Metabolic control of puberty onset: New players, new mechanisms
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
References (60)
- et al.
Childhood obesity and the timing of puberty
Trends Endocrinol. Metab.
(2009) - et al.
Neuroendocrine regulation and actions of leptin
Front Neuroendocrinol.
(1999) - et al.
KiSS-1/kisspeptins and the metabolic control of reproduction: Physiologic roles and putative physiopathological implications
Peptides
(2009) - et al.
The role of CNS fuel sensing in energy and glucose regulation
Gastroenterology
(2007) Influences on age of menarche
Lancet
(1973)- et al.
Novel signals for the integration of energy balance and reproduction
Mol. Cell Endocrinol.
(2006) - et al.
Effects of ghrelin on Kisspeptin mRNA expression in the hypothalamic medial preoptic area and pulsatile luteinising hormone secretion in the female rat
Neurosci. Lett.
(2009) - et al.
Control of GnRH neuronal activity by metabolic factors: the role of leptin and insulin
Mol. Cell Endocrinol.
(2006) - et al.
One ancestor, several peptides post-translational modifications of preproghrelin generate several peptides with antithetical effects
Mol. Cell Endocrinol.
(2006) - et al.
TSC2 mediates cellular energy response to control cell growth and survival
Cell
(2003)
Ghrelin--a hormone with multiple functions
Front Neuroendocrinol.
AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism
Cell Metab.
Sex steroids and leptin regulate the “first Kiss” (KiSS 1/G-protein-coupled receptor 54 system) in human gonadotropin-releasing-hormone-secreting neuroblasts
J. Sex Med.
Leptin and reproduction: a review
Fertil Steril
The expanding TOR signaling network
Curr. Opin. Cell Biol.
Puberty in the rat
New frontiers in kisspeptin/GPR54 physiology as fundamental gatekeepers of reproductive function
Front Neuroendocrinol.
Ghrelin levels from fetal life through early adulthood: relationship with endocrine and metabolic and anthropometric measures
J. Pediatr.
TOR, a central controller of cell growth
Cell
Targeting mammalian target of rapamycin (mTOR) for health and diseases
Drug Discov. Today
The Creb1 coactivator Crtc1 is required for energy balance and fertility
Nat. Med.
Mouse fertility is not dependent on the CREB coactivator Crtc1
Nat. Med.
Androgen Receptor Antagonism and an Insulin Sensitizer Block the Advancement of Vaginal Opening by High-Fat Diet in Mice
Biol. Reprod.
Changes in hypothalamic KiSS-1 system and restoration of pubertal activation of the reproductive axis by kisspeptin in undernutrition
Endocrinology
Effects of galanin-like peptide on luteinizing hormone secretion in the rat: sexually dimorphic responses and enhanced sensitivity at male puberty
Am. J. Physiol. Endocrinol. Metab.
Expression of hypothalamic KiSS-1 system and rescue of defective gonadotropic responses by kisspeptin in streptozotocin-induced diabetic male rats
Diabetes
Alterations in Hypothalamic KiSS-1 System in Experimental Diabetes: Early Changes and Functional Consequences
Endocrinology
Leptin's actions on the reproductive axis: perspectives and mechanisms
Biol. Reprod.
Postnatal development of kisspeptin neurons in mouse hypothalamus; sexual dimorphism and projections to gonadotropin-releasing hormone neurons
Endocrinology
Hypothalamic mTOR signaling regulates food intake
Science
Cited by (145)
Ontogeny of adropin and its receptor expression during postnatal development and its pro-gonadal role in the ovary of pre-pubertal mouse
2023, Journal of Steroid Biochemistry and Molecular BiologyIntegrating genome-wide association study and pathway analysis reveals physiological aspects affecting heifer early calving defined at different ages in Nelore cattle
2022, GenomicsCitation Excerpt :The genes that surround these regions are related to mechanisms that compose the essential gatekeepers for sexual precocity through the integration of metabolic hormone action at the brain such as IGF1 and PMCH (BTA5), GNRHR (BTA6), PLAG1, and PENK (BTA14), and KISS1 (BTA16). These genes provide an integration of multiple regulatory signals whereby links neuroendocrine and metabolic mechanisms, responsible for the transition from the pre- to post-puberty that culminates in ovulation followed by a regular estrous cycle [72]. DeAtley et al. [11], applying the peptidomics approach in Brangus heifers, observed changes in the hypothalamus and pituitary gland activation before and after puberty that influence the sexual precocity.
Interplay of KNDy and nNOS neurons: A new possible mechanism of GnRH secretion in the adult brain
2021, Reproductive BiologyEffects of Nutrition on Pubertal Timing at the Neuroendocrine and Cellular Levels
2021, Cellular Endocrinology in Health and Disease, Second EditionCentral Ceramide Signaling Mediates Obesity-Induced Precocious Puberty
2020, Cell MetabolismCitation Excerpt :This phenomenon reinforces the contention that the pubertal role of ceramides is genuinely different and goes beyond their well-known metabolic actions in adulthood, and further stresses that during puberty, key regulatory pathways of energy balance in adulthood become less prominent or are contingent on the state of accelerated weight gain. In fact, during this period, the superimposed feeding- or body weight-promoting actions of orexigenic signals, such as AMPK activation or ghrelin (Fernández-Fernández et al., 2005; Roa et al., 2010, 2018), are not overtly visible, despite their detectable actions on puberty onset. Such a lack of impact of ceramide manipulation on body weight, though, eliminates a potential confounding factor, and corroborates the genuine regulatory role of hypothalamic ceramides in the central control of puberty, which is not apparently related to their potential actions on food intake and energy balance, a contention that is also supported by the lack of major changes in gene expression of key hypothalamic neuropeptides involved in the control of feeding after central blockade of de novo synthesis of ceramides.
Sirtuin (SIRT)-1: At the crossroads of puberty and metabolism
2020, Current Opinion in Endocrine and Metabolic ResearchCitation Excerpt :In this same region resides the population of Kiss1/kisspeptin neurons largely responsible for the pulsatile control of gonadotropin hormone (GnRH) and the timely initiation of puberty and adult fertility [21–24]. Moreover, several studies point to the role of ARC Kiss1 neurons as central integrators of energy balance regulation of reproduction [25–28]. Furthermore, because the median eminence is devoid of the typical blood–brain barrier, the ARC integrates circulating hormonal and metabolic signals that impact both the melanocortin system and Kiss1 neurons as well [29–31].