Purpose

Inhibition of Notch signaling has been recently demonstrated to promote beige adipocyte biogenesis. However, most γ-secretase inhibitors (GSIs) used to achieve pharmacological inhibition of Notch signaling are at the basic research or preclinical stage, limiting the translation of fundamental findings into clinical practice. This present study aimed to evaluate the potential of several clinical candidates of GSIs as browning agents for the treatment of obesity.

Methods

Seven GSIs that are clinical candidates for the treatment of Alzheimer’s disease or cancer were selected and their impacts on Notch inhibition as well as promoting beige biogenesis were compared using in vitro culture of 3T3-L1 preadipocytes.

Results

Four compounds (i.e.RO4929097, PF-03084014, LY3039478, and BMS-906024) that efficiently inhibited the expression of Notch target genes in 3T3-L1 preadipocytes were identified. Moreover, these compounds were optimized for dose-dependent effects at three gradient concentrations (0.5, 1, and 10 μM) to promote beige adipogenesis and mitochondrial biogenesis in 3T3-L1 preadipocytes without causing severe cytotoxicity.

Conclusions

Our findings not only highlight the potential of cross-therapeutic application of these GSIs for obesity treatment via inhibition of γ-secretase-mediated processing of Notch signaling, but also provide important experimental evidence to support further design and development of clinically translatable Notch-inhibiting drug delivery systems.

中文翻译：

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γ-分泌酶抑制剂临床候选物的体外评估：对 Notch 抑制和促进米色脂肪生成和线粒体生物发生的影响。

目的

最近已经证明抑制 Notch 信号可以促进米色脂肪细胞的生物发生。然而，大多数用于实现 Notch 信号抑制的 γ-分泌酶抑制剂 (GSI) 都处于基础研究或临床前阶段，限制了将基本发现转化为临床实践。本研究旨在评估几种临床候选 GSI 作为治疗肥胖症的褐变剂的潜力。

方法

选择了作为治疗阿尔茨海默病或癌症的临床候选者的七种 GSI，并使用3T3-L1 前脂肪细胞的体外培养比较了它们对 Notch 抑制以及促进米色生物发生的影响。

结果

鉴定了有效抑制 3T3-L1 前脂肪细胞中 Notch 靶基因表达的四种化合物（即RO4929097、PF-03084014、LY3039478 和 BMS-906024）。此外，这些化合物在三个梯度浓度（0.5、1 和 10 μM）下针对剂量依赖性效应进行了优化，以促进 3T3-L1 前脂肪细胞中的米色脂肪生成和线粒体生物发生，而不会引起严重的细胞毒性。

结论

我们的研究结果不仅突出了这些 GSI 通过抑制 γ-分泌酶介导的 Notch 信号处理在肥胖症治疗中的交叉治疗应用的潜力，而且还提供了重要的实验证据，以支持进一步设计和开发临床可转化的 Notch 抑制药物递送系统。