title: Effects of Chronic Estrogen Administration in the Ventromedial Nucleus of the Hypothalamus (VMH) on Fat and Bone Metabolism in Ovariectomized Rats.
abstract: Estrogen deficiency after ovariectomy (OVX) results in increased adiposity and bone loss, which can be prevented by systemic 17-β estradiol (E2) replacement. Studies in transgenic mice suggested that in addition to direct actions of estrogen in peripheral tissues, also estrogen signaling in the hypothalamus regulates fat distribution and bone metabolism. We hypothesized that the protective effect of systemic E2 on fat and bone metabolism in the OVX model is partly mediated through the ventromedial nucleus of the hypothalamus (VMH). To test this hypothesis, we determined the effect of systemic, central, and targeted VMH administration of E2 on fat and bone metabolism in OVX rats. Subcutaneous administration of E2 for 4 weeks decreased body weight, gonadal and perirenal fat, and bone formation rate in OVX rats. This effect was completely mimicked by intracerebroventricular injections of E2, once every 4 days for 4 weeks. Administration of E2 locally in the VMH by retromicrodialysis (3 h) acutely increased expression of the lipolytic gene hormone-sensitive lipase in gonadal and perirenal fat. Finally, chronic administration of E2 in the VMH for 8 weeks decreased perirenal fat but did not affect body weight, trabecular bone volume, or cortical thickness. In conclusion, we demonstrated that intracerebroventricular E2 replacement reduces body weight gain, ameliorates intraabdominal fat accumulation, and reduces bone formation in the OVX rats. E2 administration selectively in the VMH also reduced intraabdominal fat but did not affect bone metabolism.
authors.affiliation: Department of Endocrinology and Metabolism (Z.Z., J.L., A.G.V.-V., E.Fo., A.K., A.B., E.Fl., P.H.B.), Academic Medical Center, University of Amsterdam, 1105 AZ The Netherlands; Hypothalamic Integration Mechanisms (Y.S., A.K.), Netherlands Institute for Neuroscience, 1105 BA Amsterdam, The Netherlands; Department of Internal Medicine (B.C.J.v.d.E., M.K.), Erasmus Medical Center, 3075 EA Rotterdam, The Netherlands; Department of Clinical Chemistry (N.B.), VU University Medical Center, Research Institute MOVE, 1081 BT Amsterdam, The Netherlands; and Child Health Institute of New Jersey (J.L.), Robert Wood Johnson Medical School, Rutgers University, New Jersey 08901.
authors.forename: Z
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Endocrinology and Metabolism (Z.Z., J.L., A.G.V.-V., E.Fo., A.K., A.B., E.Fl., P.H.B.), Academic Medical Center, University of Amsterdam, 1105 AZ The Netherlands; Hypothalamic Integration Mechanisms (Y.S., A.K.), Netherlands Institute for Neuroscience, 1105 BA Amsterdam, The Netherlands; Department of Internal Medicine (B.C.J.v.d.E., M.K.), Erasmus Medical Center, 3075 EA Rotterdam, The Netherlands; Department of Clinical Chemistry (N.B.), VU University Medical Center, Research Institute MOVE, 1081 BT Amsterdam, The Netherlands; and Child Health Institute of New Jersey (J.L.), Robert Wood Johnson Medical School, Rutgers University, New Jersey 08901.
authors.forename: J
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Endocrinology and Metabolism (Z.Z., J.L., A.G.V.-V., E.Fo., A.K., A.B., E.Fl., P.H.B.), Academic Medical Center, University of Amsterdam, 1105 AZ The Netherlands; Hypothalamic Integration Mechanisms (Y.S., A.K.), Netherlands Institute for Neuroscience, 1105 BA Amsterdam, The Netherlands; Department of Internal Medicine (B.C.J.v.d.E., M.K.), Erasmus Medical Center, 3075 EA Rotterdam, The Netherlands; Department of Clinical Chemistry (N.B.), VU University Medical Center, Research Institute MOVE, 1081 BT Amsterdam, The Netherlands; and Child Health Institute of New Jersey (J.L.), Robert Wood Johnson Medical School, Rutgers University, New Jersey 08901.
