Angiotensin in the Arcuate: Mechanisms Integrating Cardiometabolic Control: The 2022 COH Mid-Career Award for...

The American Heart Association has identified obesity as a primary impediment to ongoing improvements in cardiovascular diseases, including hypertension. Although drugs, exercise, diets, and surgeries can each cause weight loss, few subjects maintain a reduced weight over the long term. Dysfunctional integrative control (ie, adaptation) of resting metabolic rate (RMR) appears to underlie this failed weight maintenance, yet the neurobiology of physiological and pathophysiological RMR control is poorly understood. Here, we review recent insights into the cellular and molecular control of RMR by Ang-II (angiotensin II) signaling within the arcuate nucleus of the hypothalamus. Within a unique subset of agouti-related peptide neurons, AT₁R (Ang-II type 1 receptors) are implicated in the integrative control of RMR. Furthermore, a spontaneous G protein signal switch of AT₁R within this neuron type appears to underlie the pathogenesis of RMR adaptation by qualitatively changing the cellular response to AT₁R activation from a β-arrestin-1/Gαi (heterotrimeric G protein, α i subtype)-mediated inhibitory response to a Gαq (heterotrimeric G protein, α q subtype)-mediated stimulatory response. We conclude that therapeutic approaches to obesity are likely hampered by the plasticity of the signaling mechanisms that mediate the normal integrative control of energy balance. The same stimulus that would increase RMR in the normal physiological state may decrease RMR during obesity due to qualitative changes in second-messenger coupling. Understanding the mechanisms that regulate interactions between receptors such as AT₁R and its various second messenger signaling cascades will provide novel insights into the pathogenesis of RMR adaptation and potentially point toward new therapeutic approaches for obesity and hypertension.