Abstract 20: Angiotensin Suppresses Thermogenic Capacity Through Adipose AT2 Receptors
Selective induction of the brain renin-angiotensin system (RAS) results in hypertension, polydipsia, and elevated resting metabolic rate. Transgenic sRA mice exhibit brain-specific RAS hyperactivity through expression of human renin via the synapsin promoter, and human angiotensinogen via its own promoter. The circulating RAS in these animals is suppressed due to chronic hypertension, and the elevated resting metabolic rate of sRA mice is sensitive to peripheral propranolol or angiotensin replacement. Cultured 3T3L1 adipocytes exhibited a dose-dependent induction of uncoupling protein 1 (UCP1) by the AT2 receptor (AT2R) antagonist, PD-123,319, and suppression by the AT2R agonist, CGP-42112a (CGP). UCP1 mRNA was specifically induced within inguinal adipose of sRA mice (25-fold, P=0.02). Treatment of sRA mice with CGP (50 ng/kg/min, 8 weeks, s.c.) normalized metabolic rate (control 2.8±0.2, sRA 3.6±0.2, sRA+CGP 3.1±0.2 mL O2/100g/min) and inguinal UCP1 mRNA (sRA 24.6 vs sRA+CGP 4.6-fold of control, P=0.02), blood pH (control 7.26±0.02, sRA 7.37±0.03, sRA+CGP 7.28±0.06), bicarbonate (control 22±1, sRA 31±1, sRA+CGP 21±6 mM) and perigenital adipose mass (control 317±100, sRA 127±16, sRA+CGP 590±127 mg). Fluid and sodium intake, urine volume and electrolytes, and heart and kidney masses were different in sRA mice but unchanged by CGP treatment, and food intake was unchanged in all groups, highlighting the specificity of effects elicited by CGP. We conclude that AT2R activation blunts the thermogenic response to increased brain RAS activity. Interestingly, sRA gain weight at the same rate as control mice when fed a high fat diet, prompting the hypothesis that an elevated circulating and/or adipose RAS may result in attenuated thermogenic responses during obesity. This may suggest a positive-feedback loop between the circulating RAS and adiposity, and identify adipose AT2R as a novel therapeutic target for obesity.
- © 2012 by American Heart Association, Inc.