authors.forename: A G
authors.initials: AG
authors.lastname: Veldhuis-Vlug
authors.affiliation: Department of Endocrinology and Metabolism (Z.Z., J.L., A.G.V.-V., E.Fo., A.K., A.B., E.Fl., P.H.B.), Academic Medical Center, University of Amsterdam, 1105 AZ The Netherlands; Hypothalamic Integration Mechanisms (Y.S., A.K.), Netherlands Institute for Neuroscience, 1105 BA Amsterdam, The Netherlands; Department of Internal Medicine (B.C.J.v.d.E., M.K.), Erasmus Medical Center, 3075 EA Rotterdam, The Netherlands; Department of Clinical Chemistry (N.B.), VU University Medical Center, Research Institute MOVE, 1081 BT Amsterdam, The Netherlands; and Child Health Institute of New Jersey (J.L.), Robert Wood Johnson Medical School, Rutgers University, New Jersey 08901.
authors.forename: Y
authors.initials: Y
authors.lastname: Su
authors.affiliation: Department of Endocrinology and Metabolism (Z.Z., J.L., A.G.V.-V., E.Fo., A.K., A.B., E.Fl., P.H.B.), Academic Medical Center, University of Amsterdam, 1105 AZ The Netherlands; Hypothalamic Integration Mechanisms (Y.S., A.K.), Netherlands Institute for Neuroscience, 1105 BA Amsterdam, The Netherlands; Department of Internal Medicine (B.C.J.v.d.E., M.K.), Erasmus Medical Center, 3075 EA Rotterdam, The Netherlands; Department of Clinical Chemistry (N.B.), VU University Medical Center, Research Institute MOVE, 1081 BT Amsterdam, The Netherlands; and Child Health Institute of New Jersey (J.L.), Robert Wood Johnson Medical School, Rutgers University, New Jersey 08901.
authors.forename: E
authors.initials: E
authors.lastname: Foppen
authors.affiliation: Department of Endocrinology and Metabolism (Z.Z., J.L., A.G.V.-V., E.Fo., A.K., A.B., E.Fl., P.H.B.), Academic Medical Center, University of Amsterdam, 1105 AZ The Netherlands; Hypothalamic Integration Mechanisms (Y.S., A.K.), Netherlands Institute for Neuroscience, 1105 BA Amsterdam, The Netherlands; Department of Internal Medicine (B.C.J.v.d.E., M.K.), Erasmus Medical Center, 3075 EA Rotterdam, The Netherlands; Department of Clinical Chemistry (N.B.), VU University Medical Center, Research Institute MOVE, 1081 BT Amsterdam, The Netherlands; and Child Health Institute of New Jersey (J.L.), Robert Wood Johnson Medical School, Rutgers University, New Jersey 08901.
authors.forename: B C J
authors.initials: BC
authors.lastname: van der Eerden
authors.affiliation: Department of Endocrinology and Metabolism (Z.Z., J.L., A.G.V.-V., E.Fo., A.K., A.B., E.Fl., P.H.B.), Academic Medical Center, University of Amsterdam, 1105 AZ The Netherlands; Hypothalamic Integration Mechanisms (Y.S., A.K.), Netherlands Institute for Neuroscience, 1105 BA Amsterdam, The Netherlands; Department of Internal Medicine (B.C.J.v.d.E., M.K.), Erasmus Medical Center, 3075 EA Rotterdam, The Netherlands; Department of Clinical Chemistry (N.B.), VU University Medical Center, Research Institute MOVE, 1081 BT Amsterdam, The Netherlands; and Child Health Institute of New Jersey (J.L.), Robert Wood Johnson Medical School, Rutgers University, New Jersey 08901.
authors.forename: M
authors.initials: M
authors.lastname: Koedam
authors.affiliation: Department of Endocrinology and Metabolism (Z.Z., J.L., A.G.V.-V., E.Fo., A.K., A.B., E.Fl., P.H.B.), Academic Medical Center, University of Amsterdam, 1105 AZ The Netherlands; Hypothalamic Integration Mechanisms (Y.S., A.K.), Netherlands Institute for Neuroscience, 1105 BA Amsterdam, The Netherlands; Department of Internal Medicine (B.C.J.v.d.E., M.K.), Erasmus Medical Center, 3075 EA Rotterdam, The Netherlands; Department of Clinical Chemistry (N.B.), VU University Medical Center, Research Institute MOVE, 1081 BT Amsterdam, The Netherlands; and Child Health Institute of New Jersey (J.L.), Robert Wood Johnson Medical School, Rutgers University, New Jersey 08901.
