Integration of the regulation of reproductive function and energy balance: lactation as a model
Introduction
Lactation is a natural physiological state following parturition and is characterized by various alterations in the dam that allow her to adapt to this demanding condition. These adaptations include the cessation of reproductive cyclicity [14], [45], [107], large increases in food and water intake [43], [103], [128], induction of maternal behavior [9], [10], and increases in serum oxytocin and prolactin levels [179]. Other alterations reported in the lactating rat are the inhibition of seizure induction in response to NMDA receptor activation [1], [2], [49] and the suppression of responses to stress [93], [150], [151], [173], [172]. Thus, lactation is an ideal model to study profound changes in brain function brought about by naturally occurring physiological mechanisms.
In this review, we focus on how the hypothalamus integrates peripheral signals, such as sensory signals (suckling stimulus) and those denoting energy balance (leptin), to alter hypothalamic neuronal function regulating food intake/energy balance and reproduction. It is well established that negative energy balance, as typified by fasting, anorexia nervosa or exercise-induced amenorrhea, is associated with a suppression of reproductive function and ovarian cyclicity [18], [100], [112], [154]. Lactation is also a state characterized by negative energy balance, due to the profound energy drain resulting from milk production, and a suppression of cyclic reproductive function [14], [107], [176]. Although the specific hypothalamic neuronal systems involved in the regulation of food intake/energy balance and reproduction are not completely understood, several neuronal systems have been identified that are thought to be involved in both of these functions and, therefore, have overlapping functions. These systems likely serve as key signals to integrate and/or coordinate the status of energy balance and the neuroendocrine reproductive axis.
Section snippets
Inhibition of pulsatile LH secretion
It is well documented that pulsatile LH secretion is greatly suppressed during lactation in both ovarian intact and ovariectomized (OVX) lactators (Fig. 1) [32], [45], [82], [119], [131], [168]. Thus, regardless of the ovarian steroid hormonal profile that is present during lactation in various mammalian species, it does not directly contribute to the suppression of LH secretion. However, the suppression is directly dependent on the intensity of the suckling stimulus. OVX lactating rats
Changes in food intake/energy balance during lactation
The interrelationship between reproductive function and the status of energy balance is well established [18], [22], [44], [61], [100], [112], [154], [169]. Most notably, any condition in which negative energy balance persists is associated with an inhibition of cyclic reproductive function in all female mammalian species that have been studied. Furthermore, many of the same neuropeptides that have been shown to play a role in the regulation of food intake have overlapping functions in the
Neuroanatomical framework for changes in GnRH function during lactation
Knowledge of the neural pathways activated or inhibited by the suckling stimulus greatly facilitates an understanding of the mechanisms by which suckling induces changes in hypothalamic function. Earlier studies used either lesions [33], [34], electrical stimulation [171], [170], or 2-deoxyglucose [164] to identify central pathways for the milk-ejection reflex, and showed that impulses activated by suckling traveled through the spinal cord and were relayed through the lateral cervical nucleus
Hypothalamic integration of signals denoting food intake/energy availability with the regulation of reproductive function during lactation
As discussed earlier, data are accumulating that provide support for the notion that the suckling stimulus itself brings about neuronal changes in hypothalamic neuropeptide systems that result in an increase in food intake, in the absence of any metabolic signals of negative energy balance. These effects of the suckling stimulus are greatly reinforced through the added stimulus of negative energy balance. The relative importance of these components to the suppression of GnRH/LH secretion
Summary and conclusions
In this review, lactation has been used as a model to discuss how changes in a number of hypothalamic regulatory systems may be integrated to suppress cyclic reproductive function. What complicates our understanding of this integration is the fact that many of the hypothalamic regulatory systems have overlapping neuronal circuitry. The ARH–NPY system is presented as one example of this overlap, in that it is a major regulator of food intake/energy balance in response to the suckling stimulus
Perspectives for the future
The neuroanatomical framework presented in this review can be used to determine which components have physiological relevance to the suppression of GnRH/LH secretion during lactation. These physiological studies will be complicated by the absence of specific agonists or antagonists to orexin or MCH receptors or to the various NPY receptor subtypes. Also, because it is likely that redundant systems are in play with respect to the suppression of GnRH/LH secretion, inactivation of only one system
Acknowledgements
We express our thanks to Drs. Chien Li and Rebecca Brogan for their work that was conducted in our laboratory and discussed in this chapter. We also thank Peilin Chen, Rebecca Campbell, Dr. Patricia Williamson, Dr. Xiao Qui Xiao, and Bernadette Grayson for their ongoing work that was discussed in this chapter and their critical appraisal of the manuscript. This work was supported by U.S. Public Health Service Grants HD14643, RR00163, and HD08373.
