CONTROL OF GONADOTROPIN SECRETION DURING LACTATION

Summary

Principal Investigator: Kevin L Grove
Abstract: DESCRIPTION (provided by applicant): It is firmly established that states of energy deficiency, such as fasting, anorexia nervosa, cachexia, bulimia, lactation and exercise-induced amenorrhea, as well as states of energy overabundance, such as obesity, are both associated with disruptions in fertility. These studies focus on states of negative energy balance that are associated with a suppression of reproductive function. The identity of the specific metabolic signals or afferent neural pathways that convey information about energy balance to gonadotropin-releasing hormone (GnRH) neurons, the central hypothalamic system regulating reproduction, remains elusive. Key to elucidating this link is an understanding of the regulation of kisspeptin neurons, the primary gatekeepers in controlling GnRH neurons. Our studies use two models of negative energy balance, lactation and caloric restriction, and have shown that kisspeptin signaling is greatly suppressed during these states. A key hypothesis of this proposal is that suppression of kisspeptin signaling is the primary factor in the inhibition of GnRH during states of negative energy balance. Although it is a widely held view that hypoleptinemia is the critical factor linking energy balance and suppressed GnRH, our recent studies demonstrate that restoring leptin to normal physiological levels does not reverse the inhibition of kisspeptin r GnRH in either lactation or caloric restriction. Thus, hypoleptinemia does not appear to be the primary metabolic factor responsible for the suppression of reproductive function. The proposed studies focus on new systems for integrating metabolic signals. Our hypothesis is that brainstem systems, such as glucose sensing catecholaminergic neurons, may be the site where information about metabolic signals is relayed to hypothalamic systems regulating GnRH neurons. This proposal focuses on two hypotheses: 1) Suppression of kisspeptin signaling at the site of GnRH cell bodies and at nerve fibers and terminals are primary components in the inhibition of basal GnRH secretion during states of negative energy balance, and 2) Brainstem systems serve as a site of integration of metabolic signals and provide the afferent signals that are responsible for the suppression of kisspeptin and GnRH during negative energy balance. These studies will use transgenic and wild-type rats and mice to identify mechanisms by which a decrease in kisspeptin tone coupled with increased inhibitory input to GnRH cell bodies results in a decrease in GnRH neuronal excitability, and will explore the roles of kisspeptin and neurokinin B in regulating GnRH release from nerve terminals. Studies will also establish the functional connectivity of afferent neural input that suppresses kisspeptin neurons. We propose that once the inhibitory input to kisspeptin neurons is identified, blocking the input will not onl restore kisspeptin but also reverse the inhibition on GnRH. Elucidating the specific links between energy balance and reproductive function has been a long-term goal for the past several decades. These studies will identify new pathways that regulate kisspeptin neurons that in turn control GnRH neurons and could lead to new treatments for restoring fertility or for new contraceptive agents that inhibit fertility.
Funding Period: 1979-12-01 - 2016-06-30
more information: NIH RePORT

