Cardiac β-adrenergic responsiveness of obese Zucker rats: The role of AMPK.

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 β-adrenoceptors (β-ARs) in normal conditions. In obesity, chronic sympathetic overactivation leads to impaired cardiac β-AR responsiveness, although it is unclear whether AMPK signalling, downstream of β-ARs, contributes to this dysfunction. Therefore, we aimed to determine whether reduced AMPK signalling is responsible for the reduced β-AR responsiveness in obesity. In isolated hearts of lean and obese Zucker rats, we tested β-AR responsiveness to the β1 -AR agonist isoprenaline (ISO, 1 × 10-10 to 5 × 10-8  m) in the absence and presence of the AMPK inhibitor, compound C (CC, 10 μm). The β1 -AR expression and AMPK phosphorylation were assessed by Western blot. β-Adrenergic responsiveness was reduced in the hearts of obese rats (logEC50 of ISO-developed pressure dose-response curves: lean -8.53 ± 0.13 × 10x  m versus obese -8.35 ± 0.10 × 10x  m ; P < 0.05 lean versus obese, n = 6 per group). This difference was not apparent after AMPK inhibition (logEC50 of ISO-developed pressure curves: lean CC -8.19 ± 0.12 × 10x  m versus obese CC 8.17 ± 0.13 × 10x  m, P < 0.05, n = 6 per group). β1 -Adrenergic receptor expression and AMPK phosphorylation were reduced in hearts of obese rats (AMPK at Thr172 : 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 β-adrenergic responsiveness and AMPK signalling in the heart exists, and AMPK might be an important target to restore the reduced cardiac β-adrenergic responsiveness in obesity.