Recent Advances in Hypertension: Intersection of Metabolic and Blood Pressure Regulatory Circuits in the Central Nervous System

Abstract

Obesity represents the single greatest ongoing roadblock to improving cardiovascular health. Prolonged obesity is associated with fundamental changes in the integrative control of energy balance, including the development of selective leptin resistance, which is thought to contribute to obesity-associated hypertension, and adaptation of resting metabolic rate (RMR) when excess weight is reduced. Leptin and the melanocortin system within the hypothalamus contribute to the control of both energy balance and blood pressure. While the development of drugs to stimulate RMR and thereby reverse obesity through activation of the melanocortin system has been pursued, most of the resulting compounds simultaneously cause hypertension. Evidence supports the concept that although feeding behaviors, RMR, and blood pressure are controlled through mechanisms that utilize similar molecular mediators, these mechanisms exist in anatomically dissociable networks. New evidence supports a major change in molecular signaling within AgRP (Agouti-related peptide) neurons of the arcuate nucleus of the hypothalamus during prolonged obesity and the existence of multiple distinct subtypes of AgRP neurons that individually contribute to control of feeding, RMR, or blood pressure. Finally, ongoing work by our laboratory and others support a unique role for AT₁ (angiotensin II type 1 receptor) within one specific subtype of AgRP neuron for the control of RMR. We propose that understanding the unique biology of the AT₁-expressing, RMR-controlling subtype of AgRP neurons will help to resolve the selective dysfunctions in RMR control that develop during prolonged obesity and potentially point toward novel druggable antiobesity targets that will not simultaneously cause hypertension.

Keywords: angiotensin; biology; hypertension; leptin; obesity.

Figure 1.. Working model: labelled-line encoding of feeding, BP and RMR control in the ARC.

Evidence supports the working hypothesis that a specific subset of AgRP neurons express the AT_1A receptor (Agtr1a), and that these receptors simultaneously (i) identify the subset of AgRP neurons involved in RMR control, and (ii) serve a critical molecular role in the integrative control of RMR. We hypothesize that molecular dysfunctions specifically within the Agtr1a-expressing subset of AgRP neurons contributes to the development of SLR and weight loss-associated adaptations in RMR control. Pomc, proopiomelanocortin; αMSH, α-melanocyte stimulating hormone; Mc4r, melanocortin type 4 receptor; Agrp, Agouti-related peptide; ANG, angiotensin II; BAT SNA, brown adipose tissue sympathetic nerve activity; RMR, resting metabolic rate.