Leptin Action in Pubertal Development (2012) PDF

Review Leptin action in pubertal development: recent advances and unanswered questions Carol F. Elias Department of Internal Medicine, Division of Hypothalamic Research and Green Center for Reproductive Biology Sciences, University of Texas Southwestern (UTSW) Medical Center, Dallas, TX 75390, USA...

Review Leptin action in pubertal development: recent advances and unanswered questions Carol F. Elias Department of Internal Medicine, Division of Hypothalamic Research and Green Center for Reproductive Biology Sciences, University of Texas Southwestern (UTSW) Medical Center, Dallas, TX 75390, USA In recent years we have witnessed a considerable ad- some debate in the field. Controversial findings, alterna- vance in the understanding of the processes involved in tive interpretations and discussions on leptin actions can pubertal development. This is partially due to the dis- be accessed by examining a series of important articles covery of the kisspeptin system and its fundamental role [3–6]. Recent data generated using novel molecular tech- in the control of reproductive physiology. In addition, the niques and genetically engineered mouse models support a suspected relationship between increasing rates of permissive role for leptin in the normal progression of childhood obesity and the apparent reduction in the pubertal development, but areas of contention still exist age of puberty onset in girls has generated a growing and many relevant questions remain unanswered. interest in identifying the mechanisms by which nutri- tion may influence reproductive maturation. This review Puberty will focus on recent data unveiling the sites of leptin Puberty is a complex physiological process that can be action in pubertal development that were generated described as the continuous transition to adulthood that using novel molecular techniques and genetically engi- occurs within a defined period of time. It is discernible by neered mouse models. It will also emphasize areas of the development of genital organs, of secondary sex char- contention and the many relevant questions that remain acteristics, and the resultant ability to reproduce. In unanswered. humans and higher primates, puberty culminates with the first menstrual cycle (menarche) in females [5,7]. Im- Introduction portantly, pubertal maturation is unique from species to The role of leptin in pubertal development is a recurrent species and is distinct for each sex. Within a species, some theme in the specialized literature and several excellent aspects of pubertal development may vary as a function of reviews on this issue have been published in the last modifier genes (i.e. genetic background) and are highly decade [1–3]. Our understanding of the processes and dependent on the physiological condition of the individual. physiological contribution of metabolic cues involved in In particular, nutritional state, stage of development and pubertal development has grown significantly in recent growth are the key factors. years. This is partially due to the discovery of the kisspep- In many species puberty is initiated with increase in the tin system and its fundamental role in the control of the activity of the hypothalamic–pituitary–gonadal (HPG) ax- reproductive neuroendocrine axis, and also to the avail- is, primarily induced by reawakening of gonadotropin- ability of innovative molecular tools and animal models in releasing hormone (GnRH) neurons [5,7]. At the onset of which genes can be manipulated. In addition, increased puberty, GnRH release becomes amplified, consisting of interest in identifying the mechanisms linking metabolism secretory pulses at higher frequencies. The sustained high and reproduction has been prompted by several recent pulsatile levels of GnRH induce gonadotropin synthesis publications suggesting that there could be a causal rela- and secretion from the pituitary gland, and this in turn tionship between the increasing rate of childhood obesity drives the full development of the gonads, the synthesis and the apparent reduction in the age of puberty onset in and secretion of sex steroids, and the maturation of the girls. Puberty is a complex physiological process, and many gametes. Thus, the tight control of GnRH neuronal activity factors (e.g. circulating signals and neuroendocrine path- determines the timely onset of puberty. ways) have been found to influence the normal develop- During pubertal maturation, the increase in circulating ment of pubertal maturation. This review will highlight levels of sex steroids triggers the development of secondary recent advances in our understanding of the role of the sex characteristic [5,7]. Higher estrogen production in girls adipocyte-derived hormone leptin as a permissive factor promotes breast development and contributes to body fat for the onset of puberty. Different interpretations of the redistribution, and androgen production in boys induces effects of leptin have been suggested, and data collected in changes in the musculoskeletal system, spermatogenesis a variety of species and animal models have generated and testicular growth. As a result, the process of pubertal development is readily detectable through the identifica- Corresponding author: Elias, C.F. ([email protected]) tion of these physical cues, which are the clinical signs of 1043-2760/$ – see front matter ß 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tem.2011.09.002 Trends in Endocrinology and Metabolism, January 2012, Vol. 23, No. 1 9 Review Trends in Endocrinology and Metabolism January 2012, Vol. 23, No. 1 pubertal maturation. However, the factors or physiological take place at the normal age, the onset age is apparently changes that induce the increased frequency of GnRH reducing in obese girls [20,30,31]. These observations have pulses and resultant pubertal maturation remain uncer- generated a passionate debate and many different inter- tain. For instance, it is unknown whether prepubertal pretations have been offered. Is the timing of puberty onset GnRH neurons are under high inhibitory restraint, lack really changing or we are just measuring it differently? excitatory influence, or both [8,9]. Several studies have Some methodological inconsistencies are evident. For in- indicated that an increase in excitatory inputs and/or in stance, Tanner staging is determined by either visual the sensitivity of glutamate or kisspeptin receptors on assessment or palpation. In case of visual assessment, GnRH neurons is a key event at the onset of puberty could the early stages of breast development be mistaken [8,10–12]. On the other hand, removal of inhibitory re- for fat deposits (adipomastia)? Environmental factors in- straint or decreased sensitivity to the negative feedback cluding stress and exposure to endocrine disruptors have actions also seem to play a role [8,9,13–15]. Even so, what not been included in the analysis, and most studies have drives these physiological changes – neuronal inputs, sen- not assessed gonadotropin and sex steroid levels. This is sitivity and remodeling – remains to be determined. Thus particularly relevant because the initial stages of breast far a series of signals have been identified as permissive for development (thelarche) normally indicate gonadotropin- the onset of puberty [8,16,17]. Nutrition and sufficient induced estrogen production from the ovaries. However, energy storage are crucial factors in this process. estrogen can also be generated from aromatization of adrenal androgens, a process facilitated by increased aro- Metabolism and puberty matase production in the adipocytes. Thus, it is theo- Individual nutritional status has long been recognized as a retically possible that earlier breast development in obese determining factor for the onset of puberty [18,19]. It has girls is the consequence of an increase in estrogen produc- been documented that the age of puberty onset in girls – tion from expanded adipocytes and not from activation of defined by first clinical signs of breast development (Tan- the HPG axis, and therefore does not represent genuine ner stage 2) – has declined since the 19th and early 20th puberty onset. The lack of conclusive data showing parallel centuries [20–24]. This is thought to be due to improved reductions in the age at menarche in obese and non-obese overall public health and nutrition. Variations in nutri- girls favors this argument, suggesting a temporal dissoci- tional conditions, diet or energy expenditure can influence ation between the initial signs of thelarche and the com- the onset and progression of puberty in many species, pletion of pubertal maturation with the first menstrual including rodents and primates. This is in fact very intui- cycle (menarche) [29,33,34]. In agreement, recent studies tive because many aspects of reproductive physiology are have shown that overweight girls with slowly progressive energetically demanding for both sexes. For example, precocious breast development and premature adrenarche territoriality and mate acquisition/courtship for males, exhibit decreased LH pulsatility; this finding suggests and pregnancy and lactation for females, represent signifi- that, in this condition, adiposity could promote an appar- cant energy costs. ent early onset of puberty but with slow progression. Experimental studies by Kennedy and Mitra were Notably, although