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

doi:10.1016/j.celrep.2023.112935

Angiotensin AT_1A receptor signal switching in Agouti-related peptide neurons mediates metabolic rate adaptation during obesity

Cell Rep. 2023 Aug 29;42(8):112935. doi: 10.1016/j.celrep.2023.112935. Epub 2023 Aug 2.

Authors

Kirthikaa Balapattabi¹, Yavuz Yavuz², Jingwei Jiang³, Guorui Deng³, Natalia M Mathieu¹, McKenzie L Ritter¹, Megan A Opichka¹, John J Reho⁴, John D McCorvy⁵, Pablo Nakagawa⁶, Lisa L Morselli⁷, Gary C Mouradian Jr⁶, Deniz Atasoy², Huxing Cui², Matthew R Hodges⁸, Curt D Sigmund⁶, Justin L Grobe⁹

Affiliations

¹ Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
² 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.
³ Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.
⁴ Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Comprehensive Rodent Metabolic Phenotyping Core, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
⁵ 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.
⁶ 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.
⁷ Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Department of Medicine, Division of Endocrinology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
⁸ Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
⁹ 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. Electronic address: jgrobe@mcw.edu.

Abstract

Resting metabolic rate (RMR) adaptation occurs during obesity and is hypothesized to contribute to failed weight management. Angiotensin II (Ang-II) type 1 (AT_1A) receptors in Agouti-related peptide (AgRP) neurons contribute to the integrative control of RMR, and deletion of AT_1A 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 AT_1A and Gαi, or stimulation via Ang-II type 2 (AT₂) receptors and Gαq. Following diet-induced obesity, a subset of Ang-II/AT_1A-inhibited AgRP neurons undergo a spontaneous G-protein "signal switch," whereby AT_1A stop inhibiting the cell via Gαi and instead begin stimulating the cell via Gαq. DREADD-mediated activation of Gαi, but not Gαq, in AT_1A-expressing AgRP cells stimulates RMR in lean and obese mice. Thus, loss of AT_1A-Gαi coupling within the AT_1A-expressing AgRP neuron subtype represents a molecular mechanism contributing to RMR adaptation.

Keywords: CP: Metabolism; CP: Neuroscience; G-protein signaling; arcuate nucleus; obesity; resting metabolic rate.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Agouti-Related Protein / metabolism
Angiotensin II / metabolism
Animals
Mice
Neurons* / metabolism
Obesity* / metabolism
Receptor, Angiotensin, Type 1* / metabolism

Substances

Agouti-Related Protein
Angiotensin II
Agtr1a protein, mouse
Receptor, Angiotensin, Type 1

Abstract

Publication types

MeSH terms

Substances

Grants and funding