title: 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.
authors.affiliation: Department of Nutrition and Food Science, Faculty of Biology, University of Barcelona, Barcelona, Spain. ruth.vila@thompsonreuters.com
authors.forename: Ruth
authors.initials: R
authors.lastname: Vilà
authors.forename: Cristina
authors.initials: C
authors.lastname: Cabot
authors.forename: Laura
authors.initials: L
authors.lastname: Villarreal
authors.forename: Ana
authors.initials: A
authors.lastname: Monegal
authors.forename: Eva
authors.initials: E
authors.lastname: Ayet
authors.forename: María del Mar
authors.initials: Mdel M
authors.lastname: Romero
authors.forename: Maria del Mar
authors.initials: Mdel M
authors.lastname: Grasa
authors.forename: Montserrat
authors.initials: M
authors.lastname: Esteve
authors.forename: José Antonio
authors.initials: JA
authors.lastname: Fernández-López
authors.forename: Xavier
authors.initials: X
authors.lastname: Remesar
authors.forename: Marià
authors.initials: M
authors.lastname: Alemany
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D019440:Anti-Obesity Agents / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D004435:Eating / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D004970:Estrone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D008297:Male; D008970:Molecular Weight; D009829:Oleic Acids / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D011863:Radioimmunoassay; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction
chemical_list: D019440:Anti-Obesity Agents; D009829:Oleic Acids; D004970:Estrone; C108709:oleoyl-estrone