Abstract
The obesity epidemic impacts heavily on cardiovascular health, in part owing to changes in cardiac metabolism. AMP-activated protein kinase (AMPK) is a key regulator of energy homeostasis in the heart and is regulated by beta-adrenoceptors (beta-ARs) in normal conditions. In obesity, chronic sympathetic overactivation leads to impaired cardiac beta-AR responsiveness, although it is unclear whether AMPK signalling, downstream of beta-ARs, contributes to this dysfunction. Therefore, we aimed to determine whether reduced AMPK signalling is responsible for the reduced beta-AR responsiveness in obesity. In isolated hearts of lean and obese Zucker rats, we tested beta-AR responsiveness to the beta(1)-AR agonist isoprenaline (ISO, 1 x 10(-10) to 5 x 10(-8) M) in the absence and presence of the AMPK inhibitor, compound C (CC, 10 mu M). The beta(1)-AR expression and AMPK phosphorylation were assessed by Western blot beta-Adrenergic responsiveness was reduced in the hearts of obese rats (logEC(50) of ISO-developed pressure dose-response curves: lean -8.53 +/- 0.13 x 10(x) M versus obese -8.35 +/- 0.10 x 10(x) M; P < 0.05 lean versus obese, n = 6 per group). This difference was not apparent after AMPK inhibition (logEC(50) of ISO-developed pressure curves: lean CC -8.19 +/- 0.12 x 10(x) M versus obese CC 8.17 +/- 0.13 x 10(x) M, P < 0.05, n = 6 per group). beta(1)-Adrenergic receptor expression and AMPK phosphorylation were reduced in hearts of obese rats (AMPK at Thr(172): lean 1.73 +/- 0.17 a.u. versus lean CC 0.81 +/- 0.13 a.u., and obese 1.18 +/- 0.09 a.u. versus obese CC 0.81 +/- 0.16 a. u., P < 0.05, n = 6 per group). Thus, a direct functional link between beta-adrenergic responsiveness and AMPK signalling in the heart exists, and AMPK might be an important target to restore the reduced cardiac beta-adrenergic responsiveness in obesity.