Specific Control of Resting Metabolism by Angiotensin AT 1A receptors in Leptin‐Sensitive Cells

The brain renin‐angiotensin system (RAS) and leptin contribute to resting metabolic rate (RMR) and blood pressure (BP) control, and thus may contribute to obesity‐hypertension. Receptors for the RAS and leptin are found in the same major cardiometabolic control regions of the hypothalamus. Inhibition of the brain RAS attenuates sympathetic nerve activity (SNA) responses to leptin, leading us to hypothesize that the brain RAS mediates the RMR and BP effects of leptin. Mice lacking angiotensin AT 1A receptors in leptin receptor‐expressing cells (ObRb‐Cre x AT 1A flox ) exhibited normal baseline BP, RMR, physical activity, food intake and digestive efficiency. In contrast, ObRb‐Cre x AT 1A flox mice exhibit the complete loss of RMR responses to 45% high fat diet and SNA responses to acute leptin injection. These animals exhibit a normal hypertensive response, but a complete loss of the RMR response, to deoxycorticosterone acetate (DOCA)‐salt treatment. To localize the site of the ObRb/AT 1A interaction, we studied the brains of mice expressing GFP via the AT 1A promoter (NZ44, from GenSat). GFP was detected in a subset of red fluorescent tdTomato reporter cells in the arcuate nucleus of ObRb‐Cre x ROSA‐stop flox ‐tdTomato x NZ44 mice, indicating that specific populations of ObRb‐expressing cells express AT 1A . Within the arcuate nucleus, GFP did not colocalize with adrenocorticotropin (ACTH) by immunohistochemical staining of NZ44 mice, indicating that AT 1A is not expressed by proopiomelanocortin (POMC)‐expressing cells. Finally, GFP was detected in all red fluorescent cells of agouti related peptide (AgRP)‐Cre x ROSA‐stop flox ‐tdTomato x NZ44 mice. Together these data support a critical role for angiotensin AT 1A receptors specifically on AgRP neurons, but not POMC neurons, in metabolic rate control.