the available data for boys show several seminal in describing the effects of nutrition and body size inconsistencies, the age of pubertal maturation in obese in the onset of puberty. They observed that the time of boys appears to be later rather than earlier [36–39]. Addi- puberty onset in rats is correlated with body size, not tional and more conclusive data on this issue are yet to be chronological age. Soon after, epidemiological studies in offered and its cause, if confirmed, remains to be deter- humans reported a similar finding ; subsequently, a mined. The increased aromatization of androgens to estro- series of observations gave rise to the hypothesis that a gens driven by high adiposity might also partially explain critical amount of body fat is required for proper pubertal this phenomenon. development [25,26]. These studies emphasized that con- Although the effects of childhood obesity upon the ap- ditions of extreme leanness may delay the initiation and parent increasing rates of earlier puberty onset are debat- progression of pubertal maturation. able, it is now well-defined that the balance and interplay In the past two decades, however, we have been facing a between metabolic cues and developmental stage are in- different situation. Studies have consistently reported a strumental for the coordinated control of the onset of growing incidence of earlier puberty onset in girls [27–29]. puberty and proper sexual maturation [6,17,40]. There- In these reports, Tanner stage 2 of breast development was fore, the existence of highly redundant neural pathways considered the clinical sign of puberty onset. A cross-sec- and metabolic cues is predictable. The adipocyte-derived tional study in girls published in 1997 reported what was, hormone leptin is one of the cues that have been studied at the time, the youngest age of puberty onset ever extensively as a key permissive factor for pubertal devel- recorded in a population (9.96  1.82 years). Recent opment [1–3]. evidence, however, suggests that this phenomenon has been aggravated in the last decade. Compared with the Reproductive deficits in leptin-deficient mice and previous study , a 5–8% increase was reported in the humans number of girls at seven to eight years of ages showing Leptin is primarily synthesized and secreted by adipo- the initial stages of breast development. Of note, cytes, and in normal conditions circulating levels correlate earlier appearance of clinical signs of puberty onset was with the total amount of body fat. Mice deficient in leptin more prevalent in obese than in non-obese girls. Although (ob/ob, in a C57BL/6 genetic background) are morbidly in the general population the onset of puberty appears to obese, primarily due to hyperphagia and decreased energy 10 Review Trends in Endocrinology and Metabolism January 2012, Vol. 23, No. 1 expenditure, and display a series of neuroendocrine abnor- Sites of leptin action malities [41,42]. The increased adiposity in these mice is The biological effects of leptin are achieved by its action at observed early during postnatal development, and is read- cognate receptors located in many organs and tissue. Most ily detectable at weaning. Embryonic and postnatal devel- leptin effects, including those in reproductive physiology, opment of the reproductive organs is apparently normal, are mediated by the long (signaling) form of the leptin but males and females remain at a prepubertal stage. Food receptor that is expressed in the brain [51,52]. Of note, loss- restriction decreases their body weights, which can be of-function mutations of the long form of leptin receptor, in maintained at levels similar to age-matched wild-type humans and mice, produced a metabolic and reproductive control mice, but does not restore fertility. Pubertal devel- phenotype similar to that of leptin-deficient subjects opment and fertility is only achieved if leptin is provided [42,53]. It is well-established in different species and in [1–3]. both sexes that leptin acts in the brain to increase the Gonadotropin levels are decreased in both male and pulsatile rate of GnRH secretion [54–57]. However, wheth- female ob/ob mice, but gonadotropes respond appropriate- er leptin receptor is expressed in GnRH neurons has been a ly to GnRH challenge. Despite their massive amount of matter of intense debate. More recently, with advances body fat, which supports steroidogenesis, the circulating in conditional knockout techniques, it was demonstrated levels of sex steroids are reduced. Testes and ovaries of that leptin action in GnRH neurons is not required for leptin-deficient mice are smaller, with several morphologi- pubertal development. Mice engineered to lack leptin