Diet-Induced Increases in Adiposity, but Not Plasma Lipids, Promote Macrophage Infiltration Into White Adipose Tissue

Obesity, hyperlipidemia, and insulin resistance are cardinal features of the metabolic syndrome and individually increase the risk for developing diabetes and cardiovascular disease, a risk that is amplified when they are simultaneously present. It is becoming increasingly clear that macrophages can infiltrate white adipose tissue (WAT) in the obese state, and their presence is associated with pathophysiological consequences of obesity, such as inflammation and insulin resistance. To determine whether hyperlipidemia could potentiate macrophage infiltration into WAT in the presence of obesity, obesity-prone agouti yellow mice (A(y)/a) on a hyperlipidemia-prone LDL receptor (LDLR)-deficient (LDLR(-/-)) background were placed on chow or Western diet. In addition, A(y)/a mice that were LDLR sufficient were also placed on Western diet. Both genetics and diet increased the degree of adiposity; however, plasma lipids were elevated only in the Western diet-fed LDLR(-/-) mice. The extent of macrophage accumulation in WAT correlated with the degree of adiposity. However, hyperlipidemia did not impact macrophage recruitment to WAT or the downstream metabolic consequences of macrophage accumulation in WAT, such as inflammation and insulin resistance. These data have important implications for the pathogenesis of diet-induced obesity in humans, even when plasma lipid abnormalities are not present.