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Received: 26 November 2019 Revised: 10 January 2020 Accepted: 19 January 2020 DOI: 10.1111/obr.13005 PEDIATRICS/PHYSIOLOGY Adipokines: A gear shift in puberty Desirée Nieuwenhuis | Natàlia Pujol-Gualdo Amanda J. Kiliaan Department of Anatomy, Radboud university medical center, Donders Institute for Brain, Cognition and Behaviour, Preclinical Imaging Center PRIME, Nijmegen, The Netherlands Correspondence Amanda J. Kiliaan, PhD, Associate Professor, Department of Anatomy, Donders Institute for Brain, Cognition, and Behaviour, Preclinical Imaging Center PRIME, Radboud university medical center, 6500 HB Nijmegen, Geert Grooteplein 21N 6525 EZ Nijmegen, The Netherlands. Email: amanda.kiliaan@radboudumc.nl Funding information Europees Fonds voor Regionale Ontwikkeling (EFRO), Grant/Award Number: BriteN 2016 1 | INTRODUCTION The prevalence of obesity in adolescents and children is increasing in | Ilse A.C. Arnoldussen | Summary In this review, we discuss the role of adipokines in the onset of puberty in children with obesity during adrenarche and gonadarche and provide a clear and detailed overview of the biological processes of two major players, leptin and adiponectin. Adipokines, especially leptin and adiponectin, seem to induce an early onset of puberty in girls and boys with obesity by affecting the hypothalamic-pituitary- gonadal (HPG) axis. Moreover, adipokines and their receptors are expressed in the gonads, suggesting a role in sexual maturation and reproduction. All in all, adipokines may be a clue in understanding mechanisms underlying the onset of puberty in child- hood obesity and puberty onset variability. KEYWORDS adipokines, obesity, puberty 1,2 the age of 5 years were overweight or were with obesity in 2016, and 3 Obesity is defined by an excessive accumulation of white adipose tissue (WAT), and it is often indicated by a body mass index (BMI) 4 above 30. Two main types of adipose tissue were described: WAT and brown adipose tissue (BAT), which differ in morphology and func- 5-7 Ilse A.C. Arnoldussen and Amanda J. Kiliaan contributed equally to this work. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2020 The Authors. Obesity Reviews published by John Wiley & Sons Ltd on behalf of World Obesity Federation Obesity Reviews. 2020;21:e13005. wileyonlinelibrary.com/journal/obr 1 of 10 https://doi.org/10.1111/obr.13005 alarming rates. Specifically, worldwide, 41 million children below this number is expected to increase to 70 million in 2025. obesity is associated with various severe health complications, includ- ing increased risk of diabetes mellitus type 2, hypertension, heart dis- eases, and disturbances in sex hormone levels. 5,6 and mitochondria and plays a role in thermogenesis. Adipocytes in tion. BAT consists of adipocytes containing multiple lipid droplets WAT contain only a few mitochondria and a single lipid droplet. Adipose tissue has several functions including the storage of energy, thermogenesis, and the production and secretion of adipokines Generally, two physiological processes, adrenarche and gonadarche, 11,24 Childhood 5,7,8 a key role in puberty onset. Puberty is known as a period through which the body changes physically, being a physiological process resulting in the maturation of children, i.e. they develop sexual characteristics and obtain reproduc- 9,11 Adipokines are involved in a number of physiological processes including blood pressure, metabo- lism, glucose, and vascular homeostasis and may play amongst others 8-10 (hormones, cytokines, and peptides). tive functions. between obesity and puberty,2,12-23 the biological mechanisms under- lying obesity and puberty onset remain unclear. Hereafter, we review in detail the role of adipokines in the onset of puberty in childhood obesity. Although many studies have shown associations 2 | INITIATION OF PUBERTY PHYSIOLOGICAL PROCESSES IN THE interact to regulate the onset of puberty. During adrenarche, the adrenal cortex secretes steroid hormones (including 2 of 10 NIEUWENHUIS ET AL. androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate (DHEAS), androstenedione, and cortisol), insulin-like growth factor, and growth hormone, which contribute to the pubertal insights on new genetic loci (e.g. melanocortin-4 receptor, mitochon- drial carrier 2, and mitogen-activated protein kinase 13) and on sev- eral pathways that regulate the timing of puberty; however, it partly 34 9,24,25 Both adrenarche and gonadarche are involved