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
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.
