Angiotensin-(1-7) Activates Proopiomelanocortin Neurons in the Arcuate Nucleus

Angiotensin-(1-7) lowers blood pressure and improves metabolic outcomes in animal models of obesity and hypertension. Whether central mechanisms are involved in these protective cardiometabolic effects is poorly understood. In this study, we hypothesized that angiotensin-(1-7) engages central neurocircuits originating in the arcuate nucleus of the hypothalamus under normal conditions and in diet-induced obesity.

Male mice were placed on a control diet or 60% high-fat diet for 12 weeks. Immunohistochemistry, in situ hybridization, electrophysiology, and physiological approaches were employed to determine whether angiotensin-(1-7) activates arcuate neurocircuits, to characterize the molecular identity of activated arcuate cells, and to assess the functional importance of this neurocircuit in blood pressure regulation.

Under control diet conditions, systemic angiotensin-(1-7) administration (2 mg/kg, SC) increased the number of c-fos positive cells in the arcuate nucleus. Angiotensin-(1-7) mas receptors were highly localized to proopiomelanocortin neurons containing markers of gamma-aminobutyric acid transmission in the arcuate, with angiotensin-(1-7) increasing the firing activity of proopiomelanocortin neurons in a mas receptor-dependent manner. Acute intra-arcuate angiotensin-(1-7) administration lowered blood pressure. This effect was prevented by gamma-aminobutyric acid receptor antagonism in the downstream hypothalamic paraventricular nucleus, suggesting that angiotensin-(1-7) engages inhibitory arcuate-paraventricular circuits to lower blood pressure. Acute angiotensin-(1-7) could not activate proopiomelanocortin neurons or engage this arcuate-paraventricular neurocircuit in obese mice.

These findings suggest that angiotensin-(1-7) activates arcuate proopiomelanocortin neurons and engages arcuate-paraventricular inhibitory neurocircuits to lower blood pressure under normal conditions. In obesity, this circuit appears disrupted, which could contribute to the elevated blood pressure in this model.