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Mol Ther. 2017 Jul 5;25(7):1718-1729. doi: 10.1016/j.ymthe.2017.05.020. Epub 2017 Jun 16.

Dibenzazepine-Loaded Nanoparticles Induce Local Browning of White Adipose Tissue to Counteract Obesity.

Author information

1
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 Animal Sciences, Purdue University, West Lafayette, IN 47907, USA.
3
Bindley Bioscience Center, Purdue University, West Lafayette, IN 47907, USA; College of Pharmacy, Purdue University, West Lafayette, IN 47907, USA.
4
Department of Animal Sciences, 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 via systemic drug administration triggers conversion of white adipocytes into beige adipocytes (browning) and reduces adiposity. However, translation of this discovery into clinical practice is challenged by potential off-target side effects and lack of control over the location and temporal extent of beige adipocyte biogenesis. Here, we demonstrate an alternative approach to stimulate browning using nanoparticles (NPs) composed of FDA-approved poly(lactide-co-glycolide) that enable sustained local release of a Notch inhibitor (dibenzazepine, DBZ). These DBZ-loaded NPs support rapid cellular internalization and inhibit Notch signaling in adipocytes. Importantly, focal injection of these NPs into the inguinal white adipose tissue depots of diet-induced obese mice results in localized NP retention and browning of adipocytes, consequently improving the glucose homeostasis and attenuating body-weight gain of the treated mice. These findings offer new avenues to develop a potential therapeutic strategy for clinical treatment of obesity and its associated metabolic syndrome.

KEYWORDS:

Notch inhibitor; Notch signaling; PLGA; adipocyte; adipose tissue; browning; dibenzazepine; drug delivery; nanoparticle; obesity

PMID:
28624262
PMCID:
PMC5498918
DOI:
10.1016/j.ymthe.2017.05.020
[Indexed for MEDLINE]
Free PMC Article

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