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

OBJECTIVE: We describe the pharmacological properties of a novel spermine-c holesterol adduct, MSI 1436 (3 beta -N-1(spermine)-7 alpha, 24R-dihydroxy-5 alpha -cholestane 24-sulfate), which causes reversible suppression of food and fluid intake in mammals resulting in profound weight loss, not associa ted with other signs or symptoms of illness, and which exhibits antidiabeti c properties in genetically obese mice. METHODS: Wild-type rodents and strains with genetic obesity were studied. E ffects 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 r ats and mice, resulting in significant weight loss. MSI-1436 is active when introduced directly into the third ventricle of the rat, suggesting the co mpound acts on central targets. Pair-feeding studies suggest that MSI-1436 causes weight loss by suppressing food intake. Fluid intake is also profoun dly reduced but animals remain normally hydrated and defend both water and electrolyte balance from parenteral administration. MSI-1436 is active in o b/ob, db/db, agouti and MC4 receptor knockout mice. MSI-1436 has been admin istered to ob/ob mice over a 4 month period via a regimen that safely contr ols body weight, glucose homeostasis and serum cholesterol levels. Followin g MSI-1436 treatment, db/db mice preferentially mobilize adipose tissue and hyperglycemia is corrected. CONCLUSION: A naturally occurring spermine metabolite of cholesterol, isola ted from the dogfish shark, Squalus acanthias, has been identified that ind uces profound reduction in food and fluid intake in rodents in a setting wh ere 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 analysi s of its pharmacological properties in man.