title: Obesity-induced hypogonadism in the male: premature reproductive neuroendocrine senescence and contribution of Kiss1-mediated mechanisms.
abstract: Reproduction is sensitive to insufficient body energy reserves, especially in females. Metabolic regulation of the male reproductive axis is less obvious, and the impact of conditions of persistent energy excess has received moderate attention. Yet, the escalating prevalence of obesity and the clinical evidence of its deleterious effects on male fertility have raised considerable concerns. We report here phenotypic and mechanistic studies of the reproductive impact of postnatal nutritional manipulations (mainly overnutrition) coupled to a high-fat diet (HFD) after weaning. Metabolic and hormonal analyses in young (4 months old) and middle-aged (10 months old) animals revealed that HFD caused profound metabolic perturbations, including glucose intolerance, which were worsened by precedent postnatal overfeeding; these were detectable already in young males but aggravated in 10-month-old rats. Impairment of reproductive parameters took place progressively, and HFD alone was sufficient to explain most of these alterations, regardless of postnatal under- or overnutrition. In young males, testosterone (T) levels and steroidogenic enzyme expression were suppressed by HFD, without compensatory increases of LH levels, which were in fact partially inhibited in heavier males. In addition, obese males displayed suppressed hypothalamic Kiss1 expression despite low T, and HFD inhibited LH responses to kisspeptin. Overweight anticipated some of the neuroendocrine effects of aging, such as the suppression of hypothalamic Kiss1 expression and the decline in serum T and LH levels. Nonetheless, HFD per se caused a detectable worsening of key reproductive indices in middle-aged males, such as basal LH and FSH levels as well as LH responses to kisspeptin. Our study demonstrates that nutritional stress, especially HFD, has a profound deleterious impact on metabolic and gonadotropic function as well as on the Kiss1 system and precipitates neuroendocrine reproductive senescence in the male.
authors.affiliation: Department of Cell Biology, Physiology, and Immunology; CIBERobn Fisiopatología de la Obesidad y Nutrición; Department of Cell Biology, Physiology, and Immunology; and Instituto Maimonides de Investigación Biomedica de Cordoba (IMIBIC)/Hospital Universitario Reina Sofia (M.A.S.-G., F.R.-P., M.M.-L., S.L., D.G.-G., J.P.C., R.M.L., A.R.-R., J.M.C., L.P., M.T.-S.), University of Córdoba, 14004 Córdoba, Spain; and Department of Physiology (C.D.), University of Santiago de Compostela, 15782 Santiago de Compostela, Spain.
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: Sánchez-Garrido
authors.forename: Francisco
authors.initials: F
authors.lastname: Ruiz-Pino
authors.forename: Maria
authors.initials: M
authors.lastname: Manfredi-Lozano
authors.forename: Silvia
authors.initials: S
authors.lastname: Leon
authors.forename: David
authors.initials: D
authors.lastname: Garcia-Galiano
authors.forename: Justo P
authors.initials: JP
authors.lastname: Castaño
authors.forename: Raul M
authors.initials: RM
authors.lastname: Luque
authors.forename: Antonio
authors.initials: A
authors.lastname: Romero-Ruiz
authors.forename: Juan M
authors.initials: JM
authors.lastname: Castellano
authors.forename: Carlos
authors.initials: C
authors.lastname: Diéguez
authors.forename: Leonor
authors.initials: L
authors.lastname: Pinilla
authors.forename: Manuel
authors.initials: M
authors.lastname: Tena-Sempere
mesh_terms: D000818:Animals; D001835:Body Weight; D059305:Diet, High-Fat; D005786:Gene Expression Regulation; D005951:Glucose Tolerance Test; D007006:Hypogonadism / Q000209:etiology / Q000378:metabolism* / Q000473:pathology*; D007031:Hypothalamus / Q000378:metabolism; D017403:In Situ Hybridization; D059648:Kisspeptins / Q000378:metabolism*; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D009490:Neurosecretory Systems / Q000502:physiology*; D009765:Obesity / Q000150:complications / Q000473:pathology*; D010641:Phenotype; D051381:Rats; D017208:Rats, Wistar; D012098:Reproduction; D012737:Sex Factors; D013739:Testosterone / Q000378:metabolism; D013997:Time Factors
chemical_list: C491406:Kiss1 protein, rat; D059648:Kisspeptins; D013739:Testosterone; D007986:Luteinizing Hormone