Oral oleoyl-estrone induces the rapid loss of body fat in Zucker lean rats fed a hyperlipidic diet

Abstract

OBJECTIVE: To test whether oleoyl-estrone affects body weight when given orally, which may help curtail the secondary growth-boosting effects of derived estrone. DESIGN: The rats were fed for 15 days with a powdered hyperlipidic diet (16.97 MJakg metabolizable energy) in which 46.6% was lipid-derived and 16.1% protein-derived energy (HL group), containing 1.23 AE 0.39 m mmolakg of fatty-acyl esters of estrone. This diet was supplemented with additional oleoyl-estrone to produce diets with 2.5 m mmolakg (diet OE2.5), 4.4 m mmolakg (diet OE4.4), and 33.3 m mmolakg content in fatty-acyl estrone (diet OE33). SUBJECTS: Twelve-week old female Zucker lean (Faa?) rats initially weighing 200 ± 235 g. MEASUREMENTS: Food intake and body weight changes; urine and droppings production and nitrogen content. Body composition (water, lipid, protein) and total energy. Energy and nitrogen balances. Plasma chemistry including free amino acids. RESULTS: Oral administration of oleoyl-estrone in a hyperlipidic diet resulted in signi®cant losses of fat, energy and, ultimately, weight, which were dependent on the dose of oleoyl-estrone ingested. Treatment induced the maintenance of energy expenditure combined with lower food intake, creating an energy gap that was ®lled with internal fat stores whilst preserving body protein. The decrease in food intake was not a consequence of food aversion but of diminished appetite. Energy expenditure was practically constant for all groups except for the OE33, which showed values about 25% lower than the controls. In most of the groups studied, there was a net protein deposition in spite of severe lipid and energy drainage. Amino acid levels agreed with this N-sparing shift. In spite of lowered energy intake, the N balance was positive or near zero in all groups, with a sizeable N-gap in controls and in lower-dose groups that disappeared in the OE33 group. CONCLUSION: Treatment of rats with a hyperlipidic diet containing added oleoyl-estrone resulted in the dose-related loss of fat reserves with scant modi®cation of other metabolic parameters and preservation of body protein. The results agree with the postulated role of oleoyl-estrone as a ponderostat signal and open the way for its development as anti-obesity drug.

Effect of oral oleoyl-estrone treatment on plasma lipoproteins and tissue lipase activities of Zucker lean and obese female rats

“…Oleoyl-estrone induced a marked loss in body energy -up to 1% of the body energy content being lost daily in the same experimental conditions, mainly in the form of lipid. 8,9 However, the lack of tissue changes in lipoprotein lipase (and even its overall decrease) suggests that the amount of enzyme available in the tissues was enough to allow for the flow of lipid from WAT to liver and thence to other tissues such as muscle. The high lipoprotein lipase activity observed in the WAT of obese rats agrees with previous findings, 23 and contrasts with the limited ability of obese rats to dispose of chylomicra 21 and the maintenance of high concentrations of lipids in plasma.…”

“…6 Oleoyl-estrone elicits a loss of fat, while body protein is preserved. 8 This is accomplished by decreasing appetite but maintaining energy expenditure. 5 The loss of fat is dosedependent, 9 and independent of sex, 10 and of the mode of administration, ie continuous i.v.…”

“…injection, 5 oral gavage 9,10 or dispersed in the food. 8 A large proportion of oral oleoylestrone is absorbed unaffected by the digestive process and transferred to lipoproteins. 11 The effects of oleoyl-estrone are not mimicked by free estrone, which induces fat deposition and growth.…”

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

“…hunger pangs, hypoglycaemia), to enhance energy expenditure to speed up the process of fat disposal, or to maintain the weight loss during and after treatment. 16 OE has been used, so far without association to limited food intake, both in rodents and humans, [17][18][19] since OE limits food intake by itself, and prevents the fall in energy expenditure 5,11 that accompanies food deprivation. 4 In the present study, we have explored the combined effects of severely limited food intake and OE treatment, in order to determine whether hypocaloric diets enhance the slimming effects of OE on mature overweight male rats.…”

Short-term oral oleoyl-estrone treatment increases plasma cholesterol turnover in the rat

“…Nevertheless, the effects of oleoyl-estrone on food intake were already observable after 2 h of the oral administration of the hormone. 8 Oleoyl-estrone decreases circulating cholesterol, especially in the HDL fraction, 3 but does not alter the body cholesterol pool to a significant extent; 7 thus, any changes in plasma cholesterol dynamics may reflect modifications in lipoprotein turnover in addition to eventual changes in the rates of synthesis or excretion of cholesterol. Since the mobilisation of cholesterol and its transport via the blood is one of the most marked effects of oleoyl-estrone on lipid metabolism, we studied the turnover rate of cholesterol in rat plasma shortly after a single dose of oral oleoyl-estrone, when massive lipid mobilisation had not yet been fully established.…”