in the development growth spurt, body odor, skin oiliness, and skeletal maturation. explains puberty timing variation. Thereby, defining the role of 25 adipokines is of importance in elucidating the variability in puberty as the expression of adipokines is sex-specific and is altered with body composition, adiposity, and during growth spurts. Moreover, adipokines and their receptors are expressed in gonads and several brain regions suggesting involvement in the onset of puberty and sex- ual maturation. Lastly, adipokines interfere in processes regulating timing and duration of puberty, for instance in the HPA and HPG axes which are both key players during adrenarche and gonadarche. Involvement of adipokines in the onset of puberty and specifically in individuals with obesity will be further reviewed in the next 2,24 3 | Puberty onset in girls is assessed using different markers, such as thelarche (breast development), menarche (the start of of pubic hair. pituitary-gonadal (HPG) axis is activated,2,26 and several hormones have been identified to participate in the activation of the HPG axis During gonadarche (Figure 1), the hypothalamic- 2,27 Kisspeptin, neurokinin B, and dynorphin are released by specialized including kisspeptin, neurokinin B, dynorphin, leptin, and ghrelin. 28 key regulator of the pulsatile secretion of gonadotropin releasing neurons, the KNDy neurons in the hypothalamus. Kisspeptin is a 29,30 B stimulates, and dynorphin inhibits the release of kisspeptin, which hormone (GnRH) from the hypothalamus. In addition, neurokinin implies that both coordinate a pulsatile release of kisspeptin. 31 Sub- sections. sequently, the activated HPG axis induces the pituitary gland to secrete luteinising hormone (LH) and follicle stimulating hormone (FSH). As a result, gametogenesis occurs, and the gonads will release sex hormones. Consequently, secondary sex characteristics develop including breast development in girls and an increased testicular vol- 2,26,32 is possibly due to differences in levels of body fat, hypothalamic-pitui- THE ONSET OF PUBERTY IN GIRLS ume in boys. The age at puberty onset varies greatly among individuals, which 19 35 menstruation), and pubic hair development. 33 genome-wide association studies have provided important new tary-adrenal (HPA) axis activity, and genetic background. Recent The average age of However, this age differs between cultures and ethnicities, and since 1980, age at menarche is girls at start of menarche is 12.4 years. 36 significantly decreasing. 36-39 F I G U R E 1 Hormonal regulation in the initiation of puberty in boys and girls. The secretion of kisspeptin, neurokinin B, and dynorphin from KNDy neurons initiate the release of gonadotropin releasing hormone (GnRH) from the hypothalamus. This activates the pituitary gland to produce and secrete luteinising hormone (LH) and follicle stimulating hormone (FSH), which in turn stimulate the gonads to produce estrogen and testosterone in girls and boys, respectively 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License NIEUWENHUIS ET AL. 3 of 10 T A B L E 1 Summary of included studies Authors Year Country Study Design Primary Outcome Sex Sample Size (n) Age (y) Data Collection Lian et al21 2019 China Cross-sectional Puberty starts earlier in Chinese Han girls with obesity compared with Chinese Han girls with normal weight. Girls 2996 9-19 2012 and 2013 Biro et al12 Lazzeri et al20 2018 USA 2018 Italy Longitudinal Cross-sectional Body mass index had a greater effect on age at menarche than did race and ethnicity. Girls 946 6-16 2004-2014 Li et al23 2018 China Longitudinal For both, boys and girls, a higher BMI (ie, overweight and obese) is associated with earlier onset of puberty Girls Girls Boys Girls 542 Deng et al22 Flom et al15 2017 China Cross-sectional Increased BMI is associated with early timing spermarche and menarche. Boys Girls Girls 1278258 9-15 2005-2012 He et al24 Holmgren et al17 2017 China 2017 Sweden Cross-sectional Longitudinal Onset of puberty is not related to obesity in boys. Boys Boys Girls Girls 782 7-17 972 929 5839 Kelly et al19 2017 UK 2016 Brazil 2016 USA Longitudinal prospective cohort Higher BMI in girls is associated with the onset of menstruation at an earlier age. 11 10-18 11-17 Barcellos Gemelli et al25 Cross-sectional Longitudinal Excess weight is associated with early age of menarche. Girls 727 2014 2003-2009 Glass et al16 Lee et al26 In girls, but not in boys, greater adiposity is associated with the earlier onset