Nanoparticle-Mediated Inhibition of Notch Signaling Promotes Mitochondrial Biogenesis and Reduces Subcutaneous Adipose Tissue Expansion in Pigs

Di Huang; Naagarajan Narayanan; Mario A Cano-Vega; Zhihao Jia; Kolapo M Ajuwon; Shihuan Kuang; Meng Deng

doi:10.1016/j.isci.2020.101167

Nanoparticle-Mediated Inhibition of Notch Signaling Promotes Mitochondrial Biogenesis and Reduces Subcutaneous Adipose Tissue Expansion in Pigs

iScience. 2020 Jun 26;23(6):101167. doi: 10.1016/j.isci.2020.101167. Epub 2020 May 15.

Authors

Di Huang¹, Naagarajan Narayanan², Mario A Cano-Vega², Zhihao Jia³, Kolapo M Ajuwon³, Shihuan Kuang⁴, Meng Deng⁵

Affiliations

¹ Department of Animal Sciences, Purdue University, West Lafayette, IN 47907, USA; Department of Agricultural and Biological Engineering, Purdue University, West Lafayette, IN 47907, USA; Bindley Bioscience Center, Purdue University, West Lafayette, IN 47907, USA.
² Department of Agricultural and Biological Engineering, Purdue University, West Lafayette, IN 47907, USA; Bindley Bioscience Center, Purdue University, West Lafayette, IN 47907, USA.
³ Department of Animal Sciences, Purdue University, West Lafayette, IN 47907, USA.
⁴ Department of Animal Sciences, Purdue University, West Lafayette, IN 47907, USA; Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA. Electronic address: skuang@purdue.edu.
⁵ Department of Agricultural and Biological Engineering, Purdue University, West Lafayette, IN 47907, USA; Bindley Bioscience Center, Purdue University, West Lafayette, IN 47907, USA; School of Materials Engineering, Purdue University, West Lafayette, IN 47907, USA; Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN 47907, USA. Electronic address: deng65@purdue.edu.

Abstract

Inhibition of Notch signaling has been shown to induce white to beige transformation of adipocytes and reduce the risk of obesity in mice. However, it remains unknown whether the metabolic benefits of Notch inhibition are dependent on uncoupling protein 1 (UCP1)-mediated thermogenesis and evolutionarily relevant in other mammalian species. Here we report the effect of Notch inhibition in adipocytes of pigs, which lost the UCP1 gene during evolution. Notch inhibition using a γ-secretase inhibitor dibenzazepine (DBZ) promoted beige adipogenesis and mitochondrial biogenic gene expression in porcine adipocytes. Moreover, encapsulation of DBZ into poly(lactide-co-glycolide) nanoparticles enabled rapid cellular internalization and enhanced bioactivity to achieve sustained Notch inhibition, thereby inducing beige-specific gene expression and reducing subcutaneous adipose tissue expansion in pigs. These results demonstrate for the first time a role of Notch signaling in regulating adipose plasticity in large animals, highlighting the therapeutic potential of targeting Notch signaling in obesity treatment.

Keywords: Biological Sciences; Cell Biology; Cellular Physiology; Physiology.

Grants and funding

R43 DK115277/DK/NIDDK NIH HHS/United States