Angiotensin AT1A receptor signal switching in Agouti-related peptide neurons mediates metabolic rate adaptation during obesity

Kirthikaa Balapattabi; Yavuz Yavuz; Jingwei Jiang; Guorui Deng; Natalia M. Mathieu; McKenzie L. Ritter; Megan A. Opichka; John J. Reho; John D. McCorvy; Pablo Nakagawa; Lisa L. Morselli; Gary C. Mouradian, Jr.; Deniz Atasoy; Huxing Cui; Matthew R. Hodges; Curt D. Sigmund; Justin L. Grobe

Cell Reports (Aug 2023)

Angiotensin AT1A receptor signal switching in Agouti-related peptide neurons mediates metabolic rate adaptation during obesity

Kirthikaa Balapattabi,
Yavuz Yavuz,
Jingwei Jiang,
Guorui Deng,
Natalia M. Mathieu,
McKenzie L. Ritter,
Megan A. Opichka,
John J. Reho,
John D. McCorvy,
Pablo Nakagawa,
Lisa L. Morselli,
Gary C. Mouradian, Jr.,
Deniz Atasoy,
Huxing Cui,
Matthew R. Hodges,
Curt D. Sigmund,
Justin L. Grobe

Affiliations

Kirthikaa Balapattabi: Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
Yavuz Yavuz: Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Iowa Neuroscience Institute, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
Jingwei Jiang: Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
Guorui Deng: Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
Natalia M. Mathieu: Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
McKenzie L. Ritter: Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
Megan A. Opichka: Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
John J. Reho: Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Comprehensive Rodent Metabolic Phenotyping Core, Medical College of Wisconsin, Milwaukee, WI 53226, USA
John D. McCorvy: Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Cancer Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA
Pablo Nakagawa: Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA
Lisa L. Morselli: Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Department of Medicine, Division of Endocrinology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
Gary C. Mouradian, Jr.: Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA
Deniz Atasoy: Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Iowa Neuroscience Institute, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
Huxing Cui: Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Iowa Neuroscience Institute, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
Matthew R. Hodges: Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA
Curt D. Sigmund: Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA
Justin L. Grobe: Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Comprehensive Rodent Metabolic Phenotyping Core, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Department of Biomedical Engineering, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Corresponding author

Journal volume & issue: Vol. 42, no. 8
p. 112935

Abstract

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Summary: Resting metabolic rate (RMR) adaptation occurs during obesity and is hypothesized to contribute to failed weight management. Angiotensin II (Ang-II) type 1 (AT1A) receptors in Agouti-related peptide (AgRP) neurons contribute to the integrative control of RMR, and deletion of AT1A from AgRP neurons causes RMR adaptation. Extracellular patch-clamp recordings identify distinct cellular responses of individual AgRP neurons from lean mice to Ang-II: no response, inhibition via AT1A and Gαi, or stimulation via Ang-II type 2 (AT2) receptors and Gαq. Following diet-induced obesity, a subset of Ang-II/AT1A-inhibited AgRP neurons undergo a spontaneous G-protein “signal switch,” whereby AT1A stop inhibiting the cell via Gαi and instead begin stimulating the cell via Gαq. DREADD-mediated activation of Gαi, but not Gαq, in AT1A-expressing AgRP cells stimulates RMR in lean and obese mice. Thus, loss of AT1A-Gαi coupling within the AT1A-expressing AgRP neuron subtype represents a molecular mechanism contributing to RMR adaptation.

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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