re- cal and biochemical abnormalities, compared to those of ceptor selectively in GnRH neurons show normal progres- age-matched wild-type control mice. The lumen of the sion through puberty and exhibit normal sexual seminiferous tubules is hollow and contains fewer sperm maturation and fertility. In fact, with the development than wild-type littermates, and the steroidogenic Leydig of mouse models expressing leptin-receptor reporter genes cells are reduced in size due to decreased cytoplasmic it became clear that mouse GnRH neurons express virtu- content. The ovaries of ob/ob mice have similar num- ally no leptin receptor [58,60]. Therefore, leptin action to bers of primordial, primary and secondary follicles com- stimulate GnRH secretion is exerted via interneurons that pared to wild-type mice, but virtually no Graafian follicles converge on GnRH neurons. These neuronal populations or corpora lutea. When transplanted to wild-type were identified only recently through the use of an inno- females, ovaries of ob/ob mice produce sex steroids and vative molecular-tracing technique. It was reported viable eggs. The distribution pattern of GnRH neurons and that, although neurons expressing leptin receptor are fibers as well as of GnRH gene expression in ob/ob mice is widespread throughout the hypothalamus, only two popu- comparable to that in wild-type littermates, suggesting lations of leptin receptor-expressing neurons directly proj- that normal GnRH neuronal migration takes place during ect to GnRH neurons: those in the ventral premammillary development [43,46,47]. Thus, close evaluation of the HPG nucleus and those in the striohypothalamic nucleus, the axis of leptin-deficient ob/ob mice suggests normal post- latter of which is a newly identified neuronal population natal development and potentially adequate functioning of responsive to leptin. Alternatively, leptin effects on the gonadotropes and gonads but lack of increased GnRH reproductive neuroendocrine axis may be exerted via the pulsatility at the expected time of puberty onset. kisspeptin system which in turn controls GnRH neuronal Humans with monogenic forms of loss-of-function mu- activity [47,60,61]. tation in the leptin gene (LEP) exhibit a reproductive Kisspeptins (the products of Kiss1/KISS1 gene) and phenotype strikingly similar to the mutant ob/ob mice their receptor (Gpr54/GPR54) are fundamental players in [2,48]. These individuals display severe early-onset obesity the control of the neuroendocrine reproductive axis [62–64]. and fail to undergo puberty. Leptin treatment corrects Loss-of-function mutations in Kiss1 or GPR54/Gpr54 cause their metabolic phenotype and increases the frequency a lack of pubertal development, resulting in hypogonado- of gonadotropin secretion suggestive of puberty onset tropic hypogonadism, in humans and mice [65,66]. Because [2,49]. Importantly, leptin replacement therapy in lep- of the similarities in the reproductive phenotypes of indi- tin-deficient children conducted at an early developmental viduals with loss-of-function mutations in leptin and kis- stage did not induce precocious puberty. This indicates speptin genes and their cognate receptors, the Kiss1–GPR54 that the role of leptin in the onset of puberty depends on the system has become the leading candidate for mediating the development of the individual, strengthening the role of effects of leptin on puberty. Indeed, several research groups leptin as a permissive factor rather than as a definitive have now shown that kisspeptin neurons in the arcuate trigger of puberty. In a recent report a novel missense nucleus coexpress leptin receptors. However, some incon- variant in the leptin gene was identified in one individual sistencies are yet to be resolved. Although some laboratories from a cohort of children (78 subjects) with constitutional have reported a moderate-to-high degree of colocalization delay in growth and puberty (CDGP). The sequence [67,68], others have found very small colocalization rates variant was not detected in control subjects (112 individu- [60,61]. Despite these apparent inconsistencies, a series of als), but was identified in his mother who also exhibited a studies have indicated that conditions of low leptin levels – lean constitution and delayed pubertal maturation. It is as in mutant mice or in states of negative energy balance – intriguing, however, that this sequence variant has been result in decreased Kiss1 mRNA expression or blunted associated with delayed puberty in the context of decreased kisspeptin production [69–71]. Interestingly, mice with se- body mass index rather than obesity. Thus, whether pu- lective deletion of leptin receptors from Kiss1 neurons