References (198)
- et al.
Lactation inhibits hippocampal and cortical expression of cFos in response to NMDA but not kainate receptor agonists
Mol. Cell. Neurosci
(1992) - et al.
Cortical refractoriness to N-methyl-d, l-aspartic acid (NMA) stimulation in the lactating rat: recovery after pup removal and blockade of progesterone receptors
Brain Res
(1993) - et al.
Melanin-concentrating hormone and neuropeptide EI projections from the lateral hypothalamic area and zona incerta to the medial septal nucleus and spinal cord: a study using multiple neuronal tracers
Brain Res
(1998) - et al.
Y-receptor subtypes—How many more?
Trends Neurosci
(1997) - et al.
Prolactin–brain interactions in the induction of material behavior in rats
Psychoneuroendocrinology
(1994) - et al.
Role of the ventromedial hypothalamus in prolactin-induced hyperphagia in ring doves
Physiol. Behav
(1999) - et al.
Central leptin gene therapy suppresses body weight gain, adiposity and serum insulin without affecting food consumption in normal rats: a long-term study
Regul. Pept
(2001) - et al.
Somatosensory systems and the milk-ejection reflex in the rat. I. Lesions of the mesencephalic lateral tegmentum disrupt the reflex and damage mesencephalic somatosensory connections
Neuroscience
(1985) - et al.
Somatosensory systems and the milk-ejection reflex in the rat. II. The effects of lesions in the ventroposterior thalamic complex, dorsal columns and lateral cervical nucleus-dorsolateral funiculus
Neuroscience
(1985) - et al.
Expression of a novel neuropeptide Y receptor subtype involved in food intake: an in situ hybridization study of Y5 mRNA distribution in rat brain
Exp. Neurol
(2000)
Leptin differentially regulates NPY and POMC neurons projecting to the lateral hypothalamic area
Neuron
Hypothalamic pathways underlying the endocrine, autonomic, and behavioral effects of leptin
Physiol. Behav
Subnuclear organization of the efferent connections of the parabrachial nucleus in the rat
Brain Res. Rev
Morphological evidence for neural interactions between leptin and orexin in the hypothalamus
Regul. Pept
Resistance of the hippocampus in the lactating rat to N-methyl-d-aspartate
Brain Res
Hypothalamic orexin A-immunoreactive neurons project to the rat dorsal medulla
Neurosci. Lett
Neuropeptide Y-induced feeding and its control
Vitam. Horm
The role of corticotropin-releasing factor and urocortin in the modulation of ingestive behavior
Neuropeptides
Use of Fos-related antigens (FRAs) as markers of neuronal activity: FRA changes in dopamine neurons during proestrus, pregnancy and lactation
Brain Res
Downregulation of corticotropin-releasing factor mRNA, but not vasopressin mRNA, in the paraventricular hypothalamic nucleus of rats following nutritional stress
Brain Res. Bull
Central administration of antisense oligodeoxynucleotides to neuropeptide Y (NPY) mRNA reveals the critical role of newly synthesized NPY in regulation of LHRH release
Regul. Pept
Nutritional infertility: the role of the interconnected hypothalamic neuropeptide Y-galanin-opioid network
Front. Neuroendocrinol
Sensitivity of orexin-A binding to phospholipase C inhibitors, neuropeptide Y, and secretin
Biochem. Biophys. Res. Commun
The hypocretin/orexin ligand-receptor system: implications for sleep and sleep disorders
Trends Neurosci
Lactation decreases mRNA levels of opioid peptides in the arcuate nucleus of the rat
Brain Res
A significant participation of orexin-A, a potent orexigenic peptide, in the preovulatory luteinizing hormone and prolactin surges in the rat
Brain Res
