Angiotensin receptor G protein signal switching in AgRP neurons in cardiometabolic control

项目摘要/摘要

Project Summary / Abstract NHANES data indicate that 47.3% of Americans have high blood pressure (hypertension), 71.3% are overweight, and there is strong overlap between these groups. Hypothalamic pathways controlling blood pressure are tightly intertwined with pathways controlling resting metabolic rate (RMR). With prolonged obesity, cardiovascular- stimulating autonomic responses and blood pressure responses remain intact, but RMR control progressively desensitizes (a process termed “RMR adaptation”). RMR adaptation is thought to contribute to the resistance of the body to maintaining weight loss, and the propensity of the body to regain mass. Thus, there is a critically unmet need to understand the basic hypothalamic neurocircuitry that coordinately controls blood pressure and RMR in healthy conditions, and how this system selectively desensitizes during obesity. The renin-angiotensin system (RAS) within the brain is well known to contribute to blood pressure control through actions in multiple brain regions, and our team recently discovered that the RAS within the arcuate nucleus of the hypothalamus (ARC) is critically involved in the control of RMR. In particular, the angiotensin II (ANG) type 1A receptor (AT1A) in neurons of the ARC that express Agouti-related peptide (AgRP) are required for control of RMR but not blood pressure in response to leptin, ANG, and other stimuli. The objective of the current proposal is therefore to clarify the molecular signaling pathways within AgRP neurons that are utilized by the AT1A receptor to control RMR. Preliminary data indicate that in the lean state, (i) only a subset of AgRP neurons express AT1A, (ii) these AT1A signal via a Gi second messenger, and (iii) such signaling causes inhibition of the cell, ultimately to disinhibit melanocortin signaling in pre-autonomic target regions and thus increase RMR. Excitingly, we have discovered that following prolonged high fat feeding, a subset of AT1A-expressing AgRP neurons of the ARC spontaneously exhibit “G protein signal switching” and begin to couple to Gq instead of Gi second-messengers, which results in stimulatory effects of ANG on these cells. We therefore propose the general hypotheses that (i) in the lean state, AT1A-expressing AgRP neurons are importantly involved in RMR control, and that AT1A signals via Gi, but that (ii) after diet-induced obesity, the alteration in AT1A second-messenger cascade from Gi to Gs in these cells is causal for the development of RMR adaptation. Aim 1 will define the ‘normal’ signaling cascade of AT1A in AgRP neurons in lean animals, while Aim 2 will dissect the mechanistic contribution of G protein signal switching in these cells in the development of RMR adaptation. These studies will utilize an array of novel transgenic animal models, viral delivery methods, cutting-edge cardiometabolic phenotyping approaches, and chemogenetic methods. Completion of the project will greatly increase fundamental understanding of RMR control and adaptation biology, and provide the first in vivo evaluation of the pathophysiological significance of G protein signal switching downstream of ANG receptors in a single cell type in cardiometabolic physiology.