Abstract 4: Apolipoprotein A-IV Confers Protection Against Oxidant Stress and Adipose Tissue Inflammation in Mouse Models of Obesity

Abstract

Background: Increased lipid oxidation may initiate the chronic inflammatory state which characterizes adipose tissue in obesity. Apo A-IV is a potent in vitro antioxidant, and has been reported to confer protection against multiple inflammatory stimuli in vivo. Apo A-IV may be an especially effective antioxidant in peripheral tissues, as its labile affinity for lipoproteins results in relatively high concentrations in interstitial fluid. Hypothesis: Apo A-IV attenuates lipid peroxidation and adipose tissue inflammation in mouse models of obesity. Methods: Double heterozygote A4+/- x Ob+/- mice on a C57BL6 background were bred to generate wild type (WT), apo A-IV knockout (A4KO), Ob/Ob, and double knockout (DKO) mice. Groups of age-matched male littermates were fed pro-inflammatory high fat (HF, 42% fat, 0.2% cholesterol) or high fat/high cholesterol (HFHC, 38% fat, 1.25% cholesterol) diets; fasting plasma apo A-IV levels were measured by immunoblotting; plasma total F2 isoprostane levels (a biomarker of global lipid peroxidation) were measured by GC-MS; and expression of genes for pro-inflammatory mediators in adipose tissue was measured in WT and A4KO mice by RT-PCR. Results: Baseline plasma apo A-IV levels were higher in the Ob/Ob mice, but increased ~2-fold after 8 weeks on the HF diet. After 12 weeks on the HFHC diet, plasma total F2 isoprostane levels were elevated in Ob/Ob mice, but were highest in DKO mice, indicating that free radical lipid peroxidation in peripheral tissues was increased in the absence of intestinal apo A-IV synthesis. All mice gained weight, but DKO mice gained less than Ob/Ob mice. Adipose tissue expression of the genes for MCP1, IL6, and IL1b was elevated 2-3 fold in A4KO mice. Conclusions: These data indicate that plasma apo A-IV levels are chronically elevated by a high fat intake, and that apo A-IV expression attenuates the pro-oxidant/pro-inflammatory state in diet-induced and genetic obesity, which may thereby modulate energy balance.