show bertal delay is caused by deficient leptin signaling needs normal pubertal development, sexual maturation and fer- further investigation. tility. This indicates that direct leptin action in Kiss1 11  Review Trends in Endocrinology and Metabolism January 2012, Vol. 23, No. 1 neurons is not required for normal puberty onset in mice. to GnRH neurons [60,75]. High proportions of these neu- Following the same line, a recent report has demonstrated rons coexpress glutamate and nitric oxide, and are depo- that female mice with ablation of kisspeptin neurons exhib- larized by leptin [47,75,79,80]. Collectively, these data ited no deficits in pubertal development. Whether these indicated that the PMV neurons are potentially stimulated findings reflect systems redundancy and/or developmental by changing levels of circulating leptin, which in turn may adaptations still needs to be determined. Collectively, these activate their terminal targets (e.g. AVPV and GnRH studies have clarified the following relevant issues: (i) leptin neurons) via release of excitatory neurotransmitters (glu- receptor is expressed in Kiss1 neurons of the arcuate nucle- tamate/nitric oxide). To test this model, a series of genetic us but not in Kiss1 neurons of the preoptic area [60,61,71], manipulation and excitotoxic lesions were performed. En- (ii) Kiss1 neurons which express leptin receptors in the dogenous re-expression of leptin receptor selectively in arcuate nucleus do not directly innervate GnRH neurons PMV neurons of leptin receptor-null mice induced pubertal , and (iii) direct action of leptin on Kiss1 neurons is not development and improved fertility in females. Male mice, required for pubertal maturation and fertility. These however, did not exhibit any improvement of their repro- studies also indicate that the changes in Kiss1 mRNA ductive physiology. In addition, when PMV neurons of expression/kisspeptin production in states of low leptin ob/ob female mice were lesioned a significant delay in levels are mediated by indirect neuronal pathways or by leptin-induced pubertal development was observed. the direct action of alternative (still unidentified) metabolic These findings suggest that leptin action in PMV neurons signals. is both sufficient and necessary for normal pubertal devel- A series of studies published in recent years have dem- opment of the female mouse (Figure 1). But they also onstrated that the ventral premammillary nucleus (PMV) generated a series of new questions that are discussed plays a key role in leptin effects on puberty initiation. The in the following sections (Box 1). PMV is well-positioned to integrate signs regarding nutri- tional condition (metabolic signals), reproductive status Box 1. Unresolved questions (sex steroids) and environmental cues (odor and probably daylight in seasonal breeders) [58,73–76]. These are regu- (i) The effect of leptin on pubertal development is believed to be latory components of the reproductive physiology in mul- mediated via leptin receptors expressed in the brain. However, tiple species. The projections of PMV neurons are known to both the short and long forms of leptin receptors are found in several peripheral organs, including the gonads and the target brain sites related to reproductive control, including pituitary gland. What is the physiological relevance of leptin those directly implicated in gonadotropin secretion (e.g. receptors outside of the brain? Most of the data on the the anteroventral periventricular nucleus/AVPV and permissive effects of leptin on the onset of puberty were GnRH neurons), sexually dimorphic sites (e.g. the medial generated using models of leptin or leptin-receptor deficiency, preoptic nucleus and the bed nucleus of stria terminalis), but the role of leptin at normal physiological levels is still unclear. A nocturnal peak of leptin secretion has been described and the vomeronasal circuitry (e.g. medial nucleus of the in pubertal rats. Is there a mechanism controlling the amygdala) [77,78] which integrates sensory (odorant) expression and/or availability of circulating leptin during pathways relevant to social communication/responses pubertal development? Is there a role for the short (circulating) and sexual behavior. The PMV houses a high density of form of leptin receptor in this process? (ii) Although leptin exerts an inhibitory effect in the limiting step of neurons that express leptin receptors and project directly [(Figure_1)TD$IG] steroidogenesis [88–90], it increases aromatization and may favor estrogen production in the presence of higher androgen availability [91,92]. Is this mechanism related to the increased AVPV rate of apparently earlier puberty onset in obese