Abstract 024: Angiotensin-(1-7) Attenuates Diet-induced Obesity in Mice by Browning White Adipose Tissue to Enhance Energy Expenditure

Abstract

Overactivation of the renin-angiotensin (Ang) system, and in particular Ang II, contributes to obesity-induced insulin resistance via multiple mechanisms. Obesity is also associated with deficiency of Ang-(1-7), a beneficial hormone that opposes Ang II actions. In this study, we tested the hypothesis that Ang-(1-7) could prevent development of diet-induced obesity in mice. To test this hypothesis, adult male C57BL/6J mice received 12-week Ang-(1-7) (400 ng/kg/min; n=7) or saline (n=6) infusion via subcutaneous osmotic mini-pumps. Mice were placed on 60% high fat diet (HFD) immediately following mini-pump implantation. Body composition, energy balance, and insulin sensitivity were measured during the last week of treatment. Ang-(1-7) attenuated HFD-induced weight gain (39.7±1.3 vs. 43.9±0.7 g saline; p=0.023) and adiposity (32±1 vs. 29±1% saline; p=0.050). This weight-reducing effect was due to enhanced average energy expenditure [0.55±0.02 vs. 0.42±0.06 kcal/hour saline, p=0.038], with no changes in locomotor activity or food intake. Ang-(1-7) attenuated HFD-induced hyperinsulinemia (1.4±0.4 vs. 5.3±1.6-ng/mL saline; p=0.032) and improved the ability of intraperitoneal insulin to decrease blood glucose levels (20% reduction in area under the curve vs. saline; p=0.015), consistent with insulin-sensitizing effects. Given effects of Ang-(1-7) on energy expenditure, we performed blinded histological and semi-quantitative real-time PCR analysis of brown and white adipose tissue. Ang-(1-7) reduced HFD-induced lipid droplet accumulation in brown adipose, but did not improve thermogenesis markers (e.g. uncoupling protein-1). Ang-(1-7) improved inflammation in visceral white adipose (mean number crown-like structures: 3±1 vs. 8±2 saline; p=0.046). Ang-(1-7) reduced adipocyte size and increased gene expression of the browning marker PRDM16 (1.7±0.2 vs. 1.1±0.1; p=0.024) in subcutaneous white adipose. These data suggest that Ang-(1-7) attenuates diet-induced obesity in mice by enhancing energy expenditure, in part by browning of white adipose tissue. These overall findings provide rationale for targeting Ang-(1-7) to prevent development of obesity and related pathology such as insulin resistance and adipose inflammation.