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Animal Models

Sustained zero-order delivery of GC-1 from a nanochannel membrane device alleviates metabolic syndrome

Abstract

Background/Objectives:

Our objective was to assess the sustained, low-dose and constant administration of the thyroid receptor-β (TRβ)-selective agonist GC-1 (sobetirome) from a novel nanochannel membrane device (NMD) for drug delivery. As it known to speed up metabolism, accomplish weight loss, improve cholesterol levels and possess anti-diabetic effects, GC-1 was steadily administered by our NMD, consisting of an implantable nanochannel membrane, as an alternative to conventional daily administration, which is subject to compliance issues in clinical settings.

Subjects/Methods:

Diet-induced obese C57BL/J6 male mice were fed a very high-fat diet (VHFD) and received NMD implants subcutaneously. Ten mice per group received capsules containing GC-1 or phosphate-buffered saline (control). Weight, lean and fat mass, as well as cholesterol, triglycerides, insulin and glucose, were monitored for 24 days. After treatment, plasma levels of thyroid-stimulating hormone (TSH) and thyroxine were compared. mRNA levels of a panel of thermogenic markers were examined using real-time PCR in white adipose tissue (WAT) and brown adipose tissue (BAT). Adipose tissue, liver and local inflammatory response to the implant were examined histologically. Pancreatic islet number and β-cell area were assessed.

Results:

GC-1 released from the NMD reversed VHFD-induced obesity and normalized serum cholesterol and glycemia. Significant reductions in body weight and fat mass were observed within 10 days, whereas reductions in serum cholesterol and glucose levels were seen within 7 days. The significant decrease in TSH was consistent with TRβ selectivity for GC-1. Levels of transcript for Ucp1 and thermogenic genes PGC1a, Cidea, Dio2 and Cox5a showed significant upregulation in WAT in NMD–GC-1-treated mice, but decreased in BAT. Although mice treated by NMD–GC-1 showed a similar number of pancreatic islets, they exhibited significant increase in β-cell area.

Conclusions:

Our data demonstrate that the NMD implant achieves steady administration of GC-1, offering an effective and tightly controlled molecular delivery system for treatment of obesity and metabolic disease, thereby addressing compliance.

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Acknowledgements

We thank Carlos Favela and Dr Kemi Cui from the advanced cellular and tissue microscopy core, Dr Jianhua (James) Gu from the electron microscopy core, Dr Andreana L. Rivera and Dr Yulan Ren from the research pathology core, Solmaz Afshar for assistance with liver histology and Dr Aijun Zhang for assistance with the Eppendorf EpMotion 5075 automated pipetting system. We also thank the Pharmaceutical Science Facility, Institute of Applied Cancer Science, UT MD Anderson Cancer Center for liquid chromatography–tandem mass spectrometry analysis. This work was supported by start-up funds from Houston Methodist Research Institute (AG).

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Correspondence to A Grattoni.

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AG discloses a financial interest in NanoMedical Systems, Inc. All other authors declare no conflict of interest.

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Filgueira, C., Nicolov, E., Hood, R. et al. Sustained zero-order delivery of GC-1 from a nanochannel membrane device alleviates metabolic syndrome. Int J Obes 40, 1776–1783 (2016). https://doi.org/10.1038/ijo.2016.129

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