Oleoyl-estrone does not have direct estrogenic effects on rats

Cabot, Cristina; Grasa, María del Mar; Massanés, Rosa Maria; Matteis, Rita De; Cinti, Saverio; Fernández-López, José Antonio; Remesar, Xavier

doi:10.1016/s0024-3205(01)01159-6

Cited by 23 publications

(26 citation statements)

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“…This binding occurred at a site different from the estrogen receptor(s) to which estradiol and estrone bind, and thus did not interfere. OE did not bind the estrone receptor when incubated with nuclei, a fact that was already tested by us when we found that OE did not bind to the estrogen receptor ␤ [54].…”

Section: In Vitro Exposure Of Nuclear Receptors To Labelled Oementioning

confidence: 61%

Oleoyl-estrone is a precursor of an estrone-derived ponderostat signal

Vila

Cabot

Villarreal

et al. 2011

The Journal of Steroid Biochemistry and Molecular Biology

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Oleoyl-estrone (OE) is a powerful anti-obesity compound that decreases food intake, decreases insulin resistance and circulating cholesterol. OE stimulates a severe loss of body fat by decreasing adipose tissue lipid synthesis and maintaining lipolysis. Therefore, the body economy loses lipid energy because energy expenditure is maintained. This study analyses the discrepancy between OE effects and the distribution of labelled OE in plasma. Estrone radioimmunoassay of organic solvent plasma extracts of rats treated with OE showed the massive presence of acyl-estrone, but saponification did not release estrone, but containing similar unknown compound. Analysis of label distribution in plasma after oral gavages of (3)H-OE showed the presence of a more hydrophilic compound than OE or any estrogen as well as (3)H(2)O, formed from (3)H-OE in the acidic stomach medium. OE was not attached to a specific transporter in plasma. Through serum HPLC analysis we found W, a labelled derivative more hydrophilic than OE or estrone. The results were confirmed using (14)C-OE. HPLC-MS/MS studies showed that plasma OE levels were one order of magnitude lower than those of W. When liver cell cytosols from rats laden with (3)H-OE were incubated with nuclei from untreated rats, the OE-derived label (i.e., Ws) was found attached to nuclear DNA. Neither estradiol nor estrone interfered with its binding. W is a fairly hydrophilic compound of low molecular weight containing the estrone nucleus, but it is not an ester because saponification or esterases do not yield estrone as OE does. It is concluded that OE acts through its conversion to W, its active form; which binds to a nuclear receptor different from that of estrogen. The estimated W serum levels are proportional to the pharmacological OE effects in vivo. We postulate W as a new type of hormone that exerts the full range of in vivo effects thus far attributed to OE. The full identification of W is anticipated to open the way for the development of new OE-like anti-obesity drugs.

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Section: In Vitro Exposure Of Nuclear Receptors To Labelled Oementioning

confidence: 61%

Oleoyl-estrone is a precursor of an estrone-derived ponderostat signal

Vila

Cabot

Villarreal

et al. 2011

The Journal of Steroid Biochemistry and Molecular Biology

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“…Chronic treatment with oleoyl-estrone decreases leptin expression and circulating levels, 7 and diminishes insulin resistance and the hyperlipidaemia of Zucker obese rats. 8 Intensive oral treatment of rats with oleoyl-estrone does not produce unwanted estrogenic effects, 9 mainly because most of the estrone freed by hydrolysis in the intestine is filtered by the liver. 10 Nevertheless, most of the oleoylestrone absorbed is loaded intact into lipoproteins.…”

