Short-term treatment with oleoyl-oestrone in liposomes (Merlin-2) strongly reduces the expression of the ob gene in young rats

Abstract

Young female rats of 160-180 g were implanted with osmotic minipumps releasing 3.0 micromol/day per kg of oleoyl-oestrone in liposomes (Merlin-2) into the bloodstream for up to 14 days. Merlin-2 induced a loss of appetite in the first days, later recovered, and a decrease in body weight of 7%, which contrasts with the 15% increase in controls during the 2-week period. Neither plasma glucose nor urea was affected by treatment, but liver glycogen increased by 50% in 14 days. Insulin decreased slightly with Merlin-2 treatment. Plasma corticotropin (ACTH) and corticosterone showed a transient increase by day 6 of treatment. The expression of the ob gene in adipose tissue fell during the period studied to practically nil on day 14; circulating leptin levels decreased more than 70% from day 1 to day 14. Oestrone levels increased from 0.3 nM (controls) to a maintained 40-60 nM level for the rest of the experiment. Oleoyl-oestrone levels first increased 4-fold, to decrease again to the initial levels on day 10, increasing later to 100-fold on day 14. The three phases observed in food intake, weight loss and oleoyl-oestrone levels match fairly well, which supports the direct involvement of oleoyl-oestrone in body-weight control. However, the control of oleoyl-oestrone levels seems to be mediated in part by corticosterone. The practical disappearance of leptin synthesis coincides with the massive accumulation of oleoyl-oestrone in plasma. The results presented suggest the involvement of oleoyl-oestrone in the main mechanisms of control of body weight and its regulation by glucocorticoids and leptin.

Combined effects of oral oleoyl-estrone and limited food intake on body composition of young overweight male rats

“…11 This is accomplished essentially by facilitating the use of fatty acids by the muscle and other peripheral tissues, 13 decreasing the oxidation of glucose and increasing its storage as glycogen, 10 and, at the same time, decreasing insulin resistance. 11,26 Under OE, glucose levels are maintained in spite of a marked decrease of insulin.…”

“…11,26 Under OE, glucose levels are maintained in spite of a marked decrease of insulin. 10,11,17 In food deprivation or restriction, glycaemia is maintained at the expense of 3C fragments, essentially derived from amino acids through the glucose-alanine cycle. 27 However, under OE treatment there is no need for an enhanced liver glucose output, since peripheral utilisation of glucose is decreased, 28 which results in the sparing of protein.…”

“…27 However, under OE treatment there is no need for an enhanced liver glucose output, since peripheral utilisation of glucose is decreased, 28 which results in the sparing of protein. 10,11 However, when the rat is subjected to an additional and severe decrease in food available, the emergency mechanisms that maintain glycaemia are nevertheless activated. The higher sensitivity to insulin elicited by OE may result in enhanced hepatic gluconeogenesis, thus draining the 3C fragments available.…”

“…6 The oral administration of OE to lean, genetically obese or dietary-obese rodents induces a marked loss of body fat, 7,8 primarily due to a decrease in voluntary food intake coupled with the maintenance of energy expenditure. 9 Glucose levels are maintained in spite of marked decreases in insulin and leptin, 10 a consequence of OE-elicited increase in insulin sensitivity/decrease in insulin resistance, 11 which results in the maintenance of liver glycogen stores regardless of the severe drainage of body energy. 10 Lipid mobilisation, however, does not massively increase circulating lipids, since lipid oxidation is also increased as shown by the lowering of the respiratory quotient, 5 and marked decrease in cholesterol levels 12 coupled with enhanced muscle lipoprotein lipase activity.…”

“…9 Glucose levels are maintained in spite of marked decreases in insulin and leptin, 10 a consequence of OE-elicited increase in insulin sensitivity/decrease in insulin resistance, 11 which results in the maintenance of liver glycogen stores regardless of the severe drainage of body energy. 10 Lipid mobilisation, however, does not massively increase circulating lipids, since lipid oxidation is also increased as shown by the lowering of the respiratory quotient, 5 and marked decrease in cholesterol levels 12 coupled with enhanced muscle lipoprotein lipase activity. 13 Human obesity has been traditionally treated with hypocaloric diets, since it is assumed that a decrease in energy intake must compel the body to mobilise its fat stores to cope with the energy imbalance; however, dieting tends to decrease energy expenditure, 14 which makes much harder to significantly affect the mass of stored fat.…”