Neuropeptide Y (NPY) neurons in the arcuate nucleus (ARH) and dorsomedial nucleus (DMH), areas activated during lactation, project to the paraventricular nucleus of the hypothalamus (PVH)
Regul. Pept
Neural populations in the rat forebrain and brainstem activated by the suckling stimulus as demonstrated by cFos expression
Neuroscience
Corticotropin releasing hormone (CRH) neurons in the paraventricular nucleus (PVH) are direct targets for neuropeptide Y (NPY) neurons in the arcuate nucleus (ARM): an anterograde tracing study
Brain Res
Identification of neuronal input to the arcuate nucleus (ARH) activated during lactation: implications in the activation of neuropeptide Y neurons
Brain Res
Comparison of the expression of two immediate early gene proteins, FosB and Fos in the rat preoptic area, hypothalamus and brainstem during pregnancy, parturition and lactation
Neurosci. Res
Somatosensory contributions to c-fos activation within the caudal periaqueductal gray of lactating rat: effects of perioral, rooting and suckling stimuli from the pups
Horm. Behav
Differences in the LH and prolactin responses to multiple injections of kainate, as compared to NMA, in cycling rats
Endocrinology
Normal food intake and growth in hyperprolactinemic rats
Am. J. Physiol
The responsiveness of tuberoinfundibular dopaminergic neurons to prolactin feedback is diminished between early lactation and midlactation in the rat
Endocrinology
The locus coeruleus, A5, and A7 noradrenergic cell groups
The role of lactogenic hormones in maternal behavior in female rats
Acta Paediatr
Hypocretin/orexin- and melanin-concentrating hormone-expressing cells from distinct populations in the rodent lateral hypothalamus: relationship to the Neuropeptide Y and agouti-gene-related protein systems
J. Comp. Neurol
Neuropeptide Y innervation and neuropeptide-Y-Y1-receptor-expressing neurons in the paraventricular hypothalamic nucleus of the mouse
Neuroendocrinology
Differential regulation of leptin receptor but not orexin in the hypothalamus of the lactating rat
J. Neuroendocrinol
Suppression of leptin during lactation: effects of the suckling stimulus versus milk production
Endocrinology
Hypothalamic circuitry of neuropeptide Y regulation of neuroendocrine function and food intake via the Y5 receptor subtype
Neuroendocrinology
Exercise-related female reproductive dysfunction
J. Endocrinol. Invest
Neuropeptide Y administered chronically into the lateral ventricle profoundly inhibits both the gonadotropic and the somatotropic axis in intact adult female rats
Endocrinology
Altered expression of Agouti-Related Protein (AGRP) and its colocalization with Neuropeptide Y (NPY) in the arcuate nucleus of the hypothalamus during lactation
Endocrinology
Leptin is a metabolic gate for the onset of puberty in the female rat
Endocrinology
A reassessment of leptin's role in triggering the onset of puberty in the rat and mouse
Neuroendocrinology
Melanin-concentrating hormone stimulates the release of luteinizing hormone–releasing hormone and gonadotropins in the female rat acting at both median eminence and pituitary levels
Biol. Reprod
Leptin: a hormone of reproduction
Hum. Reprod
Cited by (163)
Lactation from the inside out: Maternal homeorhetic gastrointestinal adaptations regulating energy and nutrient flow into milk production
2023, Molecular and Cellular EndocrinologyThe Onset and Maintenance of Human Lactation and its Endocrine Regulation
2020, Maternal-Fetal and Neonatal Endocrinology: Physiology, Pathophysiology, and Clinical ManagementThe Onset and Maintenance of Human Lactation and its Endocrine Regulation
2019, Maternal-Fetal and Neonatal Endocrinology: Physiology, Pathophysiology, and Clinical Management