Site-specific effects of apolipoprotein E expression on diet-induced obesity and white adipose tissue metabolic activation

Apolipoprotein E (APOE) has been strongly implicated in the development of diet induced obesity. In the present study, we investigated the contribution of brain and peripherally expressed human apolipoprotein E3 (APOE3), the most common human isoform, to diet induced obesity. In our studies APOE3 knock-in (Apoe3(knock-in)), Apoe-deficient (apoe(-/-)) and brain-specific expressing APOE3 (Apoe3(brain)) mice were fed western-type diet for 12 week and biochemical analyses were performed. Moreover, AAV-mediated gene transfer of APOE3 to apoe(-/-) mice was employed, as a means to achieve APOE3 expression selectively in periphery, since peripherally expressed APOE does not cross blood brain barrier (BBB) or blood cerebrospinal fluid barrier (BCSFB). Our data suggest a bimodal role of APOE3 in visceral white adipose tissue (WAT) mitochondrial metabolic activation that is highly dependent on its site of expression and independent of postprandial dietary lipid deposition. Our findings indicate that brain APOE3 expression is associated with a potent inhibition of visceral WAT mitochondrial oxidative phosphorylation, leading to significantly reduced substrate oxidation, increased fat accumulation and obesity. In contrast, peripherally expressed APOE3 is associated with a notable shift of substrate oxidation towards non-shivering thermogenesis in visceral WAT mitochondria, leading to resistance to obesity.