Accumulation of inflammatory macrophages is a common feature in adipose tissue (AT) and other metabolic organs and in the atherosclerotic plaque. Diabetes further exacerbates macrophage content and inflammation, which in mouse models impairs atherosclerosis regression; and in obesity, drives insulin resistance. The overarching hypothesis of this Program is that there are factors and pathways underlying macrophage accumulation and inflammation in atherosclerotic plaques and AT that are tissue site-independent, representing common mechanisms, as well as tissue site-dependent, representing discrete regulation by the local micro-environments. Our Program will test the mechanisms affecting plaque or AT macrophage content and inflammatory states in diabetes or diet-induced obesity in relation to four key processes: recruitment of monocytes, macrophage retention/stasis, macrophage inflammation/polarization (M1 vs. M2), and macrophage regulation of metabolism. To accomplish this, we have developed three Projects as follows: Project 1 will test these concepts in diabetic atherosclerosis in the context of impaired regression after reduction of hyperlipidemia; and Projects 2 and 3 will test these concepts in diet-induced obesity mediated by high fat feeding. In this highly synergistic Program, through coordinated and systematic studies, each Project will identify the connections, cross talk, and regulatory hierarchies in the diabetic and pre-diabetic insulin resistant states by which candidate and novel factors drive macrophage content and inflammation. By comparing the results across the plaque and AT, we will identify those pathways that underlie both common and distinct mechanisms. All three Projects will test the relevance of findings in mouse macrophages to curated databases of human monocytes/macrophages and of AT macrophages retrieved from lean and obese human subjects. In “proof-of-concept” studies, all three Projects will test novel therapeutic agents targeting the key pathways under study in mouse models in a highly synergistic manner. Taken together, our ultimate goal is to identify novel therapeutic approaches to suppress exaggerated macrophage accumulation and inflammation that contribute to increased clinical cardiovascular risk.