Top Publications

  1. ncbi Prenatal development of hypothalamic neuropeptide systems in the nonhuman primate
    B E Grayson
    Division of Neuroscience, Oregon Health and Science University, Oregon National Primate Research Center, 505 NW 185th Avenue, Beaverton, OR 97006, USA
    Neuroscience 143:975-86. 2006
  2. pmc The neuroendocrine basis of lactation-induced suppression of GnRH: role of kisspeptin and leptin
    M Susan Smith
    Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University, 505 NW 185th Avenue, Beaverton, OR 97006, USA
    Brain Res 1364:139-52. 2010
  3. pmc Characterisation of arcuate nucleus kisspeptin/neurokinin B neuronal projections and regulation during lactation in the rat
    Cadence True
    Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon 97006, USA
    J Neuroendocrinol 23:52-64. 2011
  4. pmc Perinatal exposure to high-fat diet programs energy balance, metabolism and behavior in adulthood
    Elinor L Sullivan
    Department of Neuroscience, Oregon National Primate Research Center, Beaverton, OR 97006, USA
    Neuroendocrinology 93:1-8. 2011
  5. pmc Leptin is not the critical signal for kisspeptin or luteinising hormone restoration during exit from negative energy balance
    C True
    Oregon National Primate Research Center, Division of Neuroscience, Oregon Health and Science University, Beaverton, OR 97006, USA
    J Neuroendocrinol 23:1099-112. 2011
  6. pmc Beyond Leptin: Emerging Candidates for the Integration of Metabolic and Reproductive Function during Negative Energy Balance
    Cadence True
    Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University Beaverton, OR, USA
    Front Endocrinol (Lausanne) 2:53. 2011
  7. pmc Efferent projections of neuropeptide Y-expressing neurons of the dorsomedial hypothalamus in chronic hyperphagic models
    Shin J Lee
    Division of Neuroscience, Oregon National Primate Research Center, Beaverton, Oregon 97006, USA
    J Comp Neurol 521:1891-914. 2013
  8. pmc Pancreatic inflammation and increased islet macrophages in insulin-resistant juvenile primates
    L E Nicol
    Pediatrics, Division of Neurosciences, Oregon National Primate Research Center Pape Pediatric Research Institute, Oregon Health and Science University, CDRCP, 707 SW Gaines Street, Portland, Oregon 97239 3098, USA
    J Endocrinol 217:207-13. 2013
  9. pmc Cocaine- and amphetamine-regulated transcript is a potent stimulator of GnRH and kisspeptin cells and may contribute to negative energy balance-induced reproductive inhibition in females
    Cadence True
    Divisions of Diabetes, Obesity, and Metabolism, and Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006, USA
    Endocrinology 154:2821-32. 2013
  10. pmc Differential gene expression between neuropeptide Y expressing neurons of the dorsomedial nucleus of the hypothalamus and the arcuate nucleus: microarray analysis study
    Shin Draper
    Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University, 505 NW 185th Avenue, Beaverton, OR 97006 3499, USA
    Brain Res 1350:139-50. 2010

Research Grants

  1. The Kiss1 system in the neuroendocrine control of reproduction
    VICTOR MANUEL NAVARRO; Fiscal Year: 2013
  2. CARDIOVASCULAR DYNAMICS AND THEIR CONTROL
    John E Hall; Fiscal Year: 2013
  3. Neural basis of leptin action on reproduction
    Carol Fuzeti Elias; Fiscal Year: 2013
  4. Restoring Mycocardial Healing
    MARK ALAN SUSSMAN; Fiscal Year: 2013
  5. Arcuate nucleus glutamatergic neurons modulate energy homeostasis
    Anthony N van den Pol; Fiscal Year: 2013