girls? Does Kiss1(?) earlier puberty onset reflect genuine activation of the HPG axis? (?) NO Could these peripheral effects also explain delayed sexual ate/ tam maturation in obese boys? u Environmental cues Gl (iii) Studies in mice showed that leptin action in Kiss1 neurons in GnRH not required for normal pubertal development and fertility. PMV fx However, the reproductive system is highly redundant; there may be parallel mechanisms that can compensate for the ER/AR absence of leptin signaling in kisspeptin neurons. Is leptin LepRb 3v LH secretion action in kisspeptin neurons sufficient to induce puberty in the Arc absence of parallel/redundant pathways? (iv) Selective leptin action on PMV neurons is sufficient to induce Sex steroids puberty in leptin receptor-null female mice, but not in males. Is there a sexually dimorphic circuitry on which leptin acts in Puberty puberty onset? Is the lack of improvement in the infertility Leptin phenotype of leptin receptor-null male mice after reactivation of leptin receptors in the PMV a consequence of (or secondary to) TRENDS in Endocrinology & Metabolism the obese or diabetic phenotype? Does the PMV act directly on GnRH neurons, or does it activate kisspeptin neurons and/or Figure 1. Proposed neural pathway mediating the permissive effect of leptin on pubertal development. The ventral premammillary nucleus (PMV) expresses a another indirect pathway? Is this effect mediated by glutama- dense collection of leptin long form (LepRb) and sex steroid receptors (ER/estrogen tergic/nitrergic neurotransmission? Is it caused by changes in receptor and AR/androgen receptor) and is responsive to environmental cues GnRH neuron terminals (neuronal plasticity) at the median (odor and probably daylight in seasonal breeders). Leptin stimulates PMV neurons eminence? What is the role of striohypothalamic neurons? which express glutamate and nitric oxide (NO). These PMV neurons innervate (v) What are the mechanisms (signaling pathways, changes in GnRH neurons and neurons in the anteroventral periventricular nucleus (AVPV, gene expression and/or cell activity) by which leptin exerts its supposedly those expressing Kiss1). This projection facilitates the increase in permissive effect on pubertal development? frequency of GnRH pulses and LH secretion at the onset of puberty. 12 Review Trends in Endocrinology and Metabolism January 2012, Vol. 23, No. 1 Mechanisms of leptin action explanation is expected to emerge. Although some impor- The leptin receptor protein is a member of the class I tant aspects have been unveiled, several questions remain cytokine-receptor family and activates the Janus kinase/ unanswered and many others have become apparent. It is signal transducer and activator of transcription (JAK/ hoped that an integrative perspective and the use of these STAT) signaling pathway. Multiple splice variants novel tools will impel the field to open new research of leptin receptors have been identified, but only the leptin frontiers, and thereby answer some of the unsolved ques- receptor long form contains a Box 3 motif for STAT3 tions and advance our understanding of the interplay activation in its cytosolic domain, and therefore it is recog- between nutrition and the establishment of the reproduc- nized as the physiologically relevant signaling isoform. tive competence. Consistent with this, db/db mice – which lack only the leptin receptor long form – develop obesity, diabetes and Acknowledgments infertility, a phenotype virtually identical to that of obese I would like to thank members of my laboratory (Jose Donato Jr, Roberta Cravo and Renata Frazao) at the Department of Internal Medicine, leptin-deficient ob/ob mice. Neuron-specific deletion of Division of Hypothalamic Research, UTSW Medical Center, Dallas, TX STAT3 (STAT3N/) or deletion of leptin receptor-mediat- for their active participation in the studies discussed in this review. I am ed STAT3 signaling (LRbS1138 s/s) recapitulate the db/db also indebted to Drs Joel Elmquist and Jeffrey Zigman for the mouse metabolic phenotype, producing hyperphagic obesity and models used in our work. Research in my laboratory has been funded by diabetes [82,83]. However, notably, whereas STAT3N/ grants from the National Institutes of Health (R01HD061539), the Foundation for Prader–Willi Research, a Regents Scholar Award, and a mice are similarly infertile, a high proportion of LRbS1138 Young Investigator Research Award from UTSW. s/s mice are fertile. These apparently conflicting results may indicate that STAT3 expression in the brain outside References the neuronal populations expressing leptin receptor is 1 Apter, D.A.N. 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