Adipose tissue (AT)-derived cytokines are proposed to contribute to obesity-associated vascular insulin resistance. We tested the hypothesis that voluntary physical activity and diet restriction-induced maintenance of body weight would both result in decreased AT inflammation and concomitant improvements in insulin-stimulated vascular relaxation in the hyperphagic, obese Otsuka Long-Evans Tokushima fatty (OLETF) rat. Rats (aged 12 wk) were randomly assigned to sedentary (SED; n ϭ 10), wheel running (WR; n ϭ 10), or diet restriction (DR; n ϭ 10; fed 70% of SED) for 8 wk. WR and DR rats exhibited markedly lower adiposity (7.1 Ϯ 0.4 and 15.7 Ϯ 1.1% body fat, respectively) relative to SED (27 Ϯ 1.2% body fat), as well as improved blood lipid profiles and systemic markers of insulin resistance. Reduced adiposity in both WR and DR was associated with decreased AT mRNA expression of inflammatory genes (e.g., MCP-1, TNF-␣, and IL-6) and markers of immune cell infiltration (e.g., CD8, CD11c, and F4/80). The extent of these effects were most pronounced in visceral AT compared with subcutaneous and periaortic AT. Markers of inflammation in brown AT were upregulated with WR but not DR. In periaortic AT, WR-and DR-induced reductions in expression and secretion of cytokines were accompanied with a more atheroprotective gene expression profile in the adjacent aortic wall. WR, but not DR, resulted in greater insulin-stimulated relaxation in the aorta; an effect that was, in part, mediated by a decrease in insulin-induced endothelin-1 activation in WR aorta. Collectively, we show in OLETF rats that lower adiposity leads to less AT and aortic inflammation, as well as an exercise-specific improvement in insulin-stimulated vasorelaxation. calorie restriction; exercise; gene expression; inflammation; obesity MORE THAN ONE-THIRD OF AMERICANS are obese (38), and the causes underlying the obesity epidemic appear to be largely related to physical inactivity and overnutrition, a set of behaviors increasingly prevalent in our society (5-7, 11, 57). Cumulative evidence indicates that obesity is an important contributor to the development of whole body insulin resistance, Type 2 diabetes, and cardiovascular disease (21). A critical link between obesity and its associated metabolic and cardiovascular diseases is thought to be chronic low-grade systemic inflammation (21). In this regard, recent studies implicate adipose tissue (AT) as a local and systemic source of inflammatory cytokines that may be involved in the instigation of vascular insulin resistance and atherosclerosis associated with obesity (12, 13, 19, 20, 31, 33-36, 45, 46, 51, 55, 56). Indeed, excessive lipid accumulation and enlargement of adipocytes in obesity are associated with infiltration of immune cells into AT, contributing to AT inflammation and subsequent secretion of proinflammatory cytokines (52). A deeper understanding of the influence of lifestyle modifications on AT inflammation and vascular insulin resistance may lead to more effective strategies aimed at prevent...