Effect of the slimming agent oleoyl-estrone in liposomes on the body weight of Zucker obese rats

F, Balada; Sanchı́s, Daniel; Mm, Grasa; Virgili, J.; Estruch, J; Fernández-López, José Antonio; Remesar, Xavier; Alemany, M.

doi:10.1038/sj.ijo.0800475

Cited by 26 publications

(29 citation statements)

References 23 publications

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“…The effects of oleoyl-estrone in liposomes observed here, are comparable to those found in other experimental models, 6,8,9 but they are`accelerated' (that is, the percentage of loss of body weight in ADX-OE rats over four or ®ve days, is the same as that observed in normal rats treated for two weeks). The differences between SO-OE and ADX-OE rats are largely due to a synergistic effect of adrenalectomy and oleoyl-estrone treatment and not the simple addition of their separate effects (that is the sum of differences between SO and ADX and, SO and OE-SO).…”

Section: Discussionsupporting

confidence: 72%

“…The body weight lost in just one week was higher than the total amount of fat stored in a normal rat, 8 which means that the rats lost not only fat, but also lean tissue. The high urea levels suggest that protein was actively mobilized in a situation when liver glycogen had been totally exhausted and the rat had dif®culty in maintaining blood glucose.…”

Section: Discussionmentioning

confidence: 99%

“…40 Administration of oleoyl-estrone in liposomes leads to weight loss in rats, 6 greatly affecting the leptin pathway. 12 This effect is not due to modulation of leptin synthesis, since it is observed even in hyperleptinaemic 41 Zucker obese rats, 8 which lack a fully functional leptin receptor. 42,43 The amounts of¯uid drunk by SO and ADX-OE rats were similar and in the range of previous studies for the same strain 44 and we can assume that their metabolic water contribution (about one third) to the total water budget of the rat was comparable in all groups studied, since total energy consumption was also comparable (either from food consumed and from internal sources) in all groups.…”

Section: Discussionmentioning

confidence: 99%

“…5 It has been postulated that both leptin 1 and oleoyl-estrone 6 are ponderostat signals. Pharmacological doses of oleoyl-estrone in liposomes have been found to cause weight loss in normal, 6,7 genetically obese 8 and cafeteria-obese 9 rats, the loss of fat being dosedependent. 7 In humans, both plasma leptin 10 and oleoyl-estrone 11 are correlated with their fat mass.…”

Section: Introductionmentioning

confidence: 99%

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1998

Int J Obes

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OBJECTIVE: To determine the extent of glucocorticoid counter-regulatory control in the slimming action of oleoylestrone. DESIGN: Control and adrenalectomized rats were subjected to a seven-day treatment with 3.5 mmolakgad oleoylestrone in liposomes injected i.v. continuously by implanted osmotic minipumps. SUBJECTS: Sham-operated control and adrenalectomized lean Zucker rats. MEASUREMENTS: Body weight and food intake; plasma glucose, urea, insulin, leptin and corticosterone; liver glycogen. RESULTS: Treatment with oleoyl-estrone resulted in decreases in body weight and in food intake, as well as in circulating glucose, insulin and leptin. Combined adrenalectomy and oleoyl-estrone treatment resulted in a loss of almost 15% body weight in only seven days, with a severe drop in circulating glucose and insulin, almost total disappearance of plasma leptin and liver glycogen and a 3-fold rise in circulating urea. Food intake decreased sharply, which resulted in the exhaustion of energy reserves. CONCLUSION: The results presented here, strongly support the hypothesis that glucocorticoids play an important role in the modulation of oleoyl-estrone-induced imbalance of energy intake and expenditure. The large effect of oleoyl-estrone on glucose, glycogen-and protein-derived (urea levels) energy in adrenalectomized rats, provides more evidence for the assumed protective role of glucocorticoids against the oleoyl-estrone-induced net loss of energy reserves. The results also show the powerful destabilizing effects of unchecked oleoyl-estrone on energy balance. and cafeteria-obese 9 rats, the loss of fat being dosedependent. 7 In humans, both plasma leptin 10 and oleoyl-estrone 11 are correlated with their fat mass. Chronic administration of oleoyl-estrone in liposomes induces a decrease in leptin production and concentrations, as well as a transient rise in plasma glucocorticoid concentrations, 12 with only limited increases in hypothalamic CRH. 13Glucocorticoids protect the body fat stores by counter-regulating the effects of lipolytic agents. 14 High cortisol or corticosterone levels are associated with the maintenance of body fat reserves and obesity, as well as insulin resistance. 15 The increase in glucocorticoids contributes to the down-regulation of receptors when thermogenesis is stimulated by adrenergic agonists. 16 Adrenalectomy may prevent the development of some types of obesity, 17 but not all, 18 and it may affect fat accumulation of the already obese. 19The action of glucocorticoids is further modulated by corticosterone binding globulin (CBG), a protein synthesized by liver and other tissues.20 Most circulating glucocorticoid is bound to plasma CBG. 21 The expression and levels of CBG are controlled by glucocorticoids.22 Its main role is probably to compete with cell receptors for the available hormone, thus acting as a modulator of the amount of hormone that reaches the cell binding sites. 23The obese often show enhanced sensitivity to glucocorticoids, 24 and they maintain high circulating International Jour...

