Obesity and its related pathologies constitute a major cause of death, with rates increasing at an alarming pace [1]. By the beginning of the millennium, overweight adults accounted for over 15% of the world's population (body mass index > 30, World Health Organization) [2], with this number increasing to 50% within the USA and Europe [3]. Obesity develops as a result of disruption of the homeostasis between food intake and energy expenditure, and therefore factors affecting these processes are the focus of extensive Obesity is a central feature of the metabolic syndrome and is associated with increased risk for insulin resistance and type II diabetes. Here, we investigated the contribution of human apoliprotein E3 and mouse apoliprotein E to the development of diet-induced obesity in response to western-type diet. Our data show that apolipoprotein E contributes to the development of obesity and other related metabolic disorders, and that human apolipoprotein E3 is more potent than mouse apolipoprotein E in promoting obesity in response to western-type diet. Specifically, we found that apolipoprotein E3 knock-in mice fed western-type diet for 24 weeks became obese and developed hyperglycemia, hyperinsulinemia, hyperleptinemia, glucose intolerance and insulin resistance that were more severe than in C57BL/6 mice. In contrast, apolipoprotein E-deficient mice fed westerntype diet for the same period were resistant to diet-induced obesity, had normal plasma glucose, leptin and insulin levels, and exhibited normal responses to glucose tolerance and insulin resistance tests. Furthermore, low-density lipoprotein receptor-deficient mice were more sensitive to the development of diet-induced obesity and insulin resistance than apolipoprotein E-deficient mice, but were still more resistant than C57BL/6 mice, raising the possibility that low-density lipoprotein receptor mediates, at least in part, the effects of apolipoprotein E on obesity. Taken together, our findings suggest that, in addition to other previously identified mechanisms of obesity, apolipoprotein E and possibly the chylomicron pathway are also important contributors to the development of obesity and related metabolic dysfunctions in mice. , LDLrdeficient; LpL, lipoprotein lipase; VLDL, very low-density lipoprotein.