Resistance to diet induced obesity in the apolipoprotein E deficient mouse is associated with an attenuated transcriptional response in visceral fat

ABSTRACT The apolipoprotein E knockout (EKO) mouse is a well-established model of atherosclerosis. Macrophages in the arterial intima of EKO mice serve a protective role, scavenging oxidatively modified LDL in order to protect cells from toxic free cholesterol. Recent studies have highlighted a similar role for macrophage foam cells in restraining the increased rates of lipolysis in adipose tissue of obese and fasting mice. Interestingly, EKO adipocytes have been shown to have increased rates of lipolysis in vitro . Therefore, the aim of this study was to examine how apoE deficiency might alter the transcriptional response of visceral adipose tissue (VAT) to high fat diet (HFD). EKO mice fed HFD for 24 weeks gained less fat mass and were more insulin sensitive than their wild type (WT) littermates. Metabolic cages showed that HFD EKO mice had increased post-prandial oxygen consumption and increased serum β-hydroxybutyrate. DNA microarrays revealed that EKO VAT was comparatively insensitive to HFD in terms of alterations in gene expression, with only 0.1% of probe sets differentially expressed. In contrast, the VAT of WT mice had a 30 fold more extensive alteration in gene expression (3% of probes sets), characterized predominantly by increased expression of immune cell specific genes. In addition, analysis of a priori determined gene sets revealed broad down-regulation of PPARγ target and fatty acid catabolism genes in WT VAT, and increased expression of lipid storage and cholesterol synthesis genes. In comparison, expression of PPARγ target genes was not down-regulated in EKO VAT and expression of fatty acid oxidation genes was increased. In summary, we report three novel findings with regards to metabolism in the EKO mouse: 1) increased post-prandial oxygen consumption, 2) increased serum β hydroxybutyrate concentrations and 3) a dramatically less robust transcriptional response to HFD in EKO VAT. These findings suggest that limiting adipocyte exposure to dietary fatty acids may be an attractive therapy for diet induced obesity, provided that compensatory mechanisms that prevent hyperlipidemia can be activated.