of puberty. Boys Girls 135 Cabrera et al27 Leonibus et al14 2014 USA 2013 Italy Cross-sectional Longitudinal Thelarche occurred earlier than recently reported, while age of menarche remained unchanged. Girls 610 3-17.9 2007 2005-2012 Currie et al13 2012 Europe, USA, Canada Cross-sectional Overweight/obesity during childhood predicts the early onset of puberty in girls. Girls 20410 11, 13, 15 2005-2006 2017 USA Prospective birth cohort Overweight/obese status at the age of 7 ye was associated with increased risk of early menarche 788 From birth to menarche occurred Pregnancies 1959-1966 2016 USA Cross-sectional Boys with overweight enter puberty earlier compared with boys with normal weight or obesity, while puberty starts later in boys with obesity compared with boys with normal weight and overweight. Boys 3872 6-16 2005-2010 Overweight during childhood shows a relation with the early onset of puberty in girls. 6535 4259 695 11 15 5.8-12.2 2009/2010 2013/2014 2014-2017 Higher BMI during childhood is associated with early puberty. 2008 and 2009 2000-2002 Obesity during childhood is related to the earlier onset of puberty. Boys Girls 84 123 71 (Continues) 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 4 of 10 NIEUWENHUIS ET AL. 3.1 | Fat storage For the initiation of puberty, the timing of stimulation and/or inhibi- tion of different hormones is important, and additionally, a certain amount and distribution of body fat is needed in order to start menar- che, which emphasizes the importance of body fat. From an evolution- ary point of view, body fat increases in mammalian females during puberty onset, and it highlights the need to guarantee a healthy preg- 40 women with anorexia nervosa. particularly body fat localized predominantly on the gluteofemoral fat depots, is profoundly associated with start of menarche, more than nancy, offspring, and maternal survival. fat, sex-hormones, and neuroendocrine alterations can evolve in men- strual dysfunction, for instance, in women with severe obesity or in 41-43 44-46 to gluteofemoral fat depots suggesting that leptin may convey infor- amount of total body fat. mation on body fat distribution to the hypothalamus during puberty. An improper level of body Importantly, body fat distribution, Blood leptin levels are strongly related 45 3.2 | HPG axis The HPG axis is activated by the release of kisspeptin resulting in the release of GnRH from the hypothalamus, and LH and FSH from the pituitary gland. In girls, FSH is involved in the development of the folli- cles in the ovaries, and it promotes the secretion of estrogen. LH stim- ulates the production of androgen hormones and induces ovulation 48 9,47 the release of kisspeptin and neurokinin B, and kisspeptin thereby (Figure 1). The secretion of estrogen has an inhibitory effect on inhibits the GnRH release from the hypothalamus. pattern of GnRH is important for the regulation of the menstrual cycle. This roughly 28-day-cycle comprises several phases, including the follicular phase and luteal phase. During the follicular phase, increasing levels of FSH stimulate the maturation of follicles and the production of estrogen from the ovaries. This in turn inhibits the release of FSH from the pituitary gland. A high level of estrogen will induce the production of LH by the pituitary gland, resulting in ovula- tion. The matured follicle secretes progesterone thereby inhibiting the release of GnRH. When the corpus luteum is demolished, there is less 48 3.3 | Adipokines According to results from studies reported in Table 1, girls with obe- sity enter puberty earlier compared with girls with normal higher leptin concentrations inhibit the intake of food and increases inhibition of GnRH. As a consequence, the cycle will start again. whole process, starting from the activated HPG axis, results in the development of the secondary sex characteristics in girls including 9,47 thelarche and menarche. 13,14,16-23,49-51 weight. these girls might be found in the secretion of adipokines. For instance, leptin is positively associated with the amount of body fat. Generally, energy expenditure. 