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