The prevalence of obesity has increased epidemically, with little hope for effective treatments on the horizon. Rising along with obesity is an aggregation of comorbidities including insulin resistance, hepatosteatosis, dyslipidemia, hypertensionc, coagulopathy, and atherosclerosis known as the cardiometabolic syndrome. With the extent of obesity in an increasingly aging world population, this field begs for further research into the biological consequences of obesity and the associated pathologies. These chronic diseases are profoundly influenced by pathways that lie at the interface of metabolism and inflammation. Despite intense research into the crosstalk between metabolic and inflammatory pathways, there remains a gap in our knowledge regarding the nutritional modification of this crosstalk. What are the nutritional cues that can beneficially modify this crosstalk? Bioactive lipokines offer tools to study this question in depth. This application will address the nutritional modification of the crosstalk between metabolism, inflammation and stress pathways that has been shown to be a major contributor to the formation of atherosclerosis. In this application we propose to study the impact of a lipokine, palmitoleate, on atherosclerosis. Recent studies have shown that palmitoleate, has profound effects on metabolism. Lipokines can be generated from the adipose tissue and exert endocrine effects in distant tissues such as the liver and skeletal muscle. At the cellular level, palmitoleate can enhance insulin signaling and block metabolic stress pathways that could drive inflammation. Here, we will investigate the impact of palmitoleate on atherosclerosis in mice and study the mechanisms of palmitoleate action in major cell types that contribute to atherogenesis. Discoveries arising from this study could have important implications for the understanding the pathogenesis of atherosclerosis and generation of new therapeutic approaches to this devastating disease.