No abstract

Objective-Obesity is associated with an increased risk for cardiovascular disease. Although it is known that white adipose tissue (WAT) produces numerous proinflammatory and proatherogenic cytokines and chemokines, it is unclear whether adipose-derived chemotactic signals affect the chronic inflammation in atherosclerosis. Methods and Results-Histological examination showed that perivascular WAT (pWAT) is in close proximity to vascular walls, particularly at sites that have a tendency to develop atherosclerosis. In rodents, the amount of pWAT is markedly increased by a high-fat diet. At a functional level, supernatant from subcutaneous and pWAT strongly induced the chemotaxis of peripheral blood leukocytes. The migration of granulocytes and monocytes was mostly mediated by interleukin-8 and monocyte chemoattractant protein-1, respectively, whereas both chemokines contributed to the migration of activated T cells. Moreover, pWAT produces these chemokines, as shown by immunohistochemistry and by explant culture. The accumulation of macrophages and T cells at the interface between pWAT and the adventitia of human atherosclerotic aortas may reflect this prochemotactic activity of pWAT. Conclusions-Human pWAT has chemotactic properties through the secretion of different chemokines, and we propose that pWAT might contribute to the progression of obesity-associated atherosclerosis. (Arterioscler Thromb Vasc Biol. 2005;25:2594-2599.)Key Words: chemokines Ⅲ perivascular adipose tissue Ⅲ chemotaxis Ⅲ obesity Ⅲ inflammation O besity is characterized by an excess of body fat and is associated with an increased risk for cardiovascular disease. 1 Obesity is also linked to a state of chronic inflammation 2 associated with the production of pro-and antiinflammatory cytokines secreted by white adipose tissue (WAT), such as interleukin (IL)-6, tumor necrosis factor (TNF)-␣, IL-1␤, and the IL-1 receptor antagonist. 3 WAT is also known to produce chemokines such as IL-8 (also called CXCL8) 4,5 and monocyte chemoattractant protein-1 (MCP-1, also called CCL2). 5,6 Atherosclerosis is characterized by the accumulation of macrophages and T lymphocytes in the wall of large arteries, a process in which chemokines play an important role. 7,8 Many of the chemoattractant factors involved in the development of atherosclerosis are expressed in the atherosclerotic plaque and produced by endothelial and smooth muscle cells. 8 The importance of chemokines in the development of atherosclerosis has been demonstrated in a low-density lipoprotein (LDL) receptor-deficient mouse model where the invalidation of the MCP-1 gene prevented lipid deposition and macrophage infiltration in the aortic wall. 8 Similarly, irradiated LDL receptor-deficient mice received a transplant of bone marrow cells lacking the CXCR2 (murine IL-8 homologue receptor), resulting in the reduced accumulation of monocytes/macrophages in the vascular intima. 9 Because obesity is a metabolic and chronic inflammatory condition associated with cardiovascular complications, it is tempti...

Interleukin (IL)-1 is a regulator of inflammation but is also implicated in the control of energy homeostasis. Because the soluble IL-1 receptor antagonist (IL-1Ra) is markedly increased in the serum of obese patients and is overexpressed in white adipose tissue in obesity, we studied the metabolic consequences of genetic IL-1Ra ablation in mice. We have shown that IL-1Ra ؊/؊ mice have a lean phenotype due to decreased fat mass, related to a defect in adipogenesis and increased energy expenditure. The adipocytes were smaller in these animals, and the expression of genes involved in adipogenesis was reduced. Energy expenditure as measured by indirect calorimetry was elevated, and weight loss in response to a 24-h fast was increased in IL-1Ra ؊/؊ animals compared with wild-type mice. Lipid oxidation of IL-1Ra ؊/؊ mice was higher during the light period, reflecting their reduction in diurnal food intake. Interestingly, IL-1Ra؊/؊ and IL-1Ra ؉/؊ mice presented an attenuation in high-fat diet-induced caloric hyperphagia, indicating a better adaptation to hypercaloric alimentation, which is in line with the role of IL-1Ra as a mediator of leptin resistance. Taken together, we show that IL-1Ra is an important regulator of adipogenesis, food intake, and energy expenditure. Diabetes 54: [3503][3504][3505][3506][3507][3508][3509] 2005