Detail Information

Publications20

  1. ncbi Prenatal development of hypothalamic neuropeptide systems in the nonhuman primate
    B E Grayson
    Division of Neuroscience, Oregon Health and Science University, Oregon National Primate Research Center, 505 NW 185th Avenue, Beaverton, OR 97006, USA
    Neuroscience 143:975-86. 2006
    ..Additionally, because differences exist in the neuroanatomy of NPY and melanocortin circuitry the regulation of these systems may be different in primates than in rodents...
  2. pmc The neuroendocrine basis of lactation-induced suppression of GnRH: role of kisspeptin and leptin
    M Susan Smith
    Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University, 505 NW 185th Avenue, Beaverton, OR 97006, USA
    Brain Res 1364:139-52. 2010
    ..The inhibition of Kiss1 may be the key factor in the suppression of GnRH during lactation, although the mechanisms responsible for its inhibition are unknown...
  3. pmc Characterisation of arcuate nucleus kisspeptin/neurokinin B neuronal projections and regulation during lactation in the rat
    Cadence True
    Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon 97006, USA
    J Neuroendocrinol 23:52-64. 2011
    ..Furthermore, the absence of a strong ARH Kiss1/NKB projection to the POA suggests regulation of GnRH by this population occurs primarily at the ME level via local projections...
  4. pmc Perinatal exposure to high-fat diet programs energy balance, metabolism and behavior in adulthood
    Elinor L Sullivan
    Department of Neuroscience, Oregon National Primate Research Center, Beaverton, OR 97006, USA
    Neuroendocrinology 93:1-8. 2011
    ..Thus, it is critical that future studies identify therapeutic strategies that are effective at preventing maternal HFD-induced malprogramming...
  5. pmc Leptin is not the critical signal for kisspeptin or luteinising hormone restoration during exit from negative energy balance
    C True
    Oregon National Primate Research Center, Division of Neuroscience, Oregon Health and Science University, Beaverton, OR 97006, USA
    J Neuroendocrinol 23:1099-112. 2011
    ..These results suggest that, although leptin may be a permissive signal for reproductive function, hypoleptinaemia is unlikely to be the critical signal responsible for ARC Kiss1 and LH inhibition during negative energy balance...
  6. pmc Beyond Leptin: Emerging Candidates for the Integration of Metabolic and Reproductive Function during Negative Energy Balance
    Cadence True
    Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University Beaverton, OR, USA
    Front Endocrinol (Lausanne) 2:53. 2011
    ..This review will focus on emerging candidates for the integration of metabolic status and reproductive function during negative energy balance...
  7. pmc Efferent projections of neuropeptide Y-expressing neurons of the dorsomedial hypothalamus in chronic hyperphagic models
    Shin J Lee
    Division of Neuroscience, Oregon National Primate Research Center, Beaverton, Oregon 97006, USA
    J Comp Neurol 521:1891-914. 2013
    ..The present data suggest that NPY expression in the DMH during chronic hyperphagic conditions plays important roles in feeding behavior and thermogenesis by modulating neuronal functions within the hypothalamus, but not in the brainstem...
  8. pmc Pancreatic inflammation and increased islet macrophages in insulin-resistant juvenile primates
    L E Nicol
    Pediatrics, Division of Neurosciences, Oregon National Primate Research Center Pape Pediatric Research Institute, Oregon Health and Science University, CDRCP, 707 SW Gaines Street, Portland, Oregon 97239 3098, USA
    J Endocrinol 217:207-13. 2013
    ..Given the parallel development of metabolic disease between humans and NHPs, these findings have strong relevance to the early metabolic disease driven by a chronic HFD in children...
  9. pmc Cocaine- and amphetamine-regulated transcript is a potent stimulator of GnRH and kisspeptin cells and may contribute to negative energy balance-induced reproductive inhibition in females
    Cadence True
    Divisions of Diabetes, Obesity, and Metabolism, and Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006, USA
    Endocrinology 154:2821-32. 2013
    ....
  10. pmc Differential gene expression between neuropeptide Y expressing neurons of the dorsomedial nucleus of the hypothalamus and the arcuate nucleus: microarray analysis study
    Shin Draper
    Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University, 505 NW 185th Avenue, Beaverton, OR 97006 3499, USA
    Brain Res 1350:139-50. 2010
    ..These findings strongly suggest that DMH-NPY neurons could play a distinct role in the control of energy homeostasis and are differentially regulated from ARH-NPY neurons through afferent inputs and transcriptional regulators...
  11. pmc Chronic consumption of a high-fat diet during pregnancy causes perturbations in the serotonergic system and increased anxiety-like behavior in nonhuman primate offspring
    Elinor L Sullivan
    Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Sciences University, Beaverton, Oregon 97006, USA
    J Neurosci 30:3826-30. 2010
