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Oligopeptide complex for targeted non-viral gene delivery to adipocytes


Commercial anti-obesity drugs acting in the gastrointestinal tract or the central nervous system have been shown to have limited efficacy and severe side effects. Anti-obesity drug development is thus focusing on targeting adipocytes that store excess fat. Here, we show that an adipocyte-targeting fusion-oligopeptide gene carrier consisting of an adipocyte-targeting sequence and 9-arginine (ATS–9R) selectively transfects mature adipocytes by binding to prohibitin. Injection of ATS–9R into obese mice confirmed specific binding of ATS–9R to fat vasculature, internalization and gene expression in adipocytes. We also constructed a short-hairpin RNA (shRNA) for silencing fatty-acid-binding protein 4 (shFABP4), a key lipid chaperone in fatty-acid uptake and lipid storage in adipocytes. Treatment of obese mice with ATS–9R/shFABP4 led to metabolic recovery and body-weight reduction (>20%). The ATS–9R/shFABP4 oligopeptide complex could prove to be a safe therapeutic approach to regress and treat obesity as well as obesity-induced metabolic syndromes.

Figure 1: Schematic illustration.
Figure 2: The location of prohibitin.
Figure 3: In vitro cellular uptake of ATS–9R.
Figure 4: Ex vivo and in vivo fat homing of ATS–9R and transgene expression.
Figure 5: Obesity reduction and metabolic recovery.


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This work was partially supported by grants from the National Research Foundation of Korea (2013030789), the Brain Korea 21 plus program (22A20130011095), and the Korean Health Technology R&D project through the Ministry of Health & Welfare (HI13C-1938-010013). All the confocal microscopy and Cellvizio imaging experiments were carried out at Korea Basic Science Institute, Chuncheon Center, Chuncheon-city, Korea. We are sincerely grateful for their assistance in performing experiments and data analysis.

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Y-W.W., P.P.A. and Y-H.K. designed the experiments. P.P.A. and H.J.K. carried out in vitro experiments. Y-W.W., K.S.L., H.J.K. and P.P.A. carried out in vivo animal experiments. K.S.L. and J.K.K. contributed to immunoprecipitation, SDS–PAGE, western blotting, FACS assay and in vivo tissue imaging. Y-W.W., H.J.K., K.S.L., J.K.K., P.P.A., and Y-H.K. prepared the manuscript. Y-H.K. provided overall intellectual guidance and was the principal investigator of this group.

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Correspondence to Yong-Hee Kim.

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The authors declare no competing financial interests.

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Won, YW., Adhikary, P., Lim, K. et al. Oligopeptide complex for targeted non-viral gene delivery to adipocytes. Nature Mater 13, 1157–1164 (2014).

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