Integration of the regulation of reproductive function and energy balance: lactation as a model

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Abstract

Lactation is a physiological model for studying how the hypothalamus integrates peripheral signals, such as sensory signals (suckling stimulus) and those denoting energy balance (leptin), to alter hypothalamic function regulating food intake/energy balance and reproduction. The characteristics of food intake/energy balance during lactation are extreme hyperphagia, coupled with negative energy balance. The arcuate nucleus Neuropeptide Y (ARH–NPY) system is activated by: (1) brainstem projections specifically activated by the suckling stimulus, and (2) the decrease in leptin in response to the metabolic drain of milk production. NPY neurons from the ARH make direct contact with GnRH neurons and with CRH neurons in the PVH. NPY neurons also make contact with orexin and MCH neurons in the LHA, which, in turn, make contacts with GnRH neurons. Thus, the ARH–NPY system provides a neuroanatomical framework by which to integrate changes in food intake/energy with the regulation of cyclic reproductive function.

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.

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