9,52-54 An explanation for the early onset of puberty in The expression This TABLE 1 (Continued) Authors Year Country Study Design Primary Outcome Sample Sex Size (n) Age (y) Data Collection Herman-Giddens et al28 2012 USA Cross-sectional Observed mean ages of beginning genital and pubic hair growth and early testicular volumes were earlier than in past studies, depending on the characteristic and race/ethnicity. Boys 4131 6-16 2005-2010 Sorensen et al29 Aksglaede et al30 2010 2009 Denmark Denmark Cross-sectional/longitudinal Longitudinal Puberty onset at earlier ages was associated with an increased BMI in boys. Boys 1528 5.8-19.9 1991-1993/2006-2008 1930-1969 Juul et al31 Ribeiro et al32 2007 2006 Denmark Portugal Retrospective cohort Cross-sectional Higher BMI is associated with early voice break. 11-15 10-15 1990-1999 Kaplowitz et al18 Abbreviation: BMI, body mass USA Cross-sectional The early onset of puberty in Caucasian girls is likely related to an increased BMI. 5-12 1992-1993 2001 index. The higher BMI in boys and girls at 7 y of age, the earlier they enter puberty. Boys 21 612 Girls 135 223 Boys 463 Boys 382 Girls 437 Girls 10 750 Early sexual maturation in boys and girls is associated with overweight. 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License NIEUWENHUIS ET AL. 5 of 10 Leptin may possibly play a role in adrenarche as its plasma level increases with higher levels of body fat and as it can modulate both girls. 33 ing adrenarche. In coherence, in children with obesity, the androgen These findings suggested that lower reproductive status was associated with higher total adiponectin concentrations and that a higher reproductive status was related to higher HMW adiponectin the HPA and HPG axes. These axes are functionally integrated dur- DHEAS was positively associated with leptin levels. Nevertheless, concentrations in girls. In addition, individuals with obesity often another study showed that enhanced adrenal androgen secretion in girls with premature adrenarche was not explained by leptin or BMI 55 ated with androgen levels in girls ; however, it was not related to levels. and IL-6. TNF-α alters, and IL-6 inhibits the expression of 56 8 In addition, the adipokine adiponectin was negatively associ- 57 differences of adiponectin seem to develop during the progression of 56 adiponectin (Figure 2). Thereby, a low level of total adiponectin and/or high levels of inflammatory cytokines in individuals with obe- sity can promote the onset of puberty. Many more adipokines are secreted by WAT including omentin, 52,65-67 9,36,62,68 adrenarche in girls with Prader-Willi syndrome. Interestingly, sex puberty. adrenarche; however, both are not required factors. Thus, leptin and adiponectin might be able to influence In gonadarche, leptin can stimulate the secretion of kisspeptin, and subsequently activation of the HPG axis, which eventually increases the expression of estrogen and androstenedione in the ova- 58 2,60 65-67 The expression of these ries (Figure 2). Ob gene in WAT, resulting in the synthesis and secretion of leptin. Thus, high levels of leptin promote onset of puberty in girls via secre- tion of kisspeptin, and estrogen stimulates leptin secretion addition- ally. Moreover, adiponectin can affect the HPG axis due to the expression of adiponectin receptors in the hypothalamus, pituitary In return, estrogen stimulates the expression of the 59 gland, and gonads. onset as it inhibits the secretion of kisspeptin and GnRH in the hypo- thalamus and the release of GH and LH in the pituitary gland, and 2,60-62 52,60 63 girls with central precocious puberty (CPP). Moreover, total adiponectin had negative correlations with progression of puberty in girls (defined by Tanner stages), whereas HMW adiponectin had FIGURE 2 Adipokinesaffectingthe initiation of puberty in girls. Leptin stimulates the release of kisspeptin in KNDy neurons, which activates the hypothalamus to produce gonadotropin releasing hormone (GnRH). In response to the release of GnRH, the pituitary gland secretes follicle stimulating hormone (FSH) and luteinising hormone (LH), which stimulates the ovaries to release estrogen resulting in the formation of secondary sex characteristics in girls. Estrogen stimulates the production of leptin. Adiponectin inhibits GnRH release resulting in reduced levels of GnRH and thereby a delayed onset of puberty. TNF- α and IL-6 inhibit the production of adiponectin and therefore stimulate the onset of puberty In detail, adiponectin is a regulator of puberty thereby inhibiting the onset of puberty (Figure 2). with obesity often have low levels of adiponectin. et al. showed that total adiponectin was significantly lower, whereas high molecular weight (HMW) adiponectin was significantly higher in ment. 55 63 develop a chronic low-grade inflammatory state, which can be indi- cated by a high level of circulating inflammatory cytokines like TNF-α 64 Individuals Sitticharoon positive associations with LH levels and the progression of puberty in 63 visfatin, resistin, and chemerin. and visfatin are expressed in the ovaries. adipokines in the ovaries suggests a role within the reproductive sys- tem; however, the exact biological processes have to be examined. Thus, specifically leptin, adiponectin, and inflammatory cytokines pro- duced by WAT could be permissive key players during an early onset of puberty in girls with obesity. As an exception, HMW adiponectin seems to have a stimulatory effect on peripheral repro- ductive function as HMW is not able to cross the blood brain 63 barrier. 