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A spermine-coupled cholesterol metabolite from the shark with potent appetite suppressant and antidiabetic properties

International Journal of Obesity volume 25, pages 689–697 (2001)Cite this article

Abstract

OBJECTIVE: We describe the pharmacological properties of a novel spermine-cholesterol adduct, MSI 1436 (3β-N-1(spermine)-7α, 24R-dihydroxy-5α-cholestane 24-sulfate), which causes reversible suppression of food and fluid intake in mammals resulting in profound weight loss, not associated with other signs or symptoms of illness, and which exhibits antidiabetic properties in genetically obese mice.

METHODS: Wild-type rodents and strains with genetic obesity were studied. Effects on food and fluid intake, body weight and composition were examined along with pharmacological and toxicological parameters.

RESULTS: MSI-1436 induces profound inhibition of food and fluid intake in rats and mice, resulting in significant weight loss. MSI-1436 is active when introduced directly into the third ventricle of the rat, suggesting the compound acts on central targets. Pair-feeding studies suggest that MSI-1436 causes weight loss by suppressing food intake. Fluid intake is also profoundly reduced but animals remain normally hydrated and defend both water and electrolyte balance from parenteral administration. MSI-1436 is active in ob/ob, db/db, agouti and MC4 receptor knockout mice. MSI-1436 has been administered to ob/ob mice over a 4 month period via a regimen that safely controls body weight, glucose homeostasis and serum cholesterol levels. Following MSI-1436 treatment, db/db mice preferentially mobilize adipose tissue and hyperglycemia is corrected.

CONCLUSION: A naturally occurring spermine metabolite of cholesterol, isolated from the dogfish shark, Squalus acanthias, has been identified that induces profound reduction in food and fluid intake in rodents in a setting where thirst is preserved and fluid and electrolyte homeostasis appears to be functioning normally. MSI-1436 probably acts on a central target involving neural circuits that lie downstream from the leptin and the MC4 receptors. Although long-term administration can be accomplished safely in mice, the utility of this compound as a potential human therapeutic awaits an analysis of its pharmacological properties in man.

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Acknowledgements

We wish to thank Miklos Gellai for his encouragement and insightful discussions regarding the physiology of the rat; Tessa Chao, Anne Shinnar, Benny Feibush and Ilya Sharkansky (Magainin Pharmaceuticals) for help in the isolation of MSI-1436 from dogfish liver during early phases of this work; Xuehi Zhang, Meena Rao and Penina Feibush (Magainin Pharmaceuticals) for help in the synthesis of MSI-1436 and its analogs; Keith Yagaloff (Roche Pharmaceuticals) for evaluating MSI-1436 in the MC-4 knockout mouse strain; Yaniv Tomer, Andrew Pastuszak, Veronica Ferrante, Christine Weiss (Magainin Pharmaceuticals) for their assistance in the animal experiments described; Howard Hait for statistical analysis; Jamila Louahed and Lee Maloy for critical reading of the manuscript; and Barbara Zasloff for many helpful discussions.

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Authors and Affiliations

  1. Magainin Pharmaceuticals, Plymouth Meeting, Pennsylvania, USA

    M Zasloff, JI Williams, Q Chen, M Anderson, T Maeder, K Holroyd, S Jones, W Kinney, K Cheshire & M McLane

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  1. M Zasloff
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  2. JI Williams
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  8. W Kinney
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Correspondence to M Zasloff.

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Zasloff, M., Williams, J., Chen, Q. et al. A spermine-coupled cholesterol metabolite from the shark with potent appetite suppressant and antidiabetic properties. Int J Obes 25, 689–697 (2001). https://doi.org/10.1038/sj.ijo.0801599

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