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; Deniz Atasoy; Huxing Cui; Matthew R Hodges; Curt D Sigmund; Justin L Grobe

doi:10.1016/j.celrep.2023.112935

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

Journal article

Open access

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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, …

Cell reports (Cambridge), Vol.42(8), 112935

08/01/2023

DOI: 10.1016/j.celrep.2023.112935

PMCID: PMC10530419

PMID: 37540598

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https://doi.org/10.1016/j.celrep.2023.112935View

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Abstract

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.

Details

Title: Subtitle: Angiotensin AT1A receptor signal switching in Agouti-related peptide neurons mediates metabolic rate adaptation during obesity
Creators: Kirthikaa Balapattabi - Medical College of Wisconsin
Yavuz Yavuz - University of Iowa
Jingwei Jiang - University of Iowa
Guorui Deng - University of Iowa
Natalia M Mathieu - Medical College of Wisconsin
McKenzie L Ritter - Medical College of Wisconsin
Megan A Opichka - Medical College of Wisconsin
John J Reho - Medical College of Wisconsin
John D McCorvy - Medical College of Wisconsin
Pablo Nakagawa - Medical College of Wisconsin
Lisa L Morselli - Medical College of Wisconsin
Gary C Mouradian - Medical College of Wisconsin
Deniz Atasoy - University of Iowa
Huxing Cui - University of Iowa
Matthew R Hodges - Medical College of Wisconsin
Curt D Sigmund - Medical College of Wisconsin
Justin L Grobe - Medical College of Wisconsin
Resource Type: Journal article
Publication Details: Cell reports (Cambridge), Vol.42(8), 112935
DOI: 10.1016/j.celrep.2023.112935
PMID: 37540598
PMCID: PMC10530419
NLM abbreviation: Cell Rep
ISSN: 2211-1247
eISSN: 2211-1247
Language: English
Date published: 08/01/2023
Academic Unit: Molecular Physiology and Biophysics; Iowa Neuroscience Institute; Fraternal Order of Eagles Diabetes Research Center; Neuroscience and Pharmacology
Record Identifier: 9984449860102771

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