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Nongenomic Estrogen Effects on Nitric Oxide Synthase Activity in Rat Adipocytes

Département de Biochimie et de Biologie Moléculaire (A.-M.J., N.M.-M., D.S., Y.G.), Faculté de Médecine Paris-Ile de France-Ouest, Université de Versailles Saint-Quentin en Yvelines, F-78000 Versailles, France; Institut National de la Santé et de la Recherche Médicale (INSERM) Unité 755 (D.L.), Université Pierre et Marie Curie, Hôpital Hôtel-Dieu, Centre de Recherche en Nutrition Humaine, F-75004 Paris, France; and INSERM (C.R.) Unité Mixte de Recherche en Santé 747, Université Paris Descartes, Pharmacologie Toxicologie et Signalisation Cellulaire, F-75006 Paris, France

Address all correspondence and requests for reprints to: C. Ribière; Pharmacologie Toxicologie et Signalisation Cellulaire, 45 rue des Saints-Pères, 75270 Paris Cedex 06, France. E-mail: catherine.ribiere{at}paris-ouest.univ-paris5.fr.

Estrogens exert multiple genomic effects on adipose tissue through binding to nuclear estrogen receptors. However, there is evidence for additional nongenomic mechanisms whereby estrogens may exert their control on adipose tissue metabolism through rapid activation of various membrane-initiated kinase cascades. Here, we tested rapid effects of estrogens on nitric oxide production in white adipose tissue using 17-ß estradiol (E2) and its membrane impermeant albumin conjugated form (17-ß estradiol hemisuccinate BSA, E2-BSA). We found that both E2 and E2-BSA stimulate nitric oxide synthase (NOS) activity in adipocytes. These effects were abolished by 1) ICI 182–780, a selective estrogen receptor antagonist; 2) wortmannin, an inhibitor of phosphatidylinositol 3-kinase; and 3) N-[2-(p-bromocinnamylamino) ethyl]-5-isoquinolinesulfonamide (H-89) an inhibitor of protein kinase A. In contrast to NOS activation by E2, E2-BSA-induced NOS activity was abolished by UO126, an inhibitor of MAPK kinase/ERK (p42/p44 MAPKs). Immunoblotting studies have shown that both estrogens phosphorylate endothelial NOS (NOS III) on Ser¹¹⁷⁹, an effect that is prevented by wortmannin and H89, suggesting that NOS III is the target for estrogen-induced NOS activity. Furthermore, only the E2-BSA-induced NOS III phosphorylation on Ser¹¹⁷⁹ was totally abolished by UO126. These results indicate that the signaling cascades involved in adipocyte NOS stimulation by estrogens are different depending on whether estrogens are free or conjugated to albumin and therefore underline the importance of estrogen receptor locations in the nongenomic actions of estrogens in these cells.

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