Cardiometabolic control by angiotensin II type 1 receptor-expressing agouti-related peptide neurons

The National Institute of Diabetes and Digestive and Kidney Diseases awarded The Medical College of Wisconsin, Inc. $108,968 on February 17, 2027, under the Diabetes, Digestive, and Kidney Diseases Extramural Research program (CFDA 93.847) to investigate neural mechanisms governing resting metabolic rate and cardiovascular function.

The research focuses on cardiometabolic control by angiotensin II type 1 receptor-expressing agouti-related peptide neurons in the arcuate nucleus of the hypothalamus. The project examines how diet-induced obesity causes a G protein signaling switch in these neurons, altering angiotensin II signaling from inhibitory to stimulatory, and tests the hypothesis that this obesity-induced plasticity represents a maladaptive mechanism contributing to impaired metabolic homeostasis and dysregulation of both resting metabolic rate and blood pressure. Two specific aims address the contribution of type 1 agouti-related peptide neurons to cardiometabolic control in lean animals and the functional consequences of obesity-induced signaling plasticity in this neuronal population.

Performance occurs in Wauwatosa, Wisconsin. The award runs through August 31, 2030. This project grant supports basic and clinical biomedical research under the National Institutes of Health's program to improve understanding of mechanisms underlying diabetes, digestive, and kidney diseases and to advance prevention, diagnosis, and treatment approaches.

Abstract

Cardiovascular disease (CVD) remains the leading cause of mortality in the united states. Obesity and its comorbid conditions including high blood pressure (BP), type 2 diabetes, and hyperlipidemia, are significant risk factors which predispose to CVD. While weight loss is a key strategy to mitigate CVD risk, long-term weight maintenance is difficult, in part, due to metabolic adaptation, which reduces resting metabolic rate (RMR) in response to prolonged energy deficit. This proposal investigates the neural mechanisms governing RMR, focusing on the brain renin-angiotensin system (RAS) and its role in the arcuate nucleus of the hypothalamus (ARC), a critical brain region for energy homeostasis. Our laboratory has identified a novel subpopulation of agouti-related peptide (agrp) neurons within the ARC, termed 'type 1 agrp neurons,' where angiotensin II (ANG II) signaling via the ANG II type 1 receptor (AT1R) normally inhibits neuronal activity. Crucially, we have discovered that diet-induced obesity causes a g protein signaling switch in these neurons, altering ANG II/AT1R signaling from inhibitory (GΑI-coupled) to stimulatory (GΑQ-coupled). The functional consequences of obesity- induced plasticity in this neuronal population are unknown and represent a critical knowledge GAP in understanding RMR dysregulation. This project aims to elucidate the role of type 1 agrp neurons on the downstream control of RMR and cardiovascular function. The central hypothesis is that this obesity-induced signaling plasticity in type 1 agrp neurons represents a maladaptive mechanism contributing to impaired metabolic homeostasis and that these neurons serve as critical regulators of both RMR and BP. This will be addressed through two aims: aim 1: define the contribution of type 1 agrp neurons to cardiometabolic control in lean animals. We hypothesize that GΑI-mediated inhibition of type 1 agrp neurons will increase RMR and blood pressure and reduce heart rate without altering feeding behavior. This will be investigated using an intersectional genetic approach to selectively express inhibitory dreadds (HM4DI) in type 1 agrp neurons, followed by comprehensive cardiometabolic phenotyping. Aim 2: test the hypothesis that chronic activation of GΑQ in type 1 agrp neurons, simulating maladaptive g protein signaling plasticity in obesity, impairs metabolic homeostasis, impairs metabolic homeostasis and promotes weight regain. We will use an intersectional viral strategy to express GΑQ-dreadds specifically in type 1 agrp neurons to determine if chronic activation exacerbates metabolic dysfunction, impairs weight loss after obesity, and accelerates weight regain. By defining the functional and unique contribution of type 1 agrp neurons to metabolic and cardiovascular control, this work may identify new therapeutic targets to selectively modulate RMR for sustained weight loss without the adverse cardiovascular effects common to other strategies. Through this multidisciplinary project, i will gain mastery of advanced neuroscience and cardiometabolic phenotyping, providing critical training for my growth into an independent physician-scientist.