Polymyxin B and Related Cyclic Peptides Facilitate Leanness and Reduce Fat Mass and Triglyceride Content in Ageing Rats: Potential Prototype Drugs Against Obesity
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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.
KeywordsInsulin obesity polymyxin B
high-pressure liquid chromatography
insulin-receptor knockout mice
polymyxin B nonapeptide
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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