The central hypothesis of this proposal is that suppression of GnRH/LH secretion during lactation is due to suckling- induced alterations in hypothalamic neural systems that regulate food intake and energy balance. Lactation is characterized by an excessive hyperphagia and negative energy balance due to milk production. Our studies have established that several hypothalamic neuropeptide orexigenic systems involved in regulating food intake/energy balance (NPY, orexin, melanin concentrating hormone [MCH], neurokinin B [NKB}) make direct connections with GnRH neurons, thus providing a neuroanatomical framework by which signals denoting changes in food intake/energy balance can be directly transmitted to GnRH neurons. The proposed studies will use a multidisciplinary approach to explore the following basic questions: 1) Do orexigenic and anorexigenic neuropeptides directly modulate GnRH neuronal activity and exert an increased inhibitory tone during lactation? Studies will use hypothalamic explants and electrophysiology to determine if agonists and antagonists to NPY, orexin, MCH or NKB receptors have direct effects on GnRH neurons. 2) Is the lactation-specific induction of NPY in the dorsomedial hypothalamic nucleus involved in the suppression of GnRH activity? Studies will examine the functional role of the suckling-specific induction of NPY in the suppression of GnRH/LH. 3) Are the profound suppression of leptin and the hypoinsulinemia associated with lactation important permissive signals that allow arcuate nucleus neurons to drive the suppression of GnRH neuronal activity and hyperphagia? Studies will restore leptin and insulin to postlactation levels and determine effects on hypothalamic neuropeptide feeding systems and on restoration of GnRH/LH secretion. Subsequent experiments will use ablation techniques to determine the functional relevance of identified factors in the suppression of GnRH neuronal activity during lactation. The lactating rat provides a physiological model for studying a number of conditions in women (undernutrition, anorexia nervosa, bulimia, exercise-induced amenorrhea and lactation) that involve a suppression of reproductive function associated with negative energy balance. The lactating rat is also a model of chronic hyperphagia and provides the opportunity to study physiological mechanisms underlying conditions of greatly increased food intake and may provide insights into causes of obesity.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD014643-27
Application #
7860670
Study Section
Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
Program Officer
Lamar, Charisee A
Project Start
1979-12-01
Project End
2012-06-30
Budget Start
2010-07-01
Budget End
2012-06-30
Support Year
27
Fiscal Year
2010
Total Cost
$282,754
Indirect Cost
Name
Oregon Health and Science University
Department
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
True, C; Takahashi, D; Kirigiti, M et al. (2017) Arcuate nucleus neuropeptide coexpression and connections to gonadotrophin-releasing hormone neurones in the female rhesus macaque. J Neuroendocrinol 29:
Baquero, Arian F; Kirigiti, Melissa A; Baquero, Karalee C et al. (2015) Developmental changes in synaptic distribution in arcuate nucleus neurons. J Neurosci 35:8558-69
Baquero, Arian F; de Solis, Alain J; Lindsley, Sarah R et al. (2014) Developmental switch of leptin signaling in arcuate nucleus neurons. J Neurosci 34:9982-94
Verma, Saurabh; Kirigiti, Melissa A; Millar, Robert P et al. (2014) Endogenous kisspeptin tone is a critical excitatory component of spontaneous GnRH activity and the GnRH response to NPY and CART. Neuroendocrinology 99:190-203
True, Cadence; Verma, Saurabh; Grove, Kevin L et al. (2013) 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. Endocrinology 154:2821-32
Nicol, L E; Grant, W F; Grant, W R et al. (2013) Pancreatic inflammation and increased islet macrophages in insulin-resistant juvenile primates. J Endocrinol 217:207-13
Lee, Shin J; Kirigiti, Melissa; Lindsley, Sarah R et al. (2013) Efferent projections of neuropeptide Y-expressing neurons of the dorsomedial hypothalamus in chronic hyperphagic models. J Comp Neurol 521:1891-914
Lee, Shin J; Verma, Saurabh; Simonds, Stephanie E et al. (2013) Leptin stimulates neuropeptide Y and cocaine amphetamine-regulated transcript coexpressing neuronal activity in the dorsomedial hypothalamus in diet-induced obese mice. J Neurosci 33:15306-17
True, C; Kirigiti, M A; Kievit, P et al. (2011) Leptin is not the critical signal for kisspeptin or luteinising hormone restoration during exit from negative energy balance. J Neuroendocrinol 23:1099-112
Sullivan, Elinor L; Smith, M Susan; Grove, Kevin L (2011) Perinatal exposure to high-fat diet programs energy balance, metabolism and behavior in adulthood. Neuroendocrinology 93:1-8

Showing the most recent 10 out of 91 publications