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 Opichka, John J. Reho, John D. McCorvy, Pablo Nakagawa, Lisa L. Morselli, Gary Mouradian, Deniz Atasoy, Huxing Cui, Matthew R. Hodges, Curt D. Sigmund, Justin L. Grobe
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 (AT 2 ) 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.