Angiotensin AT(1A) receptor signal switching in Agouti-related peptide neurons mediates metabolic rate adaptation during obesity

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.