Atherosclerotic cardiovascular disease is a common consequence of type 2 diabetes and the metabolic syndrome, both of which are associated with visceral obesity, adipose tissue inflammation, insulin resistance, dyslipidemia and atherosclerosis. We have used in vitro and in vivo models to help understand the link between obesity and these downstream consequences. Adipocyte hypertrophy induced in vitro by exposure of differentiated 3T3-L1 cells to high glucose conditions or certain saturated fatty acids results in increased expression of the monocyte chemotactic factors, MCP-1 and the extra- hepatic isoform of serum amyloid A (SAA), SAA3. Stimulation of expression of these molecules requires generation of reactive oxygen species by NADPH oxidase 4 and activation of NFκB. Similar changes in adipose tissue were evoked in vivo by feeding LDL receptor deficient mice a high fat, high sucrose cholesterol-containing diet, which resulted in adipocyte hypertrophy, obesity, and macrophage accumulation in visceral fat. MCP-1 and SAA expression increased, consistent with these molecules playing a role in macrophage recruitment to adipose tissue. Moreover, the mice became insulin resistant, had evidence of systemic inflammation (with increased levels of the hepatic isoform of SAA) and developed atherosclerosis. These findings suggest that diet-induced obesity and adipose tissue inflammation can lead to insulin resistance and atherosclerosis by a mechanism that involves the local production of MCP-1 and SAA in adipose tissue.