Abstract 219: Adipose Angiotensin AT2 Receptors Inhibit Resting Metabolism

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The brain renin-angiotensin system (RAS) modulates blood pressure and resting metabolic rate (RMR). Double-transgenic “sRA” mice exhibit brain-specific elevations in RAS activity, as a human renin transgene is expressed via the neuron-specific synapsin promoter and a human angiotensinogen transgene is expressed via its own promoter. sRA mice have a significantly lower body weight due primarily to increased RMR, which is sustained through chronically increased sympathetic nerve activity (SNA) and a hypertension-mediated suppression of the circulating RAS. Here we identified the anatomical site of increased thermogenesis, and the components of the adipose/circulating RAS that suppress RMR in the sRA model. Expression of uncoupling protein 1 (UCP1) was elevated specifically within the inguinal fat of sRA mice, with no changes in UCP1 in interscapular or epididymal fat or skeletal muscle, and no change in UCP3 in skeletal muscle or any fat pad. UCP1 mRNA in differentiated 3T3L1 adipocytes was increased following treatment with the AT2R antagonist PD-123,319 and suppressed with the AT2R agonist CGP-42112a (CGP), but was unaffected by the AT1R antagonist losartan. Infusion of CGP (50 ng/kg/min, 8 wk, sc) into adult sRA mice normalized body mass (control n=5, 25.0±1.8; sRA n=5, 17.7±0.6*; sRA+CGP n=7, 22.7±2.0** g), epididymal fat (control 317±100, sRA 127±16*, sRA+CGP 247±45** mg/g), and RMR (control 2.8±0.2, sRA 3.6±0.2*, sRA+CGP 3.1±0.2** mL O2/100g/min). Food intake was unchanged across groups (control 10.5±0.5, sRA 9.8±0.6, sRA+CGP 11.2±0.9 kcal/d). CGP treatment did not suppress SNA to inguinal fat in sRA mice (control 9.7±1.0, sRA 14.7±1.3*, sRA+CGP 18.9±3.3* spikes/sec). sRA mice exhibit generally normal glucose tolerance but grossly increased insulin sensitivity (0.5 U/kg; control nadir 72±8, sRA nadir 27±5 mg/dL), and ongoing studies are designed to determine whether adipose insulin signaling is modulated by AT2R activation. (Throughout, * P<0.05 vs control, ** P<0.05 vs sRA.) We conclude that hyperactivity of the brain RAS stimulates RMR (and possibly insulin sensitivity) specifically within the subcutaneous inguinal fat pad, and identifies AT2R signaling as an important regulator of thermogenic activity of adipose tissue.

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