Elsevier

Physiology & Behavior

Volume 91, Issue 4, 24 July 2007, Pages 352-365
Physiology & Behavior

Neuroendocrine mechanisms of change in food intake during pregnancy: A potential role for brain oxytocin

https://doi.org/10.1016/j.physbeh.2007.04.012Get rights and content

Abstract

During pregnancy body weight, and particularly adiposity, increase, due to hyperphagia rather than decreased energy metabolism. These physiological adaptations provide the growing fetus(es) with nutrition and prepare the mother for the metabolically-demanding lactation period following birth. Mechanisms underlying the hyperphagia are still poorly understood. Although the peripheral signals that drive appetite and satiety centers of the brain are increased in pregnancy, the brain may become insensitive to their effects. For example, leptin secretion increases but hypothalamic resistance to leptin actions develops. However, several adaptations in hypothalamic neuroendocrine systems may converge to increase ingestive behavior. Oxytocin is one of the anorectic hypothalamic neuropeptides. Oxytocin neurons, both centrally-projecting parvocellular oxytocin neurons and central dendritic release of oxytocin from magnocellular neurons, may play a key role in regulating energy intake. During feeding in non-pregnant rats, magnocellular oxytocin neurons, especially those in the supraoptic nucleus, become strongly activated indicating their imminent role in meal termination. However, in mid-pregnancy the excitability of these neurons is reduced, central dendritic oxytocin release is inhibited and patterns of oxytocin receptor binding in the brain alter. Our recent data suggest that lack of central oxytocin action may partly contribute to maternal hyperphagia. However, although opioid inhibition is a major factor in oxytocin neuron restraint during pregnancy and opioids enhance food intake, an increase in opioid orexigenic actions were not observed. While changes in several central input pathways to oxytocin neurons are likely to be involved, the high level of progesterone secretion during pregnancy is probably the ultimate trigger for the adaptations.

Introduction

Although there is currently extensive interest in the cause and prevention of obesity, body weight also alters substantially in a variety of natural physiological states such as during growth and aging, in fever and disease states, and additionally in adult females during reproduction, i.e. during pregnancy and lactation. Pregnancy is a natural state of physiological hyperphagia, when body weight and adiposity increase dramatically [1], [2], providing a useful model to investigate the normal underlying causes of increased food intake and deposition of fat.

Of the many neuropeptides now known to be critically involved in the complex regulation of food intake, only oxytocin [3] has been extensively studied during pregnancy because of its key role in controlling parturition and maternal behavior. Oxytocin neurons are located in the supraoptic (SON) and paraventricular nuclei (PVN) of the hypothalamus. The magnocellular oxytocin neurons of the SON and PVN project their axons to the posterior pituitary where they secrete oxytocin into the periphery. These neurons also release very large amounts of oxytocin from their dendrites and cell bodies within the SON and PVN. Dendritic oxytocin acts locally to facilitate oxytocin neuron activity, but is also thought to diffuse to distant sites within the brain; for example, the amygdala [4]. Smaller (parvocellular) oxytocin neurons of the PVN project centrally to various hypothalamic, limbic and brainstem regions. So central oxytocin systems can provide a multi-level controlling influence on other brain regions and, thus, on behaviors, and there is growing appreciation that oxytocin has an important role in the regulatory neuronal network mediating satiety [5], [6], [7].

In this article we will detail food intake patterns that underlie maternal hyperphagia and will give an overview of the known literature on alterations in hormonal and neuroendocrine systems that control appetite and energy balance during pregnancy. Then we will discuss the role of oxytocin neurons in feeding behaviors, giving evidence for adaptations in the oxytocin system during pregnancy that may contribute to mechanisms controlling maternal nutrition and overall body homeostasis.

Section snippets

Energy balance and reproduction

The physiological mechanisms that control energy balance are reciprocally linked to those that control reproduction, and together these mechanisms optimize reproductive success under fluctuating metabolic conditions. A female mammals' reproductive cycle, particularly pregnancy and lactation, has profound effects on her consumption and utilization of metabolic fuel.

