AT1A Receptors in AgRP Neurons Disinhibit αMSH Neurotransmission

Abstract

The brain renin‐angiotensin system (RAS) and leptin contribute to the control of resting metabolic rate (RMR) and their receptors are co‐expressed in areas of the brain critical for metabolic control, supporting the concept that the central interaction between angiotensin and leptin may be critical to regulate RMR and thus obesity. We have previously demonstrated that angiotensin AT1A receptors co‐localize to leptin‐sensitive cells in the arcuate nucleus (ARC), which also express agouti‐related peptide (AgRP). Moreover, mice lacking angiotensin AT1A receptors in AgRP neurons (AT1AAgRP‐KO) exhibit attenuated brown adipose tissue sympathetic nerve activity in response to leptin (4 hrs post‐leptin, control n=4, 221±18 vs AT1AAgRP‐KO n=5, 150±10 % baseline, p<0.05). AT1AAgRP‐KO mice also exhibit suppressed stimulation of RMR in response to exogenous alpha‐melanocyte stimulating hormone (αMSH; control n=13, +0.032±0.005 vs AT1AAgRP‐KO n=9, +0.012±0.005 kcal/hr, p<0.05), leading us to hypothesize that the activation of AT1A receptors in leptin‐sensitive AgRP neurons disinhibits αMSH neurotransmission and subsequent stimulation of RMR via suppression of inhibitory signaling within the ARC. We examined brain punches from the ARC of AT1AAgRP‐KO mice for the expression of AgRP, neuropeptide Y (NPY), and genes involved in gamma‐aminobutyric acid (GABA) signaling, including the glutamate decarboxylase enzymes, GAD1 and GAD2, and the vesicular GABA transporter VGAT, in response to selective ablation of the AT1A receptor. AT1AAgRP‐KO mice (n=5) exhibited significant (p<0.05) inductions in AgRP (10.3‐fold), NPY (4.8‐fold), GAD1 (1.9‐fold), GAD2 (1.5‐fold) and VGAT (6.9‐fold) in the ARC compared to control littermates (n=10). Taken together, these data support a role for AT1A receptors within AgRP neurons of the ARC in the control of BAT SNA and RMR through suppression of inhibitory AgRP/NPY/GABA signaling and thus disinhibition of stimulatory αMSH neurotransmission.