Metabolic control of puberty onset: New players, new mechanisms

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Abstract

Puberty, as the end-point of a complex series of maturational events affecting the components of the hypothalamic-pituitary-gonadal (HPG) axis, is gated by the state of body energy reserves and sensitive to different metabolic cues; conditions of severe metabolic stress and energy unbalance (from anorexia to morbid obesity) being commonly linked to perturbation of the onset of puberty. In the last two decades, the neuroendocrine mechanisms responsible for the tight coupling between energy homeostasis and puberty onset have begun to be deciphered. These seemingly involve a plethora of metabolic hormones and neuropeptides, which impinge and integrate (mostly) at the hypothalamic centers governing reproduction. Yet, characterization of the mechanisms of action of such regulators (and even their nature and physiological relevance) still remains incomplete. In this review, we will summarize some recent developments in our knowledge of the effects and mechanisms of action of two key metabolic hormones, leptin and ghrelin, in the control of puberty onset. In addition, the roles of the hypothalamic Kiss1 system in the metabolic gating of puberty will be reviewed, with special attention to its regulation by leptin and the recent identification of the putative roles of Crtc1 and mTOR signaling as molecular conduits for the metabolic control of Kiss1 expression. Elucidation of these novel players and regulatory mechanisms will help for a better understanding of the determinants of the timing of puberty, and its eventual alterations in adverse metabolic conditions.

Introduction

Puberty, as developmental period when full awakening of the gonadotropic axis and attainment of reproductive capacity take place, is a key maturational event, associated with important somatic and behavioral changes (Parent et al., 2003, Ojeda and Skinner, 2006). As such, the physiology of puberty onset and the potential mechanisms for its perturbation have been deeply scrutinized using different model species (from laboratory rodents to humans) and experimental/analytical approaches (from classical physiological studies to recent genome-wide association scanning) (Parent et al., 2003, Ojeda and Skinner, 2006, Ong et al., 2009). The consensus exists that the major determinants of the timing of puberty in healthy conditions are of genetic origin (Parent et al., 2003). However, additional modifiers of the tempo of puberty have been recognized, with prominent roles of different environmental factors (from nutrient availability to different stressors). Indeed, puberty has been envisioned as ‘sensor’ for the dynamic interplay between genetic determinants and environmental cues throughout development. Such delicate balance between endogenous and exogenous regulators would be ultimately responsible for the proper timing of puberty, or its deviations (Parent et al., 2003). Elucidating the pathways and molecular mechanisms whereby this continuous interaction is taking place remains as an appealing challenge for the future.

Among its different putative modifiers, it has been long recognized that the state of body energy reserves is a key determinant for the onset of puberty in mammals, including humans (Parent et al., 2003). The functional coupling between energy sufficiency and puberty onset is especially, but probably not exclusively, present in the female, where threshold fat stores are needed in order to successfully cope with the considerable metabolic drainage of pregnancy and lactation (Casanueva and Dieguez, 1999). The association between a critical fat mass and the occurrence of menarche was first proposed on a rigorous basis by Frisch and colleagues in early 1970s (Frisch and Revelle, 1970, Frisch, 1973), in keeping with previous analogous observations from Kennedy and Mitra (1963) in laboratory rats. This hypothesis provided the first scientific formulation for the ancient, intuitive knowledge of the existence of a close link between fatness and fertility. Recognition of such a link paved the way for the identification of the hormonal signals and neuroendocrine mechanisms involved in this phenomenon.

