Polymyxin B and Related Cyclic Peptides Facilitate Leanness and Reduce Fat Mass and Triglyceride Content in Ageing Rats: Potential Prototype Drugs Against Obesity

  • Yoram Shechter
  • Marina Mironchik
  • Shimon Amir
  • Ben-Ami Sela
  • Haim Tsubery
  • Hailin Zheng
  • Mati Fridkin
Article

Abstract

Polymyxin B (PMXB) blocks the action of insulin on glucose uptake in vitro. In vivo, it reverses hypoglycemia induced by exogenous insulin. Here we have treated mature male rats daily with PMXB over a period of two weeks. This therapy has decreased body weight by 11%, adipose fat mass by 46% and triglyceride levels by 39%, with no indication of liver or kidney toxicity. Two suboptimal parameters, however, were a decrease in food intake in the first week of treatment and some increase in fasting glucose levels. We have screened for PMXB-analogs having less associating affinity with rat-muscle phospholipids, and revealed that the same therapy using PMXB-derived peptide (nona-PMXB) is most optimal. This PMXB-analog is devoid of antibacterial activity and is four times less toxic than PMXB. Nona-PMXB therapy lower by 10, 32, 35 and 6% body weight gain, fat mass, circulating triglycerides and fasting glucose levels, respectively, in spite of normal or even elevated food intake in nona-PMXB treated rats. In summary, we found that nona-PMXB therapy is capable if inducing leanness in mature rats, particularly at the expense of decreasing fat-mass in adipose tissue. By and large, we suggest that lowering the action of insulin, on fat build-up solely, may be a therapeutically feasible task to fight with human adiposity in the future.

Keywords

Insulin obesity polymyxin B 

Abbreviations

HPLC

high-pressure liquid chromatography

IRKO-mice

insulin-receptor knockout mice

nona-colistin

colistin-nonapeptide

nona-PMXB

polymyxin B nonapeptide

PMXB

polymyxin B

Notes

Acknowledgments

We thank Elana Friedman for typing the manuscript and Yigal Avivi for editing it. M.F. is the Lester Pearson Professor of Protein Chemistry; Y.S. is the incumbent of the C.H. Hollenberg Chair in Metabolic and Diabetes Research established by the friends and associates of Dr. C.H. Hollenberg of Toronto, Canada.

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Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  • Yoram Shechter
    • 1
    • 5
  • Marina Mironchik
    • 1
  • Shimon Amir
    • 3
  • Ben-Ami Sela
    • 4
  • Haim Tsubery
    • 1
    • 2
  • Hailin Zheng
    • 2
  • Mati Fridkin
    • 2
  1. 1.Department of Biological ChemistryThe Weizmann Institute of ScienceRehovotIsrael
  2. 2.Department of Organic ChemistryThe Weizmann Institute of ScienceRehovotIsrael
  3. 3.Department of PsychologyConcordia UniversityMontreakCanada
  4. 4.Institute of Chemical PathologySheba Medical CenterTel-HashomerIsrael
  5. 5.Department of Biological ChemistryThe Weizmann Institute of ScienceRehovotIsrael

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