Tariq R Altamimi1, Su Gao1, Qutuba G Karwi2, Arata Fukushima3, Sonia Rawat1, Cory S Wagg1, Liyan Zhang1, Gary D Lopaschuk4. 1. Cardiovascular Research Centre, Department of Pediatrics, 423 Heritage Medical Research Building, University of Alberta, Edmonton, Alberta T6G 2S2, Canada. 2. Cardiovascular Research Centre, Department of Pediatrics, 423 Heritage Medical Research Building, University of Alberta, Edmonton, Alberta T6G 2S2, Canada; Department of Pharmacology, College of Medicine, University of Diyala, Diyala, Iraq. 3. Department of Cardiovascular Medicine, Faculty of Medicine, Graduate School of Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo 060-8638, Japan. 4. Cardiovascular Research Centre, Department of Pediatrics, 423 Heritage Medical Research Building, University of Alberta, Edmonton, Alberta T6G 2S2, Canada. Electronic address: gary.lopaschuk@ualberta.ca.
Abstract
BACKGROUND: Impaired cardiac insulin signalling and high cardiac fatty acid oxidation rates are characteristics of conditions of insulin resistance and diabetic cardiomyopathies. The potential role of liver-derived peptides such as adropin in mediating these changes in cardiac energy metabolism is unclear, despite the fact that in skeletal muscle adropin can preferentially promote glucose metabolism and improve insulin sensitivity. OBJECTIVES: To determine the influence of adropin on cardiac energy metabolism, insulin signalling and cardiac efficiency. METHODS: C57Bl/6 mice were injected with either vehicle or a secretable form of adropin (450 nmol/kg, i.p.) three times over a 24-h period. The mice were fasted to accentuate the differences between animals in adropin plasma levels before their hearts were isolated and perfused using a working heart system. In addition, direct addition of adropin to the perfusate of ex vivo hearts isolated from non-fasting mice was utilized to investigate the acute effects of the peptide on heart metabolism and ex vivo function. RESULTS: In contrast to the observed fasting-induced predominance of fatty acid oxidation as a source of ATP production in control hearts, insulin inhibition of fatty acid oxidation was preserved by adropin treatment. Adropin-treated mouse hearts also showed a higher cardiac work, which was accompanied by improved cardiac efficiency and enhanced insulin signalling compared to control hearts. Interestingly, acute adropin administration to isolated working hearts also resulted in an inhibition of fatty acid oxidation, accompanied by a robust stimulation of glucose oxidation compared to vehicle-treated hearts. Adropin also increased activation of downstream cardiac insulin signalling. Moreover, both in vivo and ex vivo treatment protocols induced a reduction in the inhibitory phosphorylation of pyruvate dehydrogenase (PDH), the major enzyme of glucose oxidation, and the protein levels of the responsible kinase PDH kinase 4 and the insulin-signalling inhibitory phosphorylation of JNK (p-T183/Y185) and IRS-1 (p-S307), suggesting acute receptor- and/or post-translational modification-mediated mechanisms. CONCLUSIONS: These results demonstrate that adropin has important effects on energy metabolism in the heart and may be a putative candidate for the treatment of cardiac disease associated with impaired insulin sensitivity.
BACKGROUND: Impaired cardiac insulin signalling and high cardiac fatty acid oxidation rates are characteristics of conditions of insulin resistance and diabetic cardiomyopathies. The potential role of liver-derived peptides such as adropin in mediating these changes in cardiac energy metabolism is unclear, despite the fact that in skeletal muscle adropin can preferentially promote glucose metabolism and improve insulin sensitivity. OBJECTIVES: To determine the influence of adropin on cardiac energy metabolism, insulin signalling and cardiac efficiency. METHODS: C57Bl/6 mice were injected with either vehicle or a secretable form of adropin (450 nmol/kg, i.p.) three times over a 24-h period. The mice were fasted to accentuate the differences between animals in adropin plasma levels before their hearts were isolated and perfused using a working heart system. In addition, direct addition of adropin to the perfusate of ex vivo hearts isolated from non-fasting mice was utilized to investigate the acute effects of the peptide on heart metabolism and ex vivo function. RESULTS: In contrast to the observed fasting-induced predominance of fatty acid oxidation as a source of ATP production in control hearts, insulin inhibition of fatty acid oxidation was preserved by adropin treatment. Adropin-treated mouse hearts also showed a higher cardiac work, which was accompanied by improved cardiac efficiency and enhanced insulin signalling compared to control hearts. Interestingly, acute adropin administration to isolated working hearts also resulted in an inhibition of fatty acid oxidation, accompanied by a robust stimulation of glucose oxidation compared to vehicle-treated hearts. Adropin also increased activation of downstream cardiac insulin signalling. Moreover, both in vivo and ex vivo treatment protocols induced a reduction in the inhibitory phosphorylation of pyruvate dehydrogenase (PDH), the major enzyme of glucose oxidation, and the protein levels of the responsible kinase PDH kinase 4 and the insulin-signalling inhibitory phosphorylation of JNK (p-T183/Y185) and IRS-1 (p-S307), suggesting acute receptor- and/or post-translational modification-mediated mechanisms. CONCLUSIONS: These results demonstrate that adropin has important effects on energy metabolism in the heart and may be a putative candidate for the treatment of cardiac disease associated with impaired insulin sensitivity.
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