Faculty Collaboration Database

Angiotensin in the Arcuate: Mechanisms Integrating Cardiometabolic Control: The 2022 COH Mid-Career Award for Research Excellence. Hypertension 2024 Nov;81(11):2209-2217

Date

09/24/2024

Pubmed ID

39315447

Pubmed Central ID

PMC11483214

DOI

10.1161/HYPERTENSIONAHA.124.20524

Scopus ID

2-s2.0-85205521844 (requires institutional sign-in at Scopus site)   2 Citations

Abstract

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.

Author List

Lawton SBR, Wagner VA, Nakagawa P, Segar JL, Sigmund CD, Morselli LL, Grobe JL

Authors

Justin L. Grobe PhD Professor in the Physiology department at Medical College of Wisconsin
Lisa Morselli MD, PhD Assistant Professor in the Medicine department at Medical College of Wisconsin
Jeffrey L. Segar MD Professor in the Pediatrics department at Medical College of Wisconsin
Curt Sigmund PhD Chair, Professor in the Physiology department at Medical College of Wisconsin
Valerie Wagner Research Scientist I in the Physiology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Angiotensins
Animals
Arcuate Nucleus of Hypothalamus
Awards and Prizes
Basal Metabolism
Humans
Hypertension
Obesity
Receptor, Angiotensin, Type 1
Signal Transduction