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12. The novel adrenergic agonist ATR-127 targets skeletal muscle and brown adipose tissue to tackle diabesity and steatohepatitis

Author

Emanuela Talamonti, Jelena Davegardh, Anastasia Kalinovich, Sten M.M. van Beek, Nodi Dehvari, Carina Halleskog, Hamza M. Bokhari, Dana S. Hutchinson, Seungmin Ham, Laura J. Humphrys, Nicola C. Dijon, Aikaterini Motso, Anna Sandstrom, Evelyn Zacharewicz, Ilga Mutule, Edgars Suna, Jana Spura, Karolina Ditrychova, Leigh A. Stoddart, Nicholas D. Holliday, Shane C. Wright, Volker M. Lauschke, Soren Nielsen, Camilla Scheele, Elizabeth Cheesman, Joris Hoeks, Peter Molenaar, Roger J. Summers, Benjamin Pelcman, Gopala K. Yakala, and Tore Bengtsson

Subjects
Obesity, Type 2 diabetes, β-Adrenergic agonists, Hepatic steatosis, Skeletal muscle, Internal medicine, RC31-1245
Abstract

Objective: Simultaneous activation of β2- and β3-adrenoceptors (ARs) improves whole-body metabolism via beneficial effects in skeletal muscle and brown adipose tissue (BAT). Nevertheless, high-efficacy agonists simultaneously targeting these receptors whilst limiting activation of β1-ARs – and thus inducing cardiovascular complications – are currently non-existent. Therefore, we here developed and evaluated the therapeutic potential of a novel β2-and β3-AR, named ATR-127, for the treatment of obesity and its associated metabolic perturbations in preclinical models. Methods: In the developmental phase, we assessed the impact of ATR-127's on cAMP accumulation in relation to the non-selective β-AR agonist isoprenaline across various rodent β-AR subtypes, including neonatal rat cardiomyocytes. Following these experiments, L6 muscle cells were stimulated with ATR-127 to assess the impact on GLUT4-mediated glucose uptake and intramyocellular cAMP accumulation. Additionally, in vitro, and in vivo assessments are conducted to measure ATR-127's effects on BAT glucose uptake and thermogenesis. Finally, diet-induced obese mice were treated with 5 mg/kg ATR-127 for 21 days to investigate the effects on glucose homeostasis, body weight, fat mass, skeletal muscle glucose uptake, BAT thermogenesis and hepatic steatosis. Results: Exposure of L6 muscle cells to ATR-127 robustly enhanced GLUT4-mediated glucose uptake despite low intramyocellular cAMP accumulation. Similarly, ATR-127 markedly increased BAT glucose uptake and thermogenesis both in vitro and in vivo. Prolonged treatment of diet-induced obese mice with ATR-127 dramatically improved glucose homeostasis, an effect accompanied by decreases in body weight and fat mass. These effects were paralleled by an enhanced skeletal muscle glucose uptake, BAT thermogenesis, and improvements in hepatic steatosis. Conclusions: Our results demonstrate that ATR-127 is a highly effective, novel β2- and β3-ARs agonist holding great therapeutic promise for the treatment of obesity and its comorbidities, whilst potentially limiting cardiovascular complications. As such, the therapeutic effects of ATR-127 should be investigated in more detail in clinical studies.

Published
2024
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15. Schraubenverbindungen

Author

Spura, Christian, Fleischer, Bernhard, Wittel, Herbert, Jannasch, Dieter, Spura, Christian, Fleischer, Bernhard, Wittel, Herbert, and Jannasch, Dieter

Published
2023
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17. Nietverbindungen

Author

Spura, Christian, Fleischer, Bernhard, Wittel, Herbert, Jannasch, Dieter, Spura, Christian, Fleischer, Bernhard, Wittel, Herbert, and Jannasch, Dieter

Published
2023
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18. Kleb- und Lötverbindungen

Author

Spura, Christian, Fleischer, Bernhard, Wittel, Herbert, Jannasch, Dieter, Spura, Christian, Fleischer, Bernhard, Wittel, Herbert, and Jannasch, Dieter

