Obesity is a central feature of the
metabolic syndrome and is associated with increased risk for
insulin resistance and typeII diabetes. Here, we investigated the contribution of human apoliproteinE3 and mouse apoliproteinE to the development of diet-induced
obesity in response to western-type diet. Our data show that apolipoproteinE contributes to the development of
obesity and other related metabolic disorders, and that human apolipoproteinE3 is more potent than mouse apolipoproteinE in promoting
obesity in response to western-type diet. Specifically, we found that apolipoproteinE3 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, apolipoproteinE-deficient mice fed western-type 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 apolipoproteinE on
obesity. Taken together, our findings suggest that, in addition to other previously identified mechanisms of
obesity, apolipoproteinE and possibly the
chylomicron pathway are also important contributors to the development of
obesity and related metabolic dysfunctions in mice.