Background and Aims:
We investigated the role of natural human APOE isoforms, APOE2, APOE3 and APOE4 on diet-induced obesity and related perturbations of plasma glucose metabolism. Epidemiological studies suggested that APOE is associated with the development and progression of coronary heart disease in humans. More recent studies in mice suggest a link between Apoe and obesity. Interestingly our data showed that brain APOE3 expression leads to a potent inhibition of visceral WAT mitochondrial oxidative phosphorylation that in turn leads to significantly reduced substrate oxidation, increased fat accumulation and obesity. To the contrary, peripherally expressed APOE is associated with a notable shift of substrate oxidation towards non-shivering thermogenesis in visceral WAT mitochondria, associated with resistance to obesity.

Methods:
Groups of Apoe2knock-in, Apoe3knock-in, and Apoe4knock-in mice were formed and fed high-fat diet for 18 weeks.

Results
Our data show that Apoe2knock-in mice are more sensitive to diet-induced obesity compared to Apoe3knock-in and Apoe4knock-in. This increased sensitivity is not the result of increased peripheral deposition of dietary lipids or decreased metabolic activity of white and brown adipose tissues. Rather it appears that APOE2 isoform increases daily caloric intake. Surprisingly, the obesity of Apoe2knock-in mice fed high-fat diet for 18 weeks is not associated with any measurable disturbance of plasma glucose homeostasis. On the contrast, Apoe4knock-in mice which gained less weight than Apoe2knock-in showed disturbed glucose tolerance due to reduced sensitivity of skeletal muscle to insulin.

Conclusions:
Our data support isoform-specific effects of APOE on body weight gain and glucose metabolism. The precise mechanisms are currently under investigation.

02 - ISOFORM-SPECIFIC EFFECTS OF APOE ON BODY WEIGHT GAIN AND GLUCOSE METABOLISM