Journal of Steroid Biochemistry & Molecular Biology 124 (2011) 99–111 Contents lists available at ScienceDirect Journal of Steroid Biochemistry and Molecular Biology journal homepage: www.elsevier.com/locate/jsbmb Oleoyl-estrone is a precursor of an estrone-derived ponderostat signal Ruth Vilà a,b , Cristina Cabot a,b , Laura Villarreal a,b,1 , Ana Monegal a,b,2 , Eva Ayet a,b,3 , María del Mar Romero a,b , Maria del Mar Grasa a,b , Montserrat Esteve a,b , José Antonio Fernández-López a,b , Xavier Remesar a,b , Marià Alemany a,b,∗ a Department of Nutrition and Food Science, Faculty of Biology, University of Barcelona, Barcelona, Spain b CIBER Obesity and Nutrition, Institute of Health Carlos III, Spain article info Article history: Received 5 October 2010 Received in revised form 27 January 2011 Accepted 28 January 2011 Keywords: Oleoyl-estrone Estrone Obesity Anti-obesity drugs Estrogen Adipose tissue 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 mas- sive 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. © 2011 Elsevier Ltd. All rights reserved. ∗ Corresponding author. Current address: Department of Nutrition and Food Sci- ence, Faculty of Biology, University of Barcelona, Av. Diagonal, 645, 08028 Barcelona, Spain. Tel.: +34 934034606; fax: +34 934037064. E-mail addresses: ruth.vila@thompsonreuters.com (R. Vilà), criscm66@gmail.com (C. Cabot), lvillarreal@vhio.net (L. Villarreal), ana.monegal@iform-ieo-campus.it (A. Monegal), eayet@esteve.es (E. Ayet), marromero@ub.edu (M.M. Romero), mgrasa@ub.edu (M.M. Grasa), mesteve@ub.edu (M. Esteve), josfernandez@ub.edu (J.A. Fernández-López), xremesar@ub.edu (X. Remesar), malemany@ub.edu (M. Alemany). 1 Current address: Tumor Biomarkers Lab, Vall d’Hebron Institute of Oncology, Barcelona, Spain. 2 Current address: Dept. Experimental Oncology, European Institute of Oncology, Milan, Italy. 3 Current address: Esteve Pharma, Barcelona, Spain. 1. Introduction 1.1. Oleoyl-estrone, nature and effects Oleoyl-estrone (OE) is a powerful slimming agent [1,2]; it decreases food intake but, at the same time, maintains energy expenditure [3]. The energy gap is closed by the mobilisation of white adipose tissue (WAT) reserves [4], sparing body protein [3]. OE also decreases the high insulin [5] and hyperlipidemia of obese rats [6], particularly of cholesterol [6,7]. Liver glycogen is main- tained (or increased) by OE even under a severe loss of body lipid energy [5], also maintaining normoglycemia [8]. Treatment with OE is more effective in male than in female rats [9] and induces weight losses even under treatment with cafeteria diet [10] or other hyperlipidic diets [4,11]. A peculiarity of OE treat- ment is the permanent loss of fat, suggesting a role as ponderostat 0960-0760/$ – see front matter © 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.jsbmb.2011.01.017