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.