In female rats, food consumption alters depending on the day of the estrous cycle; at estrus, in response to rising progesterone

Patterns of food intake during pregnancy

In mammals food intake increases during pregnancy not only to meet the metabolic demands of the incubating young but also apparently to provide a large energy reserve for subsequent lactation [12], [13]. In some species, including humans, increased appetite is apparent through most of pregnancy while in others, including the rat, increased appetite and adiposity occurs mainly in the last third of pregnancy. The maximum reported increase in food intake varies, ranging from 10–100% in the rat [24]

Peripheral signals and neuroendocrine systems that control appetite and energy balance through reproduction

According to currently accepted views, mammals balance their energy intake and energy expenditure in such a way as to maintain a relatively stable body weight. This implies that the central control mechanisms involve some internally determined “set point” for body weight, and deviations from this set point, reported to the brain by signals from the periphery, are compensated for largely by changes in appetite, metabolism and locomotor activity. In late pregnancy the increase in body weight

Hunger

The meal size is thought to be governed by the dynamic balance between hunger signals and satiety signals, both of which arise from the periphery, and is also modulated by underlying signals that report on the status of the body's energy stores [35]. One acute hunger signal is mediated by the secretion of ghrelin. Ghrelin is a large peptide secreted mainly from the empty stomach, and concentrations of ghrelin in the plasma rise progressively with time elapsed since the last meal. Ghrelin acts

Central mechanisms regulating food intake in pregnancy

Without any clear evidence to suggest that altered peripheral signaling is responsible for the increase in appetite in late pregnancy, it seems more likely that altered hypothalamic and/or brainstem mechanisms are responsible, particularly as we know that several other physiological adaptations in pregnancy are accounted for in this way. Indeed, there are overt changes in many of the hypothalamic systems that are involved in appetite regulation, although it is unclear which of these might be

Oxytocin and the control of food intake

Magnocellular oxytocin cells densely express MC4 receptors, and the actions of MC4 agonists on these cells involve mobilization of intracellular calcium stores, and as a result an increase in expression of the immediate early gene c-fos, and release of oxytocin from the neuronal dendrites [81]. Indeed, activation of SON oxytocin neurons during feeding is readily indicated by the induction of Fos, the protein product of c-fos. Fos is increased in SON neurons by oropharyngeal stimulation in rats

Oxytocin acts as a neurohormone

Importantly, dendritic release of oxytocin is not regulated in the same way as oxytocin release from the nerve terminals in the posterior pituitary, and indeed the release from these two compartments often seems to be wholly independent. Oxytocin secretion from the pituitary nerve endings is governed strictly by electrical activity; exocytosis from nerve endings is triggered by calcium entry following depolarization induced by action potentials. This mechanism requires that a readily-releasable

Adaptations of oxytocin neurons during pregnancy

Many hypothalamic neurons undergo adaptation throughout pregnancy to prepare them for altered roles during subsequent birth and lactation, and to bring about maternal physiological adaptation that enables the mother's body to cope with carrying a growing demand. The oxytocin system is no exception. Adaptations of oxytocin neurons during pregnancy have been extensively reviewed recently [3], [103], [104], and so we will only give a brief overview of their relevant changes here.

Oxytocin neurons

The potential role of oxytocin in regulation of food intake during pregnancy

The previous section outlines the extensive studies of adaptations in oxytocin neuron activity and secretion during pregnancy, but the role of oxytocin in regulating food intake during this time of dramatic physiological change has not previously been reported. We investigated whether a lack of central oxytocin contributes to increased food intake in mid-pregnancy by a pharmacological approach. We performed experiments on hungry virgin and 16 day pregnant rats deprived of food for 24 h and

Opioids and food intake in pregnancy

Brain opioids are established as positive modulators of eating behaviors [32], [146] and progesterone administration mimicking levels during pregnancy increases opioid expression in the brain [74]. However, although oxytocin neurons are strongly inhibited by opioids and brain opioid expression in various locations is enhanced in mid-late pregnancy [46], [75], [76], [106], our data do not reveal a role for opioids in the adaptation of eating behavior then. We tested the role of endogenous

Conclusion

While there is an increase in leptin secretion in mid-gestation, it is followed by hypothalamic leptin resistance, so this factor may not be key in driving the hyperphagia of pregnancy. Adaptations in many relevant hypothalamic neuropeptide systems occur, including oxytocin. Whether the diminishing role of oxytocin in feeding behavior in pregnancy is due to inhibition of parvocellular or magnocellular oxytocin neurons or altered receptor distribution patterns is uncertain. Emerging evidence

Acknowledgements

We gratefully acknowledge the support of the EC, The Wellcome Trust and the BBSRC.

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