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.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
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Lamar, Charisee A
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University of Arkansas for Medical Sciences
Anatomy/Cell Biology
Schools of Medicine
Little Rock
United States
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Odle, Angela; Allensworth-James, Melody; Childs, Gwen V (2018) The War on the Placenta: The Differing Battles of High-Fat Diet and Obesity. Endocrinology 159:1642-1643
Odle, Angela K; BeneŇ°, Helen; Melgar Castillo, Andrea et al. (2018) Association of Gnrhr mRNA With the Stem Cell Determinant Musashi: A Mechanism for Leptin-Mediated Modulation of GnRHR Expression. Endocrinology 159:883-894
Allensworth-James, Melody L; Odle, Angela; Haney, Anessa et al. (2018) Sex-specific changes in postnatal GH and PRL secretion in somatotrope LEPR-null mice. J Endocrinol 238:221-230
Odle, Angela K; Akhter, Noor; Syed, Mohsin M et al. (2017) Leptin Regulation of Gonadotrope Gonadotropin-Releasing Hormone Receptors As a Metabolic Checkpoint and Gateway to Reproductive Competence. Front Endocrinol (Lausanne) 8:367
Odle, Angela Katherine; Allensworth-James, Melody; Haney, Anessa et al. (2016) Adipocyte Versus Somatotrope Leptin: Regulation of Metabolic Functions in the Mouse. Endocrinology 157:1443-56
Odle, Angela K; Allensworth-James, Melody L; Akhter, Noor et al. (2016) A Sex-Dependent, Tropic Role for Leptin in the Somatotrope as a Regulator of POU1F1 and POU1F1-Dependent Hormones. Endocrinology 157:3958-3971
Odle, Angela K; Drew, Paul D; Childs, Gwen V (2015) Giant mice reveal new roles for GH in regulating the adipose immune microenvironment. Endocrinology 156:1613-5
Allensworth-James, Melody L; Odle, Angela; Haney, Anessa et al. (2015) Sex Differences in Somatotrope Dependency on Leptin Receptors in Young Mice: Ablation of LEPR Causes Severe Growth Hormone Deficiency and Abdominal Obesity in Males. Endocrinology 156:3253-64
Odle, Angela K; Haney, Anessa; Allensworth-James, Melody et al. (2014) Adipocyte versus pituitary leptin in the regulation of pituitary hormones: somatotropes develop normally in the absence of circulating leptin. Endocrinology 155:4316-28
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

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