Obesity is accompanied by chronic, low-grade inflammation of adipose tissue, which promotes insulin resistance and type-2 diabetes. How does fat inflammation escape the powerful armamentarium of cells and molecules normally responsible for guarding against a run-away immune response? Regulatory CD4 + T cells expressing the transcription factor Foxp3 (termed T reg cells) are a lymphocyte lineage specialized in controlling immunologic reactivity. T reg cells with a unique phenotype were highly enriched in the abdominal fat of normal mice, but were strikingly and specifically reduced at this site in insulin-resistant models of obesity. In loss-offunction and gain-of-function experiments, T reg cells regulated the inflammatory state of adipose tissue and insulin resistance. Cytokines differentially synthesized by fat-resident regulatory and conventional T cells directly impacted on the synthesis of inflammatory mediators and glucose uptake by cultured adipocytes. These findings open the door to harnessing the anti-inflammatory properties of T reg cells to inhibit elements of the metabolic syndrome.

Regular physical activity improves glucose tolerance and decreases adiposity. Our aim was to investigate the effects of exercise training on subcutaneous (inguinal) and visceral (parametrial) adipose tissue in rats that were fed a chow diet (13% fat) or made insulin resistant by a high-fat diet (60% fat). Sprague-Dawley rats performed 4 wk of voluntary wheel running or were kept as sedentary controls. The training groups fed chow and the high-fat diet achieved similar running distances (8.8 +/- 1.8 and 9.3 +/- 1.9 km/day, respectively). Training improved oral glucose tolerance in chow-fed rats and prevented the glucose intolerance that occurred in sedentary rats fed the high-fat diet. In both subcutaneous and visceral adipose tissue, the high-fat diet-induced increases in fat pad weight (67% and 133%, respectively), adipocyte size (20% and 43%), and cell number (36% and 65%) were completely prevented by exercise training. Cytokine mRNA expression in visceral fat did not change with exercise training. However, in subcutaneous fat, training actually increased mRNA expression of several cytokines [IL-6: 80% (P < 0.05); TNF-alpha: 100% (P < 0.05); IL-1 receptor antagonist (IL-1Ra): 57% (P = 0.08)] with no detectable increases in serum cytokine concentrations. In summary, exercise training can overcome high-fat diet-induced impairments in glucose tolerance and increases in adipocyte size, cell number, and fat pad mass. Improved glucose tolerance was accompanied by an increase in cytokine gene expression in subcutaneous fat. This finding raises the possibility of a specific role of subcutaneous adipose tissue in adaptive responses to exercise training.

The integrin CD11b/CD18 (also known as Mac-1), which is a heterodimer of the αM (CD11b) and β2 (CD18) subunits, is critical for leukocyte adhesion and migration and for immune functions. Blocking integrin-mediated leukocyte adhesion, although beneficial in experimental models, has had limited success in treating inflammatory diseases in humans. Here, we used an alternative strategy of inhibiting leukocyte recruitment by activating CD11b/CD18 with small-molecule agonists, which we term leukadherins. These compounds increased the extent of CD11b/CD18-dependent cell adhesion of transfected cells and of primary human and mouse neutrophils, which resulted in decreased chemotaxis and transendothelial migration. Leukadherins also decreased leukocyte recruitment and reduced arterial narrowing after injury in rats. Moreover, compared to a known integrin antagonist, leukadherins better preserved kidney function in a mouse model of experimental nephritis. Leukadherins inhibited leukocyte recruitment by increasing leukocyte adhesion to the inflamed endothelium, which was reversed with a blocking antibody. Thus, we propose that pharmacological activation of CD11b/CD18 offers an alternative therapeutic approach for inflammatory diseases.

This article is available online at http://www.jlr.org is of grave consequence to human health. In fact, cardiovascular diseases, mostly as a result of long-standing metabolic dysregulations, are the leading cause of morbidity and mortality in many parts of the world.The pathogenesis of obesity-linked insulin resistance is only partially understood. Accumulating evidence has revealed a strong association between obesity-linked insulin resistance and infl ammation ( 2 ). Tumor necrosis factor-a (TNF-a ), a prototypical pro-infl ammatory cytokine, was upregulated in the epididymal fat of obese rodents, and neutralization of TNF-a ameliorated insulin resistance ( 3 ). Moreover, obese mice lacking TNF-a demonstrated improved insulin sensitivity ( 4 ). In addition, increased numbers of macrophages and their transcripts were reported in the epididymal fat of genetically and dietinduced obese (DIO) mice ( 5, 6 ). These adipose tissue macrophages (ATM) were found scattered between adipocytes (herein referred to as solitary ATM ) or forming clusters around adipocytes. Based on ultrastructural and immunohistochemical alterations, it was argued that most ATM in obese mice and humans surround dead adipocytes, forming so-called crown-like structures (CLS) ( 7 ). Subsequently, we reported that CLS were distributed differentially in abdominal fat depots of DIO mice ( 8 ). Consistent with our fi ndings, it was recently reported that CLS were also more prevalent in visceral than subcutaneous fat of leptin-defi cient ob/ob and leptin receptor-defi cient db/db mice ( 9 ).Although macrophages are critical in innate and adaptive immunity, most immune responses are the result of interplay between multiple cell types and mediators of the immune system ( 10 ). Therefore, it comes as no surprise to learn that regulatory T cells ( 11 ), CD8+ effector T cells Over the past several decades a steady increase in the prevalence of obesity across the continents, especially in the US, has been observed ( 1 ). Increased caloric intake, mostly due to consumption of a high-fat diet, and decreased physical activity seem to be major contributors. Insulin resistance, hypertension, and dyslipidemia often accompany obesity. The constellation, referred to as metabolic syndrome, This work was supported by generous funds from the Katz Family Foundation.