Angiotensin-(1-7) activates proopiomelanocortin neurons in the arcuate nucleus of the hypothalamus

Obesity is a global epidemic that reflects a chronic state of energy imbalance. There is critical need to better understand integrative mechanisms of obesity and related cardiovascular complications to develop more targeted therapies with mitigated adverse effects. The control of energy balance involves interactions of circulating hormones with brain regions including the arcuate nucleus of the hypothalamus. Within the arcuate nucleus, activation of proopiomelanocortin (POMC) neurons decreases food intake and increases energy expenditure, whereas stimulation of agouti-related protein neurons has converse effects. Our goal is to identify novel hormonal targets that can engage these neural circuits to restore energy balance in obesity. Angiotensin-(1-7), a cardioprotective renin-angiotensin hormone, induces weight loss in obese mice and may provide this ideal target. Angiotensin-(1-7) binds mas receptors, which based on our preliminary data are highly localized to arcuate POMC neurons. The extent to which angiotensin-(1-7) activates POMC neurons, however, is unknown. Thus, in this study, we tested the hypothesis that systemic angiotensin-(1-7) administration activates arcuate POMC neurons. To test this, male C57BL/6J mice were placed on a control diet or 60% high fat diet for 12 weeks (n=4-6 per group). Mice then received a single subcutaneous injection of either angiotensin-(1-7) [2 mg/kg] or saline, with brains harvested at 60 minutes post-injection. RNAscope in situ hybridization was used to determine the presence of c-fos mRNA, a marker of acute neuronal activity, in POMC neurons within the arcuate nucleus. We found that angiotensin-(1-7) significantly increases c-fos expression in arcuate POMC neurons in control diet mice (percentage c-fos/POMC positive neurons: 53±8 vs. 26±5 saline; p=0.033). This ability of angiotensin-(1-7) to increase c-fos expression, however, was not observed in high fat diet mice (percentage c-fos/POMC positive neurons: 30±13 vs. 25±6 saline; p=0.706). These findings suggest that angiotensin-(1-7) can activate arcuate POMC neurons under normal conditions, with changes to this circuit observed in the context of diet-induced obesity. Additional studies are needed to determine the physiological relevance of these findings, such as whether angiotensin-(1-7) activates these neurons to provide cardiometabolic protection. NIH R01 HL156986, NIH F31 HL170693, Pennsylvania Department of Health Tobacco CURE Funds This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.