Angiotensin‐(1‐7)‐Mediated Increases in Energy Expenditure Appear Independent of the Hypothalamic Melanocortin System
Authors: Fleeman Rebecca , Bingaman Sarah S. , Silberman Yuval , Arnold Amy C. 
Published: June 2021

Obesity is a major public health problem that greatly increases risk for cardiovascular disease and type II diabetes. Obesity represents an energy imbalance where the amount of calories consumed exceeds the amount of calories expended. This energy balance is in part controlled by activation of proopiomelanocortin (POMC) neurons or inhibition of agouti‐related protein (AgRP) neurons within the arcuate nucleus (ARC) of the hypothalamus, which activates downstream melanocortin pathways to produce satiety and increase energy expenditure. Our preliminary data show that the beneficial renin‐angiotensin system hormone angiotensin (Ang)‐(1‐7) may be an important contributor to energy balance, as it attenuates high fat diet (HFD)‐induced obesity in mice by browning subcutaneous white fat to enhance energy expenditure. In this study, we tested the hypothesis that the beneficial effects of Ang‐(1‐7) on energy expenditure may be due to actions on POMC or AgRP neurons in the ARC. To test this hypothesis, we first examined the ability of an acute subcutaneous injection of Ang‐(1‐7) to induce neuronal activation in the ARC, as measured by c‐fos gene expression, in chow fed mice. We found that Ang‐(1‐7) significantly increased the number of c‐fos positive cells within the ARC compared with saline (43±5 Ang‐(1‐7) vs. 19±3 saline; p=0.022; n=3 per group). We then performed chronic experiments in which eight‐week old male C57BL/6J mice were implanted with subcutaneous osmotic mini‐pumps to deliver saline or Ang‐(1‐7) [400 ng/kg/min]. Immediately following mini‐pump implantation, mice were placed on a 60% high fat diet (HFD) or matched control chow diet for 12 weeks. The groups of mice included in this chronic study were: (1) chow diet with saline infusion (n=5); (2) HFD with saline infusion (n=6); and (3) HFD with Ang‐(1‐7) infusion [n=9]. At the end of treatment, the hypothalamus from each mouse was collected to assess for gene expression of mas receptor, POMC, and AgRP using quantitative real‐time polymerase chain reaction methods. We found that HFD reduced gene expression for POMC (1.1±0.3 chow vs. 0.4±0.1 HFD; p=0.005) in the hypothalamus, with no significant effect on mas receptor (1.2±0.3 chow vs. 0.7±0.1 HFD; p=0.134) or AgRP (1.3±0.5 chow vs. 1.1±0.2 HFD; p=0.856). There was no effect of Ang‐(1‐7) on POMC (0.4±0.1; p=0.998), mas receptor (0.7±0.1; p=0.995) or AgRP (1.0±0.1; p=0.996) gene expression in HFD mice. These findings provide evidence that Ang‐(1‐7) can acutely induce activation of neurons in the ARC. Chronic Ang‐(1‐7) treatment was not able to restore obesity‐induced reductions in POMC gene expression, however, despite enhancing energy expenditure. Further studies are needed to evaluate if beneficial effects of Ang‐(1‐7) on energy balance involve changes in POMC neuronal activity, or melanocortin‐independent pathways.Support or Funding InformationThis study was supported by NIH grant HL122507.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.