Di Huang1,2,3, Jiamin Qiu1, Shihuan Kuang4,5, Meng Deng6,7,8,9. 1. Department of Animal Sciences, Purdue University, West Lafayette, IN, 47907, USA. 2. Department of Agricultural and Biological Engineering, Purdue University, West Lafayette, IN, 47907, USA. 3. Bindley Bioscience Center, Purdue University, West Lafayette, IN, 47907, USA. 4. Department of Animal Sciences, Purdue University, West Lafayette, IN, 47907, USA. skuang@purdue.edu. 5. Center for Cancer Research, Purdue University, West Lafayette, IN, 47907, USA. skuang@purdue.edu. 6. Department of Agricultural and Biological Engineering, Purdue University, West Lafayette, IN, 47907, USA. deng65@purdue.edu. 7. Bindley Bioscience Center, Purdue University, West Lafayette, IN, 47907, USA. deng65@purdue.edu. 8. School of Materials Engineering, Purdue University, West Lafayette, IN, 47907, USA. deng65@purdue.edu. 9. Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN, 47907, USA. deng65@purdue.edu.
Abstract
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.
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.
Authors: Jun Wu; Pontus Boström; Lauren M Sparks; Li Ye; Jang Hyun Choi; An-Hoa Giang; Melin Khandekar; Kirsi A Virtanen; Pirjo Nuutila; Gert Schaart; Kexin Huang; Hua Tu; Wouter D van Marken Lichtenbelt; Joris Hoeks; Sven Enerbäck; Patrick Schrauwen; Bruce M Spiegelman Journal: Cell Date: 2012-07-12 Impact factor: 41.582