    ..These findings have important clinical implications as they demonstrate that exposure to maternal HFD consumption during gestation, independent of obesity, increases the risk of developing behavioral disorders such as anxiety...
  12. ncbi Melanocortinergic activation by melanotan II inhibits feeding and increases uncoupling protein 1 messenger ribonucleic acid in the developing rat
    Maria M Glavas
    Oregon National Primate Research Center, Department of Physiology and Pharmacology, Oregon Health and Science University, 505 NW 185th Avenue, Beaverton, Oregon 97006, USA
    Endocrinology 148:3279-87. 2007
    ..These findings demonstrate that MTII can inhibit food intake and stimulate energy expenditure before the full development of hypothalamic feeding neurocircuitry. These effects do not appear to be mediated by changes in NPY expression...
  13. ncbi Excess weight gain during the early postnatal period is associated with permanent reprogramming of brown adipose tissue adaptive thermogenesis
    Xiao Qiu Xiao
    Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University, 505 Northwest 185th Avenue, Beaverton, Oregon 97006, USA
    Endocrinology 148:4150-9. 2007
    ..Overall, these observations provide the first evidence that postnatal excess weight gain results in abnormalities in BAT thermogenesis and sympathetic outflow, which likely increases susceptibility to obesity in adulthood...
  14. ncbi Characterization of brainstem peptide YY (PYY) neurons
    Maria M Glavas
    Division of Neuroscience, Oregon National Primate Research Center, Beaverton, Oregon 97006, USA
    J Comp Neurol 506:194-210. 2008
    ..Collectively, the projection pattern and association with orexigenic neuropeptides suggest that brainstem PYY neurons may play a role in energy homeostasis through a coordinated effect on visceral, motor, and sympathetic output targets...
  15. pmc Suppression of basal spontaneous gonadotropin-releasing hormone neuronal activity during lactation: role of inhibitory effects of neuropeptide Y
    Jing Xu
    Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University, 505 Northwest 185th Avenue, Beaverton, Oregon 97006, USA
    Endocrinology 150:333-40. 2009
    ....
  16. pmc Maternal high-fat diet triggers lipotoxicity in the fetal livers of nonhuman primates
    Carrie E McCurdy
    Department of Pediatrics, University of Colorado Denver, Aurora, Colorado 80045, USA
    J Clin Invest 119:323-35. 2009
    ..These results suggest that a developing fetus is highly vulnerable to excess lipids, independent of maternal diabetes and/or obesity, and that exposure to this may increase the risk of pediatric NAFLD...
  17. pmc Regulation of food intake and gonadotropin-releasing hormone/luteinizing hormone during lactation: role of insulin and leptin
    Jing Xu
    Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon 97006, USA
    Endocrinology 150:4231-40. 2009
    ..The chronic hyperphagia of lactation is most likely sustained by the induction of NPY in the DMH. The negative energy balance also does not appear to be a necessary prerequisite for the suppression of GnRH/LH activity...
  18. pmc Critical determinants of hypothalamic appetitive neuropeptide development and expression: species considerations
    B E Grayson
    Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University, Portland, OR 97239, USA
    Front Neuroendocrinol 31:16-31. 2010
    ....
  19. pmc Early overnutrition results in early-onset arcuate leptin resistance and increased sensitivity to high-fat diet
    Maria M Glavas
    Oregon National Primate Research Center, Oregon Health and Science University, 505 Northwest 185th Avenue, Beaverton, Oregon 97006, USA
    Endocrinology 151:1598-610. 2010
    ..These studies suggest that early overnutrition can permanently alter energy homeostasis and significantly increase susceptibility to obesity and insulin resistance...
  20. pmc Leptin stimulates neuropeptide Y and cocaine amphetamine-regulated transcript coexpressing neuronal activity in the dorsomedial hypothalamus in diet-induced obese mice
    Shin J Lee
    Division of Diabetes, Obesity and Metabolism and Division of Neuroscience, Oregon National Primate Research Center, Beaverton, Oregon 97006, and Monash Obesity and Diabetes Institute, Monash University, Clayton, Victoria, Australia 3800
    J Neurosci 33:15306-17. 2013
    ....

Research Grants30

  1. The Kiss1 system in the neuroendocrine control of reproduction
    VICTOR MANUEL NAVARRO; Fiscal Year: 2013
    ..This additional training will aid in my development of a competitive research program and contribute to my establishment as an independent investigator. ..
  2. CARDIOVASCULAR DYNAMICS AND THEIR CONTROL
    John E Hall; Fiscal Year: 2013
    ..End of Abstract) ..
  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. Restoring Mycocardial Healing
    MARK ALAN SUSSMAN; Fiscal Year: 2013
    ..The goal of this program will be to delineate these deleterious signaling mechanisms and determine how they can be overcome to restore endogenous cellular repair processes that heal the damaged heart. ..
  5. Arcuate nucleus glutamatergic neurons modulate energy homeostasis
    Anthony N van den Pol; Fiscal Year: 2013
    ..abstract_text> ..