4 | Markers that are used to assess puberty onset in boys are THE ONSET OF PUBERTY IN BOYS spermarche, voice break, testicular volume, and pubic hair develop- 35 spermarche develop in the early stages of puberty onset, voice In women, omentin, chemerin, While pubic hair development, larger testicular volume, and 69 testicular volume increases, which occurs at an average age of break usually appears in later stages of puberty. Generally, first 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 6 of 10 NIEUWENHUIS ET AL. 11.9 years, followed by the development of pubic hair at 12.2 years of average, and lastly, boys experience spermarche around an aver- 55 related with leptin levels. Thereby, leptin plausibly has a minor impact in adrenarche in boys. Since leptin receptors are found in the hypothalamus, pituitary gland, and testes, they might be involved in the onset of puberty by affecting the HPG axis during gonadarche. Leptin stimulates the release of kisspeptin and GnRH, and as a consequence, it accelerates the onset of puberty (Table 1, Figure 3). In contrast, adiponectin inhibits the secretion of GnRH, GH, LH, and FSH therewith delaying the onset of puberty. However, adiponectin levels are generally lower in men compared with women and even lower in men with obe- age age of 13.4 years. 70 4.1 | Fat storage Many aspects of the reproductive physiology are energetically demanding,71 and therefore, an adequate energy level is necessary. In boys, a dynamic change in body composition occurs around the age of 10 to 13 years, in which they gain approximately 40% of sity. culating inflammatory cytokines. levels can stimulate the HPG axis and therewith an early onset of puberty in boys. Nevertheless, leptin can inhibit the production of tes- 72 mostly consisting of lean mass, which causes exhaustion of most of fat. Subsequently, a growth spurt follows in which they gain tissue 72 in boys, an adequate amount of body fat is important in the onset of their body fat. These alterations in amount of body fat indicate that 4.2 | Puberty in boys is initiated by the release of kisspeptin. As mentioned before, this activates the HPG axis, resulting in the release of GnRH from the hypothalamus, and consequently the release of LH and FSH 9,74 puberty. tosterone from the testes, to estrogen (Figure 3). of the development of secondary sex characteristics in boys. Additionally, leptin can affect fertility in men as it can modulate the nutritional support of spermatogenesis, and moreover, dysfunction of spermatogenesis is associated with an increased leptin level and 73 58 2,60-62 HPG axis from the pituitary gland (Figure 1). and LH stimulates the secretion of testosterone from the testes, which inhibits the release of kisspeptin from the KNDy neurons and 9,48 in men, the release of kisspeptin is more consistent, causing a con- 29,48 subsequently GnRH from the hypothalamus. receptors expressed on KNDy neurons. In humans, KNDy neurons Contrarily to women, LH-induced testosterone levels lead to the stant release of LH. development of secondary sex characteristics in boys. differences between sexes in kisspeptin release are related to a sex- specific and sex steroid-dependent kisspeptin system as estrogen and progesterone modulate kisspeptin activity through the sex-steroid 48 in the infundibular nucleus are involved in negative and positive sex- 48 tal exposure to sex steroids and result in sex-specific differences in steroid feedbacks. kisspeptin release. These sexual dimorphisms are induced by perina- 75,76 4.3 | Adipokines The association between obesity and puberty onset in boys is rather controversial compared with findings in girls. Most studies reported an early onset of puberty in boys associated with increased ate adipose tissue from actual breast tissue. stages are more difficult to assess than female stages as