title: Metabolic and Gonadotropic Impact of Sequential Obesogenic Insults in the Female: Influence of the Loss of Ovarian Secretion.
abstract: The reproductive impact of persistent energy excess in the female remains incompletely defined, yet the escalating prevalence of obesity calls for better understanding of this phenomenon. Also along this line, the influence of ovarian hormones on the pathophysiology of obesity and its comorbidities merits further investigation. We study here the metabolic and gonadotropic impact of sequential obesogenic insults, namely postnatal overnutrition [by rearing in small litters (SL)] and high-fat diet (HFD) after weaning, in gonadal-intact and ovariectomized (OVX) female rats. In young (4 mo) females, SL or HFD similarly increased body weight, yet only a HFD evoked additional metabolic perturbations, some of which were worsened by precedent SL. In addition, HFD concomitantly decreased LH and estradiol levels and, when combined with SL, suppressed Kiss1 expression in the hypothalamic arcuate nucleus in 4-month females, whereas HFD up to 10-month also reduced LH responses to kisspeptin-10. OVX caused rapid deterioration of the metabolic profile, with overweight, increased energy intake, and deregulation of leptin and glucose/insulin levels, effects whose magnitude was similar to, if not higher than, HFD. Summation of previous obesogenic insults maximally increased body weight, basal leptin, insulin and glucose levels, and glucose intolerance. Yet OVX obliterated the inhibitory effects of overweight/HFD on gonadotropin levels and arcuate nucleus Kiss1 expression. Our study documents the deleterious consequences of sequential obesogenic insults on the female gonadotropin axis, which involve central impairment of the Kiss1 system. In addition, our work delineates the dramatic impact of the loss of ovarian secretions, as the menopausal model, on the metabolic profile of female rats, especially when combined with preceding obesogenic challenges.
authors.affiliation: Department of Cell Biology, Physiology, and Immunology (M.A.S.-G., F.R.-P., M.M.-L., S.L., V.H., J.M.C., J.P.C., R.M.L., M.J.V., J.R., A.R.-R., L.P., M.T.-S.), University of Córdoba, Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, and Instituto Maimónides de Investigación Biomédica de Córdoba/Hospital Universitario Reina Sofía, 14004 Córdoba, Spain; and Department of Physiology (C.D.), University of Santiago de Compostela, 15782 Santiago de Compostela, Spain.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Sánchez-Garrido
authors.affiliation: Department of Cell Biology, Physiology, and Immunology (M.A.S.-G., F.R.-P., M.M.-L., S.L., V.H., J.M.C., J.P.C., R.M.L., M.J.V., J.R., A.R.-R., L.P., M.T.-S.), University of Córdoba, Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, and Instituto Maimónides de Investigación Biomédica de Córdoba/Hospital Universitario Reina Sofía, 14004 Córdoba, Spain; and Department of Physiology (C.D.), University of Santiago de Compostela, 15782 Santiago de Compostela, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Ruiz-Pino
authors.affiliation: Department of Cell Biology, Physiology, and Immunology (M.A.S.-G., F.R.-P., M.M.-L., S.L., V.H., J.M.C., J.P.C., R.M.L., M.J.V., J.R., A.R.-R., L.P., M.T.-S.), University of Córdoba, Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, and Instituto Maimónides de Investigación Biomédica de Córdoba/Hospital Universitario Reina Sofía, 14004 Córdoba, Spain; and Department of Physiology (C.D.), University of Santiago de Compostela, 15782 Santiago de Compostela, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Manfredi-Lozano
authors.affiliation: Department of Cell Biology, Physiology, and Immunology (M.A.S.-G., F.R.-P., M.M.-L., S.L., V.H., J.M.C., J.P.C., R.M.L., M.J.V., J.R., A.R.-R., L.P., M.T.-S.), University of Córdoba, Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, and Instituto Maimónides de Investigación Biomédica de Córdoba/Hospital Universitario Reina Sofía, 14004 Córdoba, Spain; and Department of Physiology (C.D.), University of Santiago de Compostela, 15782 Santiago de Compostela, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Leon
authors.affiliation: Department of Cell Biology, Physiology, and Immunology (M.A.S.-G., F.R.-P., M.M.-L., S.L., V.H., J.M.C., J.P.C., R.M.L., M.J.V., J.R., A.R.-R., L.P., M.T.-S.), University of Córdoba, Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, and Instituto Maimónides de Investigación Biomédica de Córdoba/Hospital Universitario Reina Sofía, 14004 Córdoba, Spain; and Department of Physiology (C.D.), University of Santiago de Compostela, 15782 Santiago de Compostela, Spain.
authors.forename: Violeta
authors.initials: V
authors.lastname: Heras
authors.affiliation: Department of Cell Biology, Physiology, and Immunology (M.A.S.-G., F.R.-P., M.M.-L., S.L., V.H., J.M.C., J.P.C., R.M.L., M.J.V., J.R., A.R.-R., L.P., M.T.-S.), University of Córdoba, Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, and Instituto Maimónides de Investigación Biomédica de Córdoba/Hospital Universitario Reina Sofía, 14004 Córdoba, Spain; and Department of Physiology (C.D.), University of Santiago de Compostela, 15782 Santiago de Compostela, Spain.