Section: Introductionmentioning

confidence: 99%

Zucker obese rats store less acyl-estrone than lean controls

et al. 2003

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OBJECTIVE: To measure acyl-estrone levels in the plasma of Zucker obese rats. If these are lower than expected on the basis of their body-fat content, as observed in morbidly obese humans, this might provide a possible link relating obesity and low body estrone levels. We also examined the effect of pharmacological treatment with oral oleoyl-estrone on the accumulation of estrone. DESIGN: Undisturbed Wistar, Goto-Kakizaki and Zucker (lean Fa/?and obese fa/fa) rats were used to determine the relation between circulating acyl-estrone and body lipids, as well as the total body estrone/lipid ratios. One group of Wistar rats was used to measure the effect of oral gavages of oleoyl-estrone (from 0 to 20 mmol/kg/day) for 10 days on the body content of estrone. MEASUREMENTS: Body weight change and food intake. Total estrone intake, estrone accrual and excretion (by difference) in rats receiving oleoyl-estrone. Total body lipid and estrone. Circulating acyl-estrone levels. RESULTS: In lean rats (Wistar, Zucker and Goto-Kakizaki) there was a direct relation between body lipid content and circulating acyl-estrone; this relation was not found in Zucker obese rats. The estrone/lipid mass ratio was in a similar range in lean rats, but obese animals showed much lower values. Wistar rats receiving pharmacological doses of oleoyl-estrone did not accumulate significant amounts of estrone, but excreted almost all the estrone ingested. CONCLUSIONS: The pharmacological administration of acyl-estrone to rats does not result in the accrual of estrone within a wide range of doses, which confirms the safety of this compound. In rats there is a similar relation between the percentage of body lipids and circulating acyl-estrone to that found in humans. Likewise, obese rats showed lower levels of acyl-estrone than expected. The total content of estrone in the bodies of obese rats was also lower than expected from their high lipid content, which suggests that obese rats are deficient in acyl-estrone.

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“…Estrone has powerful energy storage effects as described above, but its easy interconversion with estradiol by means of 17β‐hydroxysteroid dehydrogenase may result in increased levels of estradiol following the massive hydrolysis of OE. Intravenous administration of OE produced significant estrogenic effects, which were not observed when OE was given orally to rats . The limited human data available suggest that there is indeed an increase in estradiol after OE administration, but of limited extent .…”

Section: Oleoyl‐estrone Estrogens and Androgensmentioning

confidence: 94%

“…): the actual levels of OE in plasma were in the range of 5–20 nM even after loading the rats with a large oral dose of OE . The results obtained using the “old” RIA method gave yields in the range of 100 nM under comparable basal conditions, with several‐fold increases after a load of OE . This difference could not be attributed to manipulation or analysis errors, since in both cases internal and external standards (tritiated, deuterated, and just unlabelled OE) were used, and the data derived from labelled OE were corrected for the actual specific activity (i.e.…”

Section: The Circulating Oleoyl‐estrone Derivative W Structure and mentioning

confidence: 99%

“…W either free or attached to lipoproteins is not susceptible to esterases as OE does; in cultured cells, exposure to microprecipitated OE (from OE solution in adequate organic solvents) results in its rapid hydrolysis . Injection of liposomes loaded with OE in vivo result in the appearance of massive amounts of estrone in plasma (a problem circumvented by oral administration), consequence of the massive hydrolysis of the real OE in tissues . In addition, as indicated above, cholesterol–ester esterase also easily hydrolyzes OE .…”

Section: Is There a “Transporting Protein”?mentioning

confidence: 99%

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Oleoyl‐Estrone

Remesar

Fernández-López

Alemany

2011

Medicinal Research Reviews

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Oleoyl-estrone (OE) is a powerful slimming agent that is also present in plasma and adipose tissue, where it is synthesized. It acts through the formation of a derivative W. OE effects (and W levels) are proportional to the dose. OE reduces food intake but maintains energy expenditure (thermogenesis). The energy gap is fulfilled with adipose tissue fat, sparing body protein and maintaining glycemia (and glycogen) with lower insulin and leptin levels. OE (in fact W) acts through specific receptors, different from those of estrogen. OE increases cholesterol catabolism, reducing hypercholesterolemia in obese rats. The main metabolic effect on adipose tissue is lowering of lipid synthesis, maintaining unchanged the intracellular lipolytic processes; the imbalance favors the progressive loss of fat, which is largely used by the muscle. OE administration induces additive effects with other antiobesity agents, such as β(3)-adrenergic agonists, forcing a massive loss of lipid. Corticosteroids markedly limit OE action by altering the liver control of lipogenesis. OE also inhibits the action of 17β-hydroxysteroid dehydrogenase, decreasing the synthesis of β-estradiol and testosterone. Discontinuous treatment allows for maximal efficacy both in rats and humans. OE has the advantage that the loss of fat is maintained and does not require additional dietary limitations.

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Oleoyl-estrone does not have direct estrogenic effects on rats

Cited by 23 publications

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Oleoyl-estrone is a precursor of an estrone-derived ponderostat signal

Oleoyl-estrone is a precursor of an estrone-derived ponderostat signal

Zucker obese rats store less acyl-estrone than lean controls

Oleoyl‐Estrone

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