boys lack a more determined marker such as menarche. Thirdly, puberty onset can be indicated by the activation of the HPG axis, and the presence of these secondary sex characteristics is the result of hormonal 2 14,17,22,23,50,51,77,78 BMI, 20,49 all while others reported no associations at Current markers used 79 16,80 or a delayed onset of puberty (Table 1). The presence of excessive adipose tissue can be involved in puberty onset in boys as the secretion of adipokines can modulate both adrenarche and gonadarche. Leptin can affect adrenarche by modulating both the HPG and HPA axes,33 and moreover, androgen levels were positively 55 nal androgen secretion in boys with premature adrenarche was not associated with plasma leptin levels. Nevertheless, enhanced adre- 9 In more detail, 61,62 adiponectin, and individuals with obesity often have high levels of cir- Moreover, inflammatory cytokines, TNF-α, and IL-6, inhibit expression of the leptin receptor in the testis. FSH induces spermatogenesis, too. function and role still have to be examined. 64 High leptin and low adiponectin and fat tissue can convert testosterone Both processes might result in the delay 29,61,79 81,82 In men, other adipokines like chemerin are found in the gonads 65 Thus, particularly high leptin and low adiponectin levels stimulate the HPG axis and thereby accelerate the onset of puberty in boys. Additionally, leptin can dysregulate the development of secondary sex characteristics and spermatogenesis by affecting testosterone levels and nutritional sup- port of spermatogenesis. 5 | LIMITATIONS AND FUTURE RESEARCH DIRECTIONS Even though multiple epidemiological studies have shown the link between puberty onset and obesity, there are some important limita- tions. Firstly, determining both the onset and stage of puberty is rather difficult. For instance, assessing the stage of breast develop- ment in girls with obesity is complicated as clinicians should differenti- 2 changes in response to the activated HPG axis. to determine the onset of puberty refer to secondary sex characteris- tics, such as testicular volume in boys and breast development in girls. A more accurate measurement of puberty onset would be to combine secondary sex characteristics with plasma or serum hormone level measurements such as LH, FSH, adipokines, e.g. leptin. Thereby, differences in puberty measurements could explain variations in the age of puberty onset between boys and girls within different Thereby, resistin is expressed in the testes of rats, but its exact 83 Secondly, male pubertal 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License NIEUWENHUIS ET AL. 7 of 10 FIGURE 3 Adipokines affecting the initiation of puberty in boys. Leptin activates kisspeptin secretion in KNDy neurons, this activates the production of gonadotropin releasing hormone (GnRH) from the hypothalamus. GnRH stimulates the pituitary gland to secrete follicle stimulating hormone (FSH) and luteinising hormone (LH), activating the production of testosterone from the testes allowing the development of secondary sex characteristics. Leptin also inhibits the production of testosterone, which may cause a delayed onset of puberty. Adiponectin inhibits GnRH release. Low levels of adiponectin, as a result of TNF-α and IL-6 expression, lead to a reduced inhibition of GnRH. In response to GnRH release, the pituitary gland will secrete FSH and LH, and the testes will produce testosterone resulting in the development of secondary sex characteristics in boys countries, and In addition, the inclusion of a of puberty. ferent time points is complicated, as subjects examined several decades ago presented pronounced differences concerning lifestyle patterns such as nutrition and exercise habits. Lastly, obesity or over- weight is often determined by BMI, a classification based on weight and height measurements. Additionally, it is important that all studies studies or across continents, ethnicities proper age range (8-16 years) is important when assessing the onset (Figure 4). 