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

Abstract

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.

Do the Interactions between Glucocorticoids and Sex Hormones Regulate the Development of the Metabolic Syndrome?

“…The list of factors potentially modifying body fat set-point is longer: estrone (Ferrer-Lorente et al, 2005; and the ponderostat signal derived from estrone; Vilà et al, 2011) dehydroepiandrosterone (Tchernof and Labrie, 2004), progesterone, aldosterone. In addition, the possibilities of regulation include retinoids (Kriegsfeld and Silver, 2004), hydroxycalciferols (Wortsman et al, 2000), hormone-transporting globulins (Barat et al, 2005; Li et al, 2010), and especially, hormone receptors (Mauvais-Jarvis, 2011).…”

“…Deranged maintenance of ponderostat settings caused by –or parallel to– altered secretion/detection of ponderostat signals, including sensitivity to peptides [leptin (Eikelis et al, 2007), adiponectin (Tomita et al, 2008)] and the postulated estrone-derived ponderostat signal (Vilà et al, 2011). …”

“…Glucocorticoids inhibit its lipostatic effects (Grasa et al, 2007), and oleoyl-estrone modulates increases glucocorticoid synthesis (Romero et al, 2010) and decreases the synthesis of testosterone (Romero et al, 2009). However, recent studies have shown that oleoyl-estrone is not the active agent producing changes in ponderostat setting and metabolic changes, but a derivative of this compound, which structure has not yet been discovered but which is nonetheless related to estrogens too (Vilà et al, 2011). …”

Oleoyl‐Estrone

“…Thus, the HPLC‐MS/MS values obtained for true OE levels in rat plasma (even after an oral load of OE) were only a tiny fraction of the results obtained using the hydrolysis‐RIA methods, and in no way justified the high levels of labelled estrone found in plasma after an oral gavage of 3 H‐or 2 H‐labelled OE. The analysis of samples with tritium or 14 C‐labelled estrone proved that the estrone nucleus label did not correspond to the elution time of OE in the HPLC‐MS/MS setting . The data unequivocally proved, then, that the active form of OE transported in the plasma does not correspond to the chemical structure of OE.…”

Metabolic syndrome: is equine disease comparable to what we know in humans?

“…As the secretion capacity of leptin differs within different fat depots depending on the age, gender, and circadian rhythm, the likelihood that leptin represents a true ponderostat signal is low (79, 80, 81, 82). Recent studies have demonstrated that oleoyl-estrone itself cannot be responsible for the control of body fat, but a derivate might (83). In other words, the brain is involved in the pathogenesis of metabolic syndrome, but the exact mechanisms remain obscure.…”