Abstract 032: Cardiometabolic Control by Angiotensin II Type 1 Receptor-Expressing Agouti-Related Peptide Neurons

Agouti-related peptide (AgRP) neurons in the hypothalamic arcuate nucleus (ARC) canonically control feeding and resting metabolic rate (RMR) and may contribute to blood pressure (BP) control. Thus, their dysfunction may contribute to obesity-associated hypertension. Our recent studies revealed three distinct ARC AgRP neuron subtypes, distinguishable by their patterns of angiotensin II (ANG) receptor expression and electrophysiological responses to ANG. One subtype (“Type 1” AgRP neurons) expresses the ANG Type 1 receptor (AT 1 R) and is inhibited by ANG via a AT 1 R/Gi-mediated signaling cascade. Within a subset of these Type 1 neurons, diet-induced obesity causes AT 1 R to spontaneously change its second-messenger signaling, to instead stimulate the cell via the Gq cascade. This G protein “signal switch” appears to represent maladaptive neuroplasticity that may ultimately exaggerate obesity by suppressing RMR. We hypothesized that chemogenetic inhibition of AT 1 R + Type 1 AgRP neurons would increase RMR and alter cardiovascular control (i.e., BP and HR). To target Type 1 neurons, adult mice (11-12 weeks, n=5) expressing Cre-recombinase via the Agrp locus and flippase-recombinase (FLPo) via the Agtr1a promoter were instrumented with radiotelemetric BP/core temperature transducers (DSI, HD-X10). One week later, an AAV vector encoding Cre+FLPo-dependent expression of the inhibitory hM4Di DREADD and mCherry was microinjected into the ARC. Chronic DREADD-mediated inhibition of Type 1 AgRP neurons (via deschloroclozapine (DCZ) in drinking water) significantly reduced HR (Vehicle: 532±22; DCZ: 509±18 bpm, p=0.01) while systolic BP remained unchanged (Vehicle: 117±1; DCZ: 117±1 mmHg). Food and water intakes were also unaffected. Acute inhibition of Type 1 neurons (via IP injection of DCZ) significantly increased RMR (Vehicle: 0.174±0.009; DCZ: 0.193±0.008 kcal/h, p=0.0006). Following an overnight fast (≈18h), acute inhibition did not affect refeeding rates. These results demonstrate that AT 1 R + Type 1 AgRP neurons contribute to cardiovascular and RMR control, without affecting food intake. By extension, we hypothesize that the observed neuroplasticity of Type 1 AgRP neurons during obesity could mechanistically contribute to the alterations in cardiovascular function and energy balance characteristic of obesity.