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

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

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.

Citation

Talamonti, E., Davegardh, J., Kalinovich, A., van Beek, S. M. M., Dehvari, N., Halleskog, C., Bokhari, H. M., Hutchinson, D. S., Ham, S., Humphrys, L. J., Dijon, N. C., Motso, A., Sandstrom, A., Zacharewicz, E., Mutule, I., Suna, E., Spura, J., Ditrychova, K., Stoddart, L. A., Holliday, N. D., …Bengtsson, T. (2024). The novel adrenergic agonist ATR-127 targets skeletal muscle and brown adipose tissue to tackle diabesity and steatohepatitis. Molecular Metabolism, 85, Article 101931. https://doi.org/10.1016/j.molmet.2024.101931

• Journal Article Type: Article
• Acceptance Date: Mar 29, 2024
• Online Publication Date: May 17, 2024
• Publication Date: Jul 1, 2024
• Deposit Date: Sep 6, 2024
• Publicly Available Date: Sep 13, 2024
• Journal: Molecular Metabolism
• Electronic ISSN: 2212-8778
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 85
• Article Number: 101931
• DOI: https://doi.org/10.1016/j.molmet.2024.101931
• Keywords: Type 2 diabetes, Obesity, Skeletal muscle, Hepatic steatosis, β-Adrenergic agonists
• Public URL: https://nottingham-repository.worktribe.com/output/36000360