Published
2023
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19. Tribologie

Author

Spura, Christian, Fleischer, Bernhard, Wittel, Herbert, Jannasch, Dieter, Spura, Christian, Fleischer, Bernhard, Wittel, Herbert, and Jannasch, Dieter

Published
2023
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22. Dichtungen

Author

Spura, Christian, Fleischer, Bernhard, Wittel, Herbert, Jannasch, Dieter, Spura, Christian, Fleischer, Bernhard, Wittel, Herbert, and Jannasch, Dieter

Published
2023
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25. Kettengetriebe

Author

Spura, Christian, Fleischer, Bernhard, Wittel, Herbert, Jannasch, Dieter, Spura, Christian, Fleischer, Bernhard, Wittel, Herbert, and Jannasch, Dieter

Published
2023
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26. Riemengetriebe

Author

Spura, Christian, Fleischer, Bernhard, Wittel, Herbert, Jannasch, Dieter, Spura, Christian, Fleischer, Bernhard, Wittel, Herbert, and Jannasch, Dieter

Published
2023
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27. Umlaufgetriebe

Author

Spura, Christian, Fleischer, Bernhard, Wittel, Herbert, Jannasch, Dieter, Spura, Christian, Fleischer, Bernhard, Wittel, Herbert, and Jannasch, Dieter

Published
2023
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28. Kupplungen und Bremsen

Author

Spura, Christian, Fleischer, Bernhard, Wittel, Herbert, Jannasch, Dieter, Spura, Christian, Fleischer, Bernhard, Wittel, Herbert, and Jannasch, Dieter

Published
2023
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30. Festigkeitsberechnung

Author

Spura, Christian, Fleischer, Bernhard, Wittel, Herbert, Jannasch, Dieter, Spura, Christian, Fleischer, Bernhard, Wittel, Herbert, and Jannasch, Dieter

Published
2023
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31. Wälzlager

Author

Spura, Christian, Fleischer, Bernhard, Wittel, Herbert, Jannasch, Dieter, Spura, Christian, Fleischer, Bernhard, Wittel, Herbert, and Jannasch, Dieter

Published
2023
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32. Gleitlager

Author

Spura, Christian, Fleischer, Bernhard, Wittel, Herbert, Jannasch, Dieter, Spura, Christian, Fleischer, Bernhard, Wittel, Herbert, and Jannasch, Dieter

Published
2023
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33. Elastische Federn

Author

Spura, Christian, Fleischer, Bernhard, Wittel, Herbert, Jannasch, Dieter, Spura, Christian, Fleischer, Bernhard, Wittel, Herbert, and Jannasch, Dieter

Published
2023
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35. Achsen, Wellen und Zapfen

Author

Spura, Christian, Fleischer, Bernhard, Wittel, Herbert, Jannasch, Dieter, Spura, Christian, Fleischer, Bernhard, Wittel, Herbert, and Jannasch, Dieter

Published
2023
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43. 24 Umlaufgetriebe

Author

Spura, Christian, Wittel, Herbert, Jannasch, Dieter, Spura, Christian, Wittel, Herbert, and Jannasch, Dieter

Published
2023
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44. 17 Kettengetriebe

Author

Spura, Christian, Wittel, Herbert, Jannasch, Dieter, Spura, Christian, Wittel, Herbert, and Jannasch, Dieter

Published
2023
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45. 16 Riemengetriebe

Author

Spura, Christian, Wittel, Herbert, Jannasch, Dieter, Spura, Christian, Wittel, Herbert, and Jannasch, Dieter

Published
2023
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48. 10 Elastische Federn

Author

Spura, Christian, Wittel, Herbert, Jannasch, Dieter, Spura, Christian, Wittel, Herbert, and Jannasch, Dieter

Published
2023
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50. 14 Wälzlager

Author

Spura, Christian, Wittel, Herbert, Jannasch, Dieter, Spura, Christian, Wittel, Herbert, and Jannasch, Dieter

Published
2023
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