authors.forename: N
authors.initials: N
authors.lastname: Bravenboer
authors.affiliation: Department of Endocrinology and Metabolism (Z.Z., J.L., A.G.V.-V., E.Fo., A.K., A.B., E.Fl., P.H.B.), Academic Medical Center, University of Amsterdam, 1105 AZ The Netherlands; Hypothalamic Integration Mechanisms (Y.S., A.K.), Netherlands Institute for Neuroscience, 1105 BA Amsterdam, The Netherlands; Department of Internal Medicine (B.C.J.v.d.E., M.K.), Erasmus Medical Center, 3075 EA Rotterdam, The Netherlands; Department of Clinical Chemistry (N.B.), VU University Medical Center, Research Institute MOVE, 1081 BT Amsterdam, The Netherlands; and Child Health Institute of New Jersey (J.L.), Robert Wood Johnson Medical School, Rutgers University, New Jersey 08901.
authors.forename: A
authors.initials: A
authors.lastname: Kalsbeek
authors.affiliation: Department of Endocrinology and Metabolism (Z.Z., J.L., A.G.V.-V., E.Fo., A.K., A.B., E.Fl., P.H.B.), Academic Medical Center, University of Amsterdam, 1105 AZ The Netherlands; Hypothalamic Integration Mechanisms (Y.S., A.K.), Netherlands Institute for Neuroscience, 1105 BA Amsterdam, The Netherlands; Department of Internal Medicine (B.C.J.v.d.E., M.K.), Erasmus Medical Center, 3075 EA Rotterdam, The Netherlands; Department of Clinical Chemistry (N.B.), VU University Medical Center, Research Institute MOVE, 1081 BT Amsterdam, The Netherlands; and Child Health Institute of New Jersey (J.L.), Robert Wood Johnson Medical School, Rutgers University, New Jersey 08901.
authors.forename: A
authors.initials: A
authors.lastname: Boelen
authors.affiliation: Department of Endocrinology and Metabolism (Z.Z., J.L., A.G.V.-V., E.Fo., A.K., A.B., E.Fl., P.H.B.), Academic Medical Center, University of Amsterdam, 1105 AZ The Netherlands; Hypothalamic Integration Mechanisms (Y.S., A.K.), Netherlands Institute for Neuroscience, 1105 BA Amsterdam, The Netherlands; Department of Internal Medicine (B.C.J.v.d.E., M.K.), Erasmus Medical Center, 3075 EA Rotterdam, The Netherlands; Department of Clinical Chemistry (N.B.), VU University Medical Center, Research Institute MOVE, 1081 BT Amsterdam, The Netherlands; and Child Health Institute of New Jersey (J.L.), Robert Wood Johnson Medical School, Rutgers University, New Jersey 08901.
authors.forename: E
authors.initials: E
authors.lastname: Fliers
authors.affiliation: Department of Endocrinology and Metabolism (Z.Z., J.L., A.G.V.-V., E.Fo., A.K., A.B., E.Fl., P.H.B.), Academic Medical Center, University of Amsterdam, 1105 AZ The Netherlands; Hypothalamic Integration Mechanisms (Y.S., A.K.), Netherlands Institute for Neuroscience, 1105 BA Amsterdam, The Netherlands; Department of Internal Medicine (B.C.J.v.d.E., M.K.), Erasmus Medical Center, 3075 EA Rotterdam, The Netherlands; Department of Clinical Chemistry (N.B.), VU University Medical Center, Research Institute MOVE, 1081 BT Amsterdam, The Netherlands; and Child Health Institute of New Jersey (J.L.), Robert Wood Johnson Medical School, Rutgers University, New Jersey 08901.
authors.forename: P H
authors.initials: PH
authors.lastname: Bisschop
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004958:Estradiol / Q000008:administration & dosage*; D005260:Female; D005269:Femur / Q000187:drug effects* / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects*; D010012:Osteogenesis / Q000187:drug effects*; D010052:Ovariectomy; D051381:Rats; D002787:Sterol Esterase / Q000235:genetics / Q000378:metabolism; D014697:Ventromedial Hypothalamic Nucleus / Q000187:drug effects*
chemical_list: D004958:Estradiol; D002787:Sterol Esterase