Glycemic control by the brain renin‐angiotensin system: Role for peripheral AT2 receptors

• DOI: 10.1096/fasebj.27.1_supplement.1120.2
• Publication Date: 2021-06-21T14:59:00Z
• Authors: Benjamin J. Weide...; Nicole K. Littlejohn; Curt D. Sigmund; Justin L. Grobe
• Keywords: 0301 basic medicine; 03 medical and health sciences

The effect of hyperactivity of the brain renin‐angiotensin system (RAS) on metabolism was explored using double‐transgenic “sRA” mice, which express human renin via the synapsin promoter and human angiotensinogen via its own promoter. sRA mice exhibit hypertension, polydipsia, and elevated resting metabolic rate (RMR). Compared to control littermates (n=9), body mass was lower in sRA (n=9) mice (25.11±1.26 vs 18.95±0.87 g, P<0.05), and i.p. glucose tolerance (ipGTT, 2 g/kg total body) was improved (genotype x time P=0.03). Lean mass by NMR was reduced in sRA (16.54±0.79 vs 12.62±0.63, P<0.05), but proportional lean mass was normal (66.1±.52 vs 66.69±1.48 % total). Lean ipGTT (2g/kg lean body, P=0.29) was normal, and tolerance to a bolus dose of glucose was reduced (28 mg/mouse, P<0.001). sRA mice were more sensitive to insulin, as i.p. insulin (0.5 U/kg total body) caused dramatic drops in blood glucose (control nadir 72±8 vs sRA nadir 27±5 mg/dL and occasionally death, genotype x time P<0.02). As the RMR increase in sRA is mediated through suppression of adipose AT2 receptor activation, we tested the effects of chronic infusion of CGP‐42112a (50 ng/kg/min) on ipGTT. Chronic CGP‐42112a significantly reduced ipGTT (2 g/kg total body, AUC +23%, P=0.008) in both control and sRA mice. Together, these data suggest that the brain RAS may improve glycemic control through tonic suppression of peripheral AT2 activation.