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
Affiliations
Di Huang
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
Naagarajan Narayanan
Department of Agricultural and Biological Engineering, Purdue University, West Lafayette, IN 47907, USA; Bindley Bioscience Center, Purdue University, West Lafayette, IN 47907, USA
Mario A. Cano-Vega
Department of Agricultural and Biological Engineering, Purdue University, West Lafayette, IN 47907, USA; Bindley Bioscience Center, Purdue University, West Lafayette, IN 47907, USA
Zhihao Jia
Department of Animal Sciences, Purdue University, West Lafayette, IN 47907, USA
Kolapo M. Ajuwon
Department of Animal Sciences, Purdue University, West Lafayette, IN 47907, USA
Shihuan Kuang
Department of Animal Sciences, Purdue University, West Lafayette, IN 47907, USA; Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA; Corresponding author
Meng Deng
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; Corresponding author
Summary: 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.