authors.forename: Juan M
authors.initials: JM
authors.lastname: Castellano
authors.affiliation: Department of Cell Biology, Physiology, and Immunology (M.A.S.-G., F.R.-P., M.M.-L., S.L., V.H., J.M.C., J.P.C., R.M.L., M.J.V., J.R., A.R.-R., L.P., M.T.-S.), University of Córdoba, Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, and Instituto Maimónides de Investigación Biomédica de Córdoba/Hospital Universitario Reina Sofía, 14004 Córdoba, Spain; and Department of Physiology (C.D.), University of Santiago de Compostela, 15782 Santiago de Compostela, Spain.
authors.forename: Justo P
authors.initials: JP
authors.lastname: Castaño
authors.affiliation: Department of Cell Biology, Physiology, and Immunology (M.A.S.-G., F.R.-P., M.M.-L., S.L., V.H., J.M.C., J.P.C., R.M.L., M.J.V., J.R., A.R.-R., L.P., M.T.-S.), University of Córdoba, Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, and Instituto Maimónides de Investigación Biomédica de Córdoba/Hospital Universitario Reina Sofía, 14004 Córdoba, Spain; and Department of Physiology (C.D.), University of Santiago de Compostela, 15782 Santiago de Compostela, Spain.
authors.forename: Raúl M
authors.initials: RM
authors.lastname: Luque
authors.affiliation: Department of Cell Biology, Physiology, and Immunology (M.A.S.-G., F.R.-P., M.M.-L., S.L., V.H., J.M.C., J.P.C., R.M.L., M.J.V., J.R., A.R.-R., L.P., M.T.-S.), University of Córdoba, Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, and Instituto Maimónides de Investigación Biomédica de Córdoba/Hospital Universitario Reina Sofía, 14004 Córdoba, Spain; and Department of Physiology (C.D.), University of Santiago de Compostela, 15782 Santiago de Compostela, Spain.
authors.forename: María J
authors.initials: MJ
authors.lastname: Vázquez
authors.affiliation: Department of Cell Biology, Physiology, and Immunology (M.A.S.-G., F.R.-P., M.M.-L., S.L., V.H., J.M.C., J.P.C., R.M.L., M.J.V., J.R., A.R.-R., L.P., M.T.-S.), University of Córdoba, Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, and Instituto Maimónides de Investigación Biomédica de Córdoba/Hospital Universitario Reina Sofía, 14004 Córdoba, Spain; and Department of Physiology (C.D.), University of Santiago de Compostela, 15782 Santiago de Compostela, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Roa
authors.affiliation: Department of Cell Biology, Physiology, and Immunology (M.A.S.-G., F.R.-P., M.M.-L., S.L., V.H., J.M.C., J.P.C., R.M.L., M.J.V., J.R., A.R.-R., L.P., M.T.-S.), University of Córdoba, Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, and Instituto Maimónides de Investigación Biomédica de Córdoba/Hospital Universitario Reina Sofía, 14004 Córdoba, Spain; and Department of Physiology (C.D.), University of Santiago de Compostela, 15782 Santiago de Compostela, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Romero-Ruiz
authors.affiliation: Department of Cell Biology, Physiology, and Immunology (M.A.S.-G., F.R.-P., M.M.-L., S.L., V.H., J.M.C., J.P.C., R.M.L., M.J.V., J.R., A.R.-R., L.P., M.T.-S.), University of Córdoba, Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, and Instituto Maimónides de Investigación Biomédica de Córdoba/Hospital Universitario Reina Sofía, 14004 Córdoba, Spain; and Department of Physiology (C.D.), University of Santiago de Compostela, 15782 Santiago de Compostela, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Diéguez
authors.affiliation: Department of Cell Biology, Physiology, and Immunology (M.A.S.-G., F.R.-P., M.M.-L., S.L., V.H., J.M.C., J.P.C., R.M.L., M.J.V., J.R., A.R.-R., L.P., M.T.-S.), University of Córdoba, Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, and Instituto Maimónides de Investigación Biomédica de Córdoba/Hospital Universitario Reina Sofía, 14004 Córdoba, Spain; and Department of Physiology (C.D.), University of Santiago de Compostela, 15782 Santiago de Compostela, Spain.
authors.forename: Leonor
authors.initials: L
authors.lastname: Pinilla
authors.affiliation: Department of Cell Biology, Physiology, and Immunology (M.A.S.-G., F.R.-P., M.M.-L., S.L., V.H., J.M.C., J.P.C., R.M.L., M.J.V., J.R., A.R.-R., L.P., M.T.-S.), University of Córdoba, Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, and Instituto Maimónides de Investigación Biomédica de Córdoba/Hospital Universitario Reina Sofía, 14004 Córdoba, Spain; and Department of Physiology (C.D.), University of Santiago de Compostela, 15782 Santiago de Compostela, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Tena-Sempere
mesh_terms: D000375:Aging / Q000502:physiology; D000818:Animals; D059305:Diet, High-Fat / Q000009:adverse effects; D005260:Female; D052681:Gonadotrophs / Q000378:metabolism / Q000502:physiology*; D009747:Nutritional Physiological Phenomena; D009765:Obesity / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D010053:Ovary / Q000378:metabolism* / Q000503:physiopathology; D044343:Overnutrition / Q000378:metabolism* / Q000503:physiopathology*; D051381:Rats; D017208:Rats, Wistar; D012098:Reproduction / Q000502:physiology