Abstract 444: Angiotensinogen Influences Metabolic Rate and Metabolome in Plasma and Hepatic Tissue
Background and Objective: Angiotensinogen(AGT) is the only known substrate of the renin-angiotensin system. We have reported previously that mice with whole body reduction of AGT (hypomorphic AGT mice) resists diet-induced weight gain. We have subsequently demonstrated that hepatocyte-derived AGT is primarily responsible for the observed phenotype. In order to define the potential mechanism, we determined the effects of AGT deficiency on metabolic rate in hepatocyte-specific AGT deficient mice (Agthpt-/-) and the metabolome of both plasma and liver in hypomorphic AGT mice.
Methods and Results: Agthpt-/- mice were generated by breeding AGT floxed mice with transgenic mice expressing Cre under the control of albumin promoter. Male Agthpt-/- mice and the littermates were fed a saturated fat-enriched diet (21% wt/wt milk fat) for 3 months. Agthpt-/- mice had significantly lower body weight than their littermates (30.9 ± 1.6 versus 41.1 ± 1.9 g, p < 0.01). While two groups exhibited no difference in lean mass, Agthpt-/- mice had 40% less fat mass compared to their littermates (6.2 ± 1.1 versus 11.9 ± 1.6 g, p < 0.05). This phenotype was not attributed to intestinal fat absorption. To determine metabolic rates, Agthpt-/- mice were single-housed for 5 consecutive days after 3 days of acclimation in a metabolic phenotyping system (TSE Systems, MO). The following parameters were recorded every 30 minutes: food intake, water consumption, O2 consumption, CO2 production and locomotion. Data were normalized to lean mass. Food intake and locomotion were not different between two groups. However, we found that Agthpt-/- mice had significantly increased O2 consumption (by 21% at day cycle and 15% at night cycle) and CO2 production (by 23% at day cycle and 14% at night cycle). While mice with whole body reduction of AGT exhibited a similar lean phenotype, mass spectrometric analyses of the metabolome showed that approximately one third of the 300 metabolites analyzed had significant changes in the liver and plasma in hypomorphic AGT mice when compared to their wild type littermates. These changes ranged from bile acid production to free fatty acid metabolism.
Conclusion: Angiotensinogen contributes to metabolic rate and influences metabolome in plasma and hepatic tissue in mice.
- © 2012 by American Heart Association, Inc.