12-15,17,20-23,49,77-79,84,85 30,47 Furthermore, comparison between studies from dif- 86 Specifically in children, BMI is often dependent on age and growth use the same anthropometric standards and sex-specific cut-offs. 13,14,16-23,49-51,77-80 fat and would represent a more accurate measurement in its regard. Based on this review, several suggestions can be made for further research. Firstly, the roles of adipokines like resistin, chemerin, visfatin, and omentin in puberty onset, fertility, and sexual maturation should be examined in detail. Secondly, future research examining the onset of puberty should combine indicators of puberty onset (e.g. breast development or testicular volume) with plasma or serum hor- mone measurements such as LH, FSH, sex-steroids, adipokines (e.g. spurts. ment in case of growth spurts. distribution of body fat should be taken into account in determining puberty and obesity in children. For instance, the body adiposity index (BAI), which was introduced in 2011 by Bergman et al.,87 uses hip cir- cumference and height in order to estimate the percentage of body 87 Thereby, BMI is a less accurate measure- F I G U R E 4 87,88 Therefore, both percentage and Average age of puberty onset in Europe, China, and the United States according to several studies from Table 1. Age of puberty onset ranges from 8.47 to 13.33 years in girls and from 8.63 leptin), and body fat distribution (e.g. BAI,87 waist-hip ratio's and/or dual-energy X-ray absorptiometry (DXA)2). Additionally, defining con- sistent and general measurements of puberty in both boys and girls, combined with a proper age range (8-16 years), would facilitate the comparisons between different studies and their results. 12-15, 17, 20-23, 25-29, 31 to 13.7 years in boys. included if average age of markers used to assess puberty was not reported. Pink: girls. Blue: boys Studies (Table 1) were not 39, 56 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 8 of 10 NIEUWENHUIS ET AL. 6 | CONCLUSION In conclusion, epidemiological data regarding obesity and puberty onset in girls show similar outcomes as adiposity results in the early onset of puberty in girls. The majority of the studies examining boys with obesity indicate an early onset of puberty, while not all reported an earlier onset of puberty. In detail, high leptin, TNF-α, and IL-6 levels combined with low adiponectin levels stimulate the activation of the HPG axis in girls and boys with obesity, and 5, 45, 50, 51 REFERENCES 1. Kumar S, Kelly AS. Review of childhood obesity: from epidemiology, etiology, and comorbidities to clinical assessment and treatment. May- o Clin Proc. 2017;92(2):251-265. 2. Reinehr T, Roth CL. Is there a causal relationship between obesity and puberty? The Lancet Child & adolescent health. 2019;3(1):44-54. 3. WorldHealthOrganization. Facts and figures on childhood obesity. 2017. 4. Guglielmi V, Sbraccia P. Obesity phenotypes: depot-differences in adipose tissue and their clinical implications. Eat Weight Disord. 2018; 23(1):3-14. 5. Gomez-Hernandez A, Beneit N, Diaz-Castroverde S. Escribano O. 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BMC Womens Health. 2018;18(1):168-174. thereby an early onset of obesity. leptin can inhibit the production of testosterone in boys and subse- quently inhibit the development of secondary sex characteristics affecting spermatogenesis. for other adipokines, like resistin and omentin, are present in the testes and ovaries suggesting a role in puberty or reproduction; 58, 71 however, their plausible function is still unknown. that adipokines may be key regulators in an early onset of puberty in both girls and boys with obesity, specifically by affecting the HPG axis during gonadarche. Future research should focus on assessing puberty onset by measuring consistent puberty markers and determine the percentage of body fat and its distribution and adipokines and hormone serum levels particularly involved in the HPG axis. CONFLICTS OF INTEREST The authors declare no conflict of interest. FUNDING INFORMATION This research was funded by Europees Fonds voor Regionale Ontwikkeling (EFRO), project BriteN 2016. ORCID Ilse A.C. Arnoldussen Amanda J. Kiliaan https://orcid.org/0000-0002-7395-5284 https://orcid.org/0000-0002-2158-6210 13, 14, 16-26, 29-32 Furthermore, several receptors Nevertheless, We conclude Search strategy We searched PubMed for articles published before Novem- ber 15th, 2019 using relevant keywords, including ‘onset of puberty and adiposity/obesity’, ‘onset of puberty’, ‘children with obesity’, ‘adipose tissue’, ‘childhood obesity’, ‘adiposity’, ‘obesity’, ‘adipokine(s)’, ‘HPG axis’, ‘adipokines ovary/ova- ries’, or ‘adipokines testes’, either alone or in combination. 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Obesity Reviews. 