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.
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.
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.
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.
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Brown adipose tissues
CCAAT/enhancer binding protein family proteins
Cell death-inducing DNA fragmentation factor alpha-like effector A
Cytochrome c oxidase subunit 5B
(N-[N-(3,5-Difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester)
Type 2 deiodinase
Fatty acid binding protein 4
Notch intracellular domain
Peroxisomal proliferator-activated receptor family proteins
Peroxisome proliferator-activated receptor gamma coactivator 1-alpha
PR domain containing 16
Recombination signal binding protein for immunoglobulin kappa J region
Transmembrane protein 26
Uncoupling protein 1
White adipose tissue
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The authors appreciate the funding support from the National Institute of Diabetes and Digestive and Kidney Diseases (R43DK115277 to M. D.) and National Cancer Institute (R01CA212609 to S. K.).
Declaration of Interests
M. D., D. H., and S. K. have applied for patents related to this study. M. D. is founder of Adipo Therapeutics, a university startup developing polymer technologies for applications in adipocytes.
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Huang, D., Qiu, J., Kuang, S. et al. In Vitro Evaluation of Clinical Candidates of γ-Secretase Inhibitors: Effects on Notch Inhibition and Promoting Beige Adipogenesis and Mitochondrial Biogenesis. Pharm Res 37, 185 (2020). https://doi.org/10.1007/s11095-020-02916-7
- Notch signaling pathway
- γ-secretase inhibitor
- Adipose browning
- 3T3-L1 preadipocytes