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

New Findings: What is the central question of the study? Is the reduced signalling of AMP‐activated protein kinase (AMPK), a key regulator of energy homeostasis in the heart, responsible for the reduced β‐adrenergic responsiveness of the heart in obesity? What is the main finding and its importance? Inhibition of AMPK in isolated hearts prevented the reduced cardiac β‐adrenergic responsiveness of obese rats, which was accompanied by reduced phosphorylation of AMPK, a proxy of AMPK activity. This suggests a direct functional link between β‐adrenergic responsiveness and AMPK signalling in the heart, and it suggests that AMPK might be an important target to restore the β‐adrenergic responsiveness in the heart in obesity. 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 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 μ m). 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 × 10^x  m versus obese −8.35 ± 0.10 × 10^x  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 × 10^x  m versus obese CC 8.17 ± 0.13 × 10^x  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. [ABSTRACT FROM AUTHOR]