Smokers exhibit a high degree of cardiovascular mortality. This is surprising considering both smoking and nicotine cause weight loss and the weight loss should be protective against cardiovascular disease. A major advance in the understanding of the relationship between smoking and cardiovascular disease came from a study showing that smokers are more insulin resistant and have dyslipidemia compared to non-smokers. Later, it was demonstrated that nicotine is the likely component in cigarette smoke leading to insulin resistance. In spite of the formative data between smoking and insulin resistance and the public health mplications of this connection, there is a paucity of studies exploring the mechanisms of thenicotine-induced nsulin resistance in rodents. As nicotine and cigarette smoking induce hypercortisolemia and glucocorticoid jxcess is known to induce insulin resistance, it has been suggested that glucocorticoids are the missing link between cigarette smoking and insulin resistance. However to complicate the matter, recent studies in rodents and humans suggest a role for tissue rather than plasma glucocorticoid excess in the development of obesity and the metabolic syndrome. This occurs via intracellular steroid reactivation of active glucocorticoids in liver and adipose fat by the enzyme, llp-hydroxysteroid dehydrogenase, type 1 (11(3-HSD1). By amplifying intracellular glucocorticoid availability, 11J3-HSD1 has been implicated to be a potent pathophysiological factor leading to insulin resistance and obesity. Additionally, glucocorticoid action is mediated by the glucocorticoid receptor (GR), and thus, up-regulation of GRs can also amplify glucocorticoid action. We wish to explore this exciting relationship between nicotine and tissue glucocorticoids mediating insulin resistance by studyingthe following hypotheses in this pilot (R21) grant: 1) Nicotine induces/exacerbates insulin resistance and its sequelae in normal mice and mice with diet- induced obesity (DIO). 2) The nicotine-induction of insulin resistance is mediated by increased 11|3-HSD1 expression and GR expression leading to increased tissue glucocorticoid action. We expect that these studies will uncover the mechanisms underlyingnicotine-induction of insulin resistance and its sequelae that would provide a rationale basis for preventing some of the devastatingcardiovascular consequences of smoking.