STRUCTURAL DETERMINANTS OF OLEOYL-ESTRONE SLIMMING EFFECTS

Female adult 9-week old Wistar rats were implanted with osmotic minipu mps releasing for 14 days a liposome suspension (controls) loaded with oleoyl-estrone or other compounds of the Merlin series: estrone, estr adiol, oleoyl-estradiol, oleoyl-DHEA, stearoyl-estrone, palmitoyl-estr one, oleoyl-diethylstilbestrol (DES), estrone oleoyl-ether and oleoyl- 3-methoxy-estrone. All compounds were given at the same dose of 3.5 mu mol/day kg for 14 days. The effects on body weight and food intake we re recorded. In the case of estrone esters, the body composition and n itrogen balance were also determined. The chronic administration of ol eoyl-estrone in liposomes to rats lowers food intake, maintaining ener gy consumption, thus inducing the active utilization of internal store s and, consequently, the loss of body weight. This loss is mainly due to a decrease in fat, with lower proportional losses of water and a li mited consumption of body protein. Free estrone had no effects on body weight, but estradiol did induce a decrease in body weight, similar t o that of oleoyl-estradiol. Oleoyl-DHEA had no significant effect on b ody weight nor in food intake. Oleoyl-DES mimicked fairly well the eff ects of oleoyl-estrone, both affecting food intake and body weight. Th ere was a relative lack of effects of estrone oleoyl-ether and of oleo yl-3-methoxy-estrone. The effects of oleoyl-estrone were in part mimic ked by stearoyl-and palmitoyl-estrone, but their activity on a molar b asis was lower, which suggests that the fatty acid moiety significantl y influences the activity of the estrone ester as a slimming agent. Th e differences observed in the appetite suppression and overall slimmin g power of the stearoyl and palmitoyl-estrone clearly indicate that th e sites of action of the physiological agonist oleoyl-estrone are at l east two; the shape of the molecule, thus, may elicit a different degr ee of response of the systems controlled by oleoyl-estrone levels. Fro m this interaction a series of global effects are elicited, such as ap petite suppression and the loss of body (fat) weight, the latter in pa rt (but not only) due to decreased food intake. The results shown here also suggest that the overall configuration of fatty acyl-estrone is more constrictive for its function as slimming agent than for its role as appetite suppressant, which hints to different target organs or si tes of action endowed with receptors showing different degrees of fulf illing the structural constrictions of the agonist molecule.