is partially attributable to the absence of TH1 cells. Our results suggest an important role of TH1 cells in regulating inflammation and insulin resistance in obesity.

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