Angiotensinergic signaling in the brain controls whole‐body metabolism: Role of adipose AT2 receptors

Abstract

Transgenic “sRA” mice exhibit elevated brain renin‐angiotensin system (RAS) activity through expression of a human angiotensinogen transgene and a neuron‐specific human renin transgene. sRA mice exhibit elevated metabolic rate, partially mediated through a suppression of the circulating RAS. Uncoupling protein‐1 (UCP1; 24.6‐fold, n=5, P<0.01), and PPARγ‐coactivator‐1α (PGC‐1α; 2.8‐fold, n=5, P=0.01) mRNA were increased selectively in subcutaneous adipose (scWAT) of sRA mice, suggesting an increased brown adipocyte content. Treating differentiated 3T3‐L1 preadipocytes with the AT2 antagonist PD‐123,319 induced PGC1α (2.4‐fold) and the PGC1α target, catalase (3.4‐fold), while the AT1 antagonist Losartan had no effect. Treating sRA mice with the AT2 agonist CGP‐42112a (90 ng/hr, s.c., 8 weeks) normalized scWAT UCP1 mRNA (vehicle 24.6 vs CGP 2.1‐fold of control, n=5,7, P<0.05), suppressed resting metabolic rate (3.59±0.22 vs 3.12±0.17 mL O2/100g/min, P<0.01), and increased body weight (17.8±0.5 vs 23.1±2.1 grams, P=0.01), but had no effect on food intake (3.1±0.2 vs 3.6±0.3 g/day, P=0.72). These data support a model where AT2 receptor‐mediated suppression of adipose transdifferentiation mediates increased thermogenic capacity in animals with elevated brain RAS activity. Selective antagonism of AT2 receptors in adipose tissue may therefore represent a novel therapeutic strategy for obesity.