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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD059056-05
Application #
8496514
Study Section
Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
Program Officer
Lamar, Charisee A
Project Start
2009-08-15
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2013
Total Cost
$266,315
Indirect Cost
$79,165
Name
University of Arkansas for Medical Sciences
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
122452563
City
Little Rock
State
AR
Country
United States
Zip Code
72205
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Akhter, Noor; CarlLee, Tyler; Syed, Mohsin M et al. (2014) Selective deletion of leptin receptors in gonadotropes reveals activin and GnRH-binding sites as leptin targets in support of fertility. Endocrinology 155:4027-42
Syed, Mohsin; Cozart, Michael; Haney, Anessa C et al. (2013) Ghrelin restoration of function in vitro in somatotropes from male mice lacking the Janus kinase (JAK)-binding site of the leptin receptor. Endocrinology 154:1565-76
Luque, Raul M; Gahete, Manuel D; Cordoba-Chacon, Jose et al. (2011) Does the pituitary somatotrope play a primary role in regulating GH output in metabolic extremes? Ann N Y Acad Sci 1220:82-92
Childs, Gwen V; Akhter, Noor; Haney, Anessa et al. (2011) The somatotrope as a metabolic sensor: deletion of leptin receptors causes obesity. Endocrinology 152:69-81