The Significance of Leptin Signals to Neonatal Somatotropes and Gonadotropes

Summary

Principal Investigator: Gwen V Childs
Abstract: DESCRIPTION (provided by applicant): Adipocyte leptin has been considered as "permissive" for normal reproduction;however, its exact role is uncertain. In humans, serum leptin levels rise to a peak by midgestation, just before the appearance and expansion of populations of somatotropes and gonadotropes. In rodents, there is a similar rise in leptin level during the neonatal development period (which is equivalent to midgestation in humans), with a peak that matches the timing of the postnatal expansion in both somatotropes and gonadotropes. The novel hypothesis being explored in this study is that leptin may serve as an early postnatal regulator of reproductive function by supporting somatotrope and gonadotrope development early in their development. This is supported by data showing that gonadotropes and somatotropes express leptin receptors (Ob-R). Furthermore, both cell types are reduced in number in mutant rats or mice that are deficient in leptin or Ob-R. Humans with mutations in leptin or Ob-R are infertile and those who have mutated Ob-R do not grow normally. We hypothesize that leptin's role in the pituitary complements its well established role in the hypothalamus by stimulating an expansion of somatotropes and gonadotropes and thus facilitating normal responses to hypothalamic stimulation. This role may be played before the neuropeptide pulses are mature. Our hypothesis will be tested with mouse models in which Ob-R have been selectively ablated or truncated in either the somatotrope or gonadotrope populations. This approach will isolate the effects of Ob-R on one cell type at a time, thus eliminating confounding effects seen in mice or rats with global Ob-R knockout. Mutant mice with cell-specific deletion of the Ob-R gene (Lepr) will be created by crossing founders carrying the Cre- recombinase transgene driven by the rat growth hormone promoter (rGHp-Cre) or the rat luteinizing hormone- 2 promoter (rLH2p-GFP-Cre) with mice carrying the Ob-R gene flanked by loxP sequences ("floxed"). Aim 1 studies will test the effect of ablating Ob-R in somatotropes on the postnatal development of somatotropes and their responses to growth hormone-releasing hormone (GHRH) and insulin-like growth factor-1 (IGF-1). Aim 2 studies will test the effect of deleting Ob-R in gonadotropes on the postnatal development of gonadotropes and their responses to gonadotropin-releasing hormone (GnRH) and neuropeptide Y (NPY). Both sets of studies will also investigate the role of leptin in the postnatal development of lactotropes, timing of puberty, fertility, development of the reproductive organs, and somatotrope or gonadotrope responses to gonadal steroids. These studies will provide for the first time a focused view of the importance of leptin receptors to either gonadotropes or somatotropes and a subset of somatomamotropes. PUBLIC HEALTH RELEVANCE: Leptin is a hormone produced by fat that plays a key role in regulating energy intake and expenditure. After birth, leptin levels rise just before gonadotropes and somatotropes, cells of the anterior pituitary gland that produce hormones essential for reproduction, grow in number and reach adult levels by age 10-15 days. This study will test the hypothesis that this postnatal rise in leptin levels promotes this early increase in the number of somatotropes and gonadotropes to levels that are vital for normal reproduction. This proposal thus addresses important questions about how leptin can affect reproductive competence at the level of the pituitary.
Funding Period: 2009-08-15 - 2014-06-30
more information: NIH RePORT

Top Publications

  1. pmc The somatotrope as a metabolic sensor: deletion of leptin receptors causes obesity
    Gwen V Childs
    Professor and Chair, Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA
    Endocrinology 152:69-81. 2011
  2. pmc Does the pituitary somatotrope play a primary role in regulating GH output in metabolic extremes?
    Raul M Luque
    Department of Cell Biology, Physiology and Immunology, University of Cordoba, Instituto Maimonides de Investigacion Biomedica de Cordoba, CIBER Fisiopatologia de la Obesidad y Nutricion, Cordoba, Spain
    Ann N Y Acad Sci 1220:82-92. 2011
  3. pmc Ablation of leptin signaling to somatotropes: changes in metabolic factors that cause obesity
    Noor Akhter
    Department of Neurobiology and Developmental Sciences, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA
    Endocrinology 153:4705-15. 2012
  4. pmc Ghrelin restoration of function in vitro in somatotropes from male mice lacking the Janus kinase (JAK)-binding site of the leptin receptor
    Mohsin Syed
    Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, College of Medicine, 4301 West Markham, Slot 510, Little Rock, Arkansas 72205, USA
    Endocrinology 154:1565-76. 2013

Research Grants

  1. Harvard Reproductive Endocrine Sciences Center
    William Francis Crowley; Fiscal Year: 2013
  2. Clinical and Basic Studies in Polycystic Ovarian Syndrome
    John C Marshall; Fiscal Year: 2013
  3. Neural basis of leptin action on reproduction
    Carol Fuzeti Elias; Fiscal Year: 2013
  4. Prenatal Programming of Reproductive Health and Disease
    Vasantha Padmanabhan; Fiscal Year: 2013
  5. Functional Consequences of Impaired Autophagy in Aging
    ANA M CUERVO; Fiscal Year: 2013
  6. EARLY EVENTS IN ALZHEIMER PATHOGENESIS
    SUE TILTON GRIFFIN; Fiscal Year: 2013
  7. Molecular and Cellular Basis for Digestive Diseases
    Richard M Peek; Fiscal Year: 2013
  8. Simultaneous Insulin and Leptin Signaling in POMC Neurons Promotes Fertility and
    LATRICE DOREEN FAULKNER; Fiscal Year: 2013
  9. Role of Dicer in Gonadotrope and Reproductive Function
    T Rajendra Kumar; Fiscal Year: 2013
  10. Translational Research in Cystic Fibrosis
    Mitchell L Drumm; Fiscal Year: 2013