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Section: Discussionsupporting

confidence: 72%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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1998

Int J Obes

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“…1,2 The ability to induce the loss of weight is closely dependent on its structure, since modi®cation of the fatty acid or the steroid nucleus deeply alters its effectivity. 3 Treatment with oleoyl-estrone of lean, 1 obese, 4 and cafeteria diet-fed rats 5 reduces their fat content, sparing protein 1,2 and decreasing fat cell size, 6 but maintaining unchanged plasma metabolite levels in the rat. 7 Circulating oleoyl-estrone, present mainly in the lipoproteins, is related to body mass in humans, 8 but not in the morbidly obese (unpublished results).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2000

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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.

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Differential Short‐Term Distribution of Estrone and Oleoyl‐Estrone Administered in Liposomes to Lean and Obese Zucker Rats

F¹,

Sanchı́s²,

Mm³

et al. 1998

Obesity Research

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rats were injected through a cannula inserted in the left jugular vein with 1 mL/kg of 3H-labeled oleoyl-estrone in liposomes (Merlin-2) (i.e., 670 fmol, 84 kBq). The rats were killed 10 minutes later and dissected. The presence of intact or hydrolyzed oleoylestrone was later determined in all samples. The pattern of distribution of estrone was quite different from that of oleoyl-estrone both in rats that were lean and in those that were obese. Estrone was better retained by white adipose tissue than oleoyl-estrone. Liver, spleen, and lungs accumulated more oleoyl-estrone and split part of it, from 4.7% (lung, obese) to 27% (liver, lean). The overall high retention of estrone by the rat tissues results in its very low circulating levels. The fast splitting of liposome-carried oleoyl-estrone by most tissues (up to more than 67% by intestine and skin of lean rats) may help explain the rise in blood free estrone. The differences between lean and obese Zucker rats are mainly quantitative in the case of estrone, the main differences being found in blood and adipose tissues. However, when we compare the data for oleoyl-estrone, the differences cannot be dismissed simply as due to differences in body size or the extent of fat deposits. A large portion of the label remained in the blood of the rats that were obese but not in those that were lean, the tissues of which took up more label. Brown adipose tissue shows a fair affinity for oleoyl-estrone in the rats that were lean but practically does not retain label in the rats that were obese, suggesting that oleoyl-estrone may have a direct effect on brown adipose tissue. The decreased uptake of oleoyl-estrone in rats that were obese shows that the mechanism regulating the turnover or disposal of this signal is altered in this type of genetic obesity.

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Effect of the slimming agent oleoyl-estrone in liposomes on the body weight of Zucker obese rats

Cited by 26 publications

References 23 publications

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

Differential Short‐Term Distribution of Estrone and Oleoyl‐Estrone Administered in Liposomes to Lean and Obese Zucker Rats

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