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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.

目的

β2-和β3-肾上腺素能受体（ARs）的同时激活通过对骨骼肌和棕色脂肪组织（BAT）的有益作用改善全身代谢。然而，目前同时针对这些受体且限制β1-AR 激活的高效激动剂——从而引发心血管并发症——并不存在。因此，我们在此开发并评估了新型β2-和β3-AR，称为 ATR-127，在临床前模型中治疗肥胖及其相关代谢紊乱的治疗潜力。

方法

在开发阶段，我们评估了 ATR-127 对 cAMP 积累的影响与非选择性β-AR 激动剂异丙肾上腺素在各种啮齿动物β-AR 亚型（包括新生大鼠心肌细胞）中的关系。进行这些实验后，用 ATR-127 刺激 L6 肌肉细胞，以评估其对 GLUT4 介导的葡萄糖摄取和肌内 cAMP 积累的影响。此外，还进行了体外和体内评估，以测量 ATR-127 对 BAT 葡萄糖摄取和产热的影响。最后，用 5mg/kg ATR-127 治疗饮食诱导肥胖的小鼠 21 天，以研究其对葡萄糖稳态、体重、脂肪量、骨骼肌葡萄糖摄取、BAT 产热和肝脂肪变性的影响。

结果

尽管肌内 cAMP 积累较低，但 ATR-127 暴露于 L6 肌肉细胞中可强烈增强 GLUT4 介导的葡萄糖摄取。同样，ATR-127 显著增加 BAT 葡萄糖摄取和产热，无论是在体外还是体内。长期用 ATR-127 治疗饮食诱导肥胖的小鼠可显著改善葡萄糖稳态，这一作用伴随着体重和脂肪量的降低。这些作用伴随着骨骼肌葡萄糖摄取的增强、BAT 产热的改善以及肝脂肪变性的改善。