During the last two decades, considerable progress has been made towards the elucidation of the neurohormonal pathways responsible for the metabolic control of puberty onset and gonadotropic function. Without discussion, a major breakthrough in this field was the identification of the adipose hormone, leptin, as an essential neuroendocrine integrator responsible for the coupling of the state of body energy stores and different hormonal functions, including reproduction (Casanueva and Dieguez, 1999, Tena-Sempere, 2007). A number of additional peripheral hormones from key metabolic tissues, such as the gastrointestinal tract, the pancreas and the adipose, have been also proposed as putative regulators of the gonadotropic axis (Fernandez-Fernandez et al., 2006); these likely include the gut–hormone, ghrelin, whose role as functional antagonist of leptin in terms of food intake control may apply as well to the regulation of puberty (Tena-Sempere, 2008a, Tena-Sempere, 2008b). Similarly, different central neuropeptides have been described as potential mediators in this phenomenon; kisspeptins being the most recently identified (and likely one of the most important) players in the central control of puberty onset by metabolic cues (Tena-Sempere, 2006, Castellano et al., 2009a). While systematic description of every molecule and mechanism reported so far in this context clearly exceeds the scope of this review, we aim to provide herein a succinct and up-dated summary of some recent developments in our knowledge of the signals and neuroendocrine pathways singled out above (leptin, ghrelin, kisspeptins), which will help to highlight and better define physiologically-relevant mechanisms for the modulation of the timing of puberty by metabolic factors in mammals.

Section snippets

Leptin signaling and puberty onset: recent developments

As stated above, identification of leptin, as product of the ob gene, was a revolutionary finding in contemporary Endocrinology, as it allowed unveiling the mechanisms underlying quite diverse regulatory functions, from body weight control to metabolic gating of fertility (Casanueva and Dieguez, 1999, Tena-Sempere, 2007). For the sake of concision, description of the fundamental features of leptin as adipose signal controlling reproductive maturation and function will be omitted, as these can

Ghrelin and puberty onset: modulatory actions in the male and female

While the role of leptin, as signal of energy abundance, in the metabolic gating of puberty was recognized (and universally accepted) shortly after its cloning in 1994, identification of additional metabolic hormones with the potential to modulate puberty onset has remained elusive. Among other possible candidates, ghrelin, as circulating orexigenic factor that signals energy insufficiency, has emerged in recent years as putative modifier of the timing of puberty (Tena-Sempere, 2008a,

Central pathways for the metabolic regulation of puberty: the role of kisspeptins

Among the central signals responsible for the neuroendocrine control of the gonadotropic axis, kisspeptins, the products of Kiss1 gene that operate via the G protein-coupled receptor, GPR54, have emerged very recently as essential gatekeepers of puberty onset and fertility, by virtue of its pivotal roles in mediating key reproductive phenomena, including sexual differentiation of the brain, the pubertal activation of the GnRH system, the feedback control of gonadotropin secretion and the

Novel players in the metabolic regulation of Kiss1: the roles of Crtc1 and mTOR

While the ability of leptin to regulate the hypothalamic expression of Kiss1 was demonstrated by initial studies, the intracellular mechanisms for such an action have remained elusive for years. Recent findings, however, suggest the involvement of the Creb1-regulated transcription coactivator-1 (Crct1) in mediating leptin effects on the Kiss1 system at the hypothalamus. Thus, in a recent elegant study, Altarejos et al. (2008) demonstrated that mice engineered to lack functional Crtc1 were not

Obesity and puberty onset

Most of the experimental evidence summarized in previous sections originates from studies in models of negative energy balance. These are enormously instrumental to unveil putative metabolic regulators of puberty onset, and very helpful to predict the patho-physiological mechanisms and consequences of puberty disruption due to (e.g.) strenuous exercise or anorexia nervosa. Admittedly, however, these may not provide a proper insight into pubertal alterations linked to conditions of energy

Conclusions

While the contention that puberty onset critically depends on adequate body energy stores has been known for Ages, the neuroendocrine substrate for such a metabolic regulation of puberty and fertility has begun to revealed only recently. Nevertheless, in the last decades, significant progress has been achieved in this area, and several peripheral hormones, with key roles in the control of metabolism, have been demonstrated to influence the timing of puberty, through the modulation of diverse

Disclosure

The authors have nothing to disclose.

Acknowledgments

The authors are indebted with the members of the research team at the Physiology Section of the University of Cordoba, who actively participated in the generation of experimental data discussed herein. The work from the authors’ laboratory reviewed in this article was supported by grants BFU 2005-07446 and BFU 2008-00984 (Ministerio de Ciencia e Innovación, Spain), funds from Instituto de Salud Carlos III (Red de Centros RCMN C03/08 and Project PI042082; Ministerio de Sanidad, Spain), Project

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