Reproduction is calorically expensive. The energy demands of mate seeking, gamete
production, pregnancy, and lactation require increased food consumption and appropriate
regulation of energy expenditure. Therefore, control of the reproductive function
by the brain must be responsive to the metabolic state of the animal. Conversely,
when survival is threatened by insufficient fuels or increased energy demands, males
and females of most species divert energy away from reproduction by reducing copulatory
motivation and behavior, halting ovulation, terminating pregnancies, or ceasing lactation.
In addition, when prepubertal animals, including humans, are exposed to energy deprivation,
the onset of puberty is delayed or even blocked, until a favorable energy balance
is achieved. These mechanisms serve to optimize reproductive success in environments
where energy availability fluctuates. Recent studies suggest that excess body fat
can trigger early onset of puberty, especially in females. In males, on the other
hand, the prevalence of delayed puberty is about fivefold higher than in females,
indicating sexual dimorphism in the sensitivity of the reproductive axis to metabolic
cues. Understanding the interaction between energy balance and fertility has critical
implications for the treatment reproductive deficits caused by metabolic dysfunction.
Given the involvement of the hypothalamus in the management of food intake, energy
use, reproductive behavior, and the hormonal control of gametogenesis and ovulation,
ongoing studies are focused on the interplay between the hypothalamic circuits driving
these functions. Gonadotropin releasing hormone (GnRH) neurons are specialized neurons
often described as the “master regulators” of the hypothalamus-pituitary-gonads (HPG)
axis. The intermittent release of GnRH controls pituitary release of luteinizing hormone
(LH) and follicle stimulating hormone (FSH) and, by extension, function of the gonads.
Surprisingly, few GnRH neurons are sufficient to initiate puberty in males and females
and to maintain fertility in the male. However, more are required for females to generate
LH surges and ovulate. These additional GnRH neurons may modulate GnRH pulsatility
in response to environmental, nutrition, stress, or other cues conveying adverse situations.
However, GnRH neurons on their own seem to sense few metabolic cues. Instead, neighboring
neurons and glia may perceive circulating factors, such as leptin, insulin, and ghrelin
that serve as signals of the nutritional state of the individual. If these cells are
not able to sense metabolic cues, for example in states of insulin or leptin resistance,
the repercussions may include both imbalanced metabolic homeostasis and reproductive
dysfunction. Indeed, leptin-deficient patients become hyperphagic, massively obese,
and infertile. This eBook has assembled multidisciplinary specialists to provide up-to-date
information on recent advances in understanding the complex physiologic interaction
between metabolism and reproduction.
In the initial article, True et al. (2011) discuss the role of the adipocyte hormone
leptin as a key metabolic signal and predominant focus of interest in the field. In
their review, it is emphasized that although leptin may be an important permissive
signal for reproductive function as indicated by many years of research, factors other
than leptin must critically contribute to negative energy balance-induced reproductive
inhibition. Schneider et al. (2012) call attention to the “metabolic hypothesis,”
which predicts that sensory systems monitor the availability of oxidizable metabolic
fuels and allow behavioral responses to optimize reproductive success. Following these
provocative introductory articles, three reviews discuss the role of specific groups
of neurons in this physiologic regulation. Bianco (2012) highlights the Kisspeptin
system as the converging target of environmental, metabolic, and hormonal signals,
and proposes a potential correlation between the existence of a sexual dimorphism
of pubertal disorders in children of different ethnicities and the sexually dimorphic
expression of kisspeptin neurons. Supported by recent genetic studies, Xu et al. (2012)
focused their review on two sets of hypothalamic neurons: the pro-opiomelanocortin
(POMC) neurons in the arcuate nucleus and the steroidogenic factor-1 (SF1) neurons
in the ventromedial hypothalamic nucleus. Their discussion calls attention to exciting
new findings showing that disruption of metabolic signals (e.g., leptin and insulin)
or reproductive signals (e.g., estradiol) in these neurons leads to impaired regulation
of both energy homeostasis and fertility. Donato and Elias (2011) discuss the role
of the ventral premammillary nucleus as integrator of environmental, metabolic, and
reproductive cues, and its emergence as a critical previously unrecognized hypothalamic
site linking metabolism and reproduction. Acosta-Martínez (2012) proposes a role for
phosphatidylinositol-3-kinase (PI3K) signaling pathway as potential integrator of
a number of peripheral metabolic cues, including insulin and leptin, in the metabolic
control of the reproductive function. Tolson and Chappell (2012) offer an insightful
discussion on pubertal timing, outlining a potential role of endogenous timing mechanisms
including cellular circadian clocks in pubertal initiation. They propose that these
clocks may be altered by metabolic factors leading to reproductive deficits. In a
provocative review, Clasadonte et al. (2011) discuss the action of non-neuronal components
in GnRH regulation. They suggest that synaptically associated astrocytes and perijunctional
tanycytes are integral modulatory elements of GnRH neuronal function at the cell soma/dendrite
and terminal levels. Finally, two important articles call the attention to differences
in the metabolic modulation of the reproductive physiology in different species. Klingerman
et al. (2011) highlight the metabolic influence on sexual behavior, and food intake
or food hoarding in hamsters, and suggest a role for neuropeptide Y (NPY) and gonadotropin
inhibiting hormone (GnIH) expressing cells in these processes. Amstalden et al. (2011)
emphasize observations made in ruminant species in a very welcome comparative perspective.
Clearly, research examining the metabolic control of reproduction is advancing at
a rapid pace. The articles in this eBook highlight some of the most critical and intriguing
areas for future study.