Detail Information

Publications4

  1. pmc The somatotrope as a metabolic sensor: deletion of leptin receptors causes obesity
    Gwen V Childs
    Professor and Chair, Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA
    Endocrinology 152:69-81. 2011
    ..The specific ablation of the Lepr exon 17 gene in somatotropes resulted in GH deficiency with a consequential reduction in lipolytic activity normally maintained by GH and increased adiposity...
  2. pmc Does the pituitary somatotrope play a primary role in regulating GH output in metabolic extremes?
    Raul M Luque
    Department of Cell Biology, Physiology and Immunology, University of Cordoba, Instituto Maimonides de Investigacion Biomedica de Cordoba, CIBER Fisiopatologia de la Obesidad y Nutricion, Cordoba, Spain
    Ann N Y Acad Sci 1220:82-92. 2011
    ....
  3. pmc Ablation of leptin signaling to somatotropes: changes in metabolic factors that cause obesity
    Noor Akhter
    Department of Neurobiology and Developmental Sciences, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA
    Endocrinology 153:4705-15. 2012
    ..These findings signify that leptin signals to somatotropes are vital for the normal metabolic activity needed to optimize body composition...
  4. pmc Ghrelin restoration of function in vitro in somatotropes from male mice lacking the Janus kinase (JAK)-binding site of the leptin receptor
    Mohsin Syed
    Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, College of Medicine, 4301 West Markham, Slot 510, Little Rock, Arkansas 72205, USA
    Endocrinology 154:1565-76. 2013
    ..These discoveries suggest that leptin may optimize somatotrope function by facilitating expression of membrane GHRH receptors and the production or maintenance of GH stores...

Research Grants30

  1. Harvard Reproductive Endocrine Sciences Center
    William Francis Crowley; Fiscal Year: 2013
    ..abstract_text> ..
  2. Clinical and Basic Studies in Polycystic Ovarian Syndrome
    John C Marshall; Fiscal Year: 2013
    ..s. ..
  3. Neural basis of leptin action on reproduction
    Carol Fuzeti Elias; Fiscal Year: 2013
    ..In addition, we will also assess the requirement of leptin signaling in both (PMV and Kiss1) neuronal population (Aim3) for the full rescue of the infertility phenotype of LepR null mice. ..
  4. Prenatal Programming of Reproductive Health and Disease
    Vasantha Padmanabhan; Fiscal Year: 2013
    ..abstract_text> ..
  5. Functional Consequences of Impaired Autophagy in Aging
    ANA M CUERVO; Fiscal Year: 2013
    ..Significance: These studies may ultimately lead to fundamental insights for understanding, treating or preventing the metabolic alterations and declined cognitive and immune function characteristic of elders. ..
  6. EARLY EVENTS IN ALZHEIMER PATHOGENESIS
    SUE TILTON GRIFFIN; Fiscal Year: 2013
    ..The synergy between our aims, approaches, and measures will enable us to meet our goal of defining early cellular interactions toward development of rational interventions in AD. ..
  7. Molecular and Cellular Basis for Digestive Diseases
    Richard M Peek; Fiscal Year: 2013
    ..The Administrative Core also contains Biostatistics and Enrichment Programs and oversees the financial management and operation of the VDDRC. ..
  8. Simultaneous Insulin and Leptin Signaling in POMC Neurons Promotes Fertility and
    LATRICE DOREEN FAULKNER; Fiscal Year: 2013
    ..Collectively, these experiments will establish whether the absence of insulin and leptin signaling in POMC neurons elevates LH pulse secretion and testosterone release, thus impairing the steroidal negative feedback. ..
  9. Role of Dicer in Gonadotrope and Reproductive Function
    T Rajendra Kumar; Fiscal Year: 2013
    ..Delineation of mechanisms of gonadotropin secretion is fundamental to physiology of reproduction and offers long-term clinical benefits of diagnosing and treating gonadotropin-dependent fertility/infertility disorders. ..
  10. Translational Research in Cystic Fibrosis
    Mitchell L Drumm; Fiscal Year: 2013
    ..This goal is also a function of the Biomedical Research Cores. ..
  11. Dissecting hormonal &neural control of social behavior in a transgenic cichlid
    SCOTT ALAN JUNTTI; Fiscal Year: 2013
    ..abstract_text> ..
  12. ApoE Receptor Biology and Neurodegeneration
    Mary Jo Ladu; Fiscal Year: 2013
    ..This Program will thus provide new and valuable information about how apoE and apoE receptors affect the pathogenesis of Alzheimer's disease. ..