2020;21:e13005. https://doi.org/ 10.1111/obr.13005 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are goverYaama I'm Jack Evans and you're watching BTN. Here's what's coming up. We uncover the story behind this famous photo, learn about First Nations seasons and find out the history of Book Week. What is Statehood? Reporter: Tatenda Chibika INTRO: But first, the Prime Minister Anthony Albanese has announced that Australia will join other countries in recognising Palestine as an independent state. So, what does that mean? Tatenda found out. Anthony Albanese, Prime Minister: Australia will recognise the state of Palestine. Australia will recognise the right of the Palestinian people to a state of their own. We will work with the international community to make this right a reality. Tatenda Chibika, Reporter: That's the moment our Prime Minister said Australia would recognise Palestine as an independent state at the upcoming United Nations General assembly next month. It's something other countries, including France and Canada, have said they'll be doing too. So, what does that mean exactly? To be considered an independent state under international law a place needs to have its own land or territories with defined borders, it needs to have people who permanently live there, have a working government and it has to be able to talk and make deals with other countries. Once a place meets all those rules, it can ask to be recognised by other independent states and countries. But a big step in becoming an independent state is being fully recognised by the United Nations. To do that you first need to get approval from at least nine members of the UN's Security Council. That's a group of countries responsible for maintaining international peace and security. But even then, that tick of approval can still be blocked by one of the Security Council's five permanent members Russia, China, the UK, the US and France. If the Security Council approves, the decision then goes to the UN's General Assembly where at least two thirds of the UN's 193 members have to agree to make it official. Yeah, it's a pretty complex process which is why we've only seen a handful of countries recognised by the UN in recent years like South Sudan and Montenegro. Others like Kosovo are only 'partially' recognised which means they have some recognition but not enough to become a full member state at the UN. Right now, Palestine is recognised by more than 140 countries — that's more than two thirds of the UN General Assembly. So, why hasn't it become a UN member state yet? Well, it came pretty close last year when 12 members of the Security Council voted in favour of it. VANESSA FRAZIER, AMBASSADOR OF MALTA, APRIL 2024 UNSC PRESIDENT: I shall now put the draft resolution to the vote. But the US, a close ally to Israel, used its special powers to block Palestine from becoming a member state. VANESSA FRAZIER: Those against? At the time, the U.S said Palestine and Israel needed to come to an agreement on their own first. Throughout the years, there have been attempts to figure out a way for both Palestine and Israel to exist peacefully alongside each other but that hasn't happened yet. And now Israel has said that recognising Palestine as an independent state would be rewarding Hamas the group in charge of Gaza which was responsible for the terror attacks on October 7th, 2023. But the Palestinian Authority which governs parts of the West Bank says Hamas won't have a role in any future state of Palestine which will exist peacefully alongside Israel. Australia, like the US, had previously said that it wanted Israel and Palestine to figure out things by themselves first but because of how the war has been going the Australian government is worried that if it continues to wait, there might not be a Palestinian state to recognise. ANTHONY ALBANESE, PRIME MINISTER: There has been too many lives lost, both Israeli's and Palestinians and the world is saying we need a solution to this conflict, we need to end the cycle of violence and the way to do that is to have a two-state solution. News Quiz Russia's President Vladimir Putin stepped foot on American Soil for the first time in a decade to meet with US President Donald Trump. What state did they meet in? Alabama, Alaska or Arizona?It's Alaska. The two leaders met to discuss a way to end the war in Ukraine but weren't able to make any final agreements. DONALD TRUMP, US PRESIDENT: There were many, many points that we agreed on. Most of them, I would say, a couple of big ones, that we haven't quite got there, but we've made some headway. There's no deal until there's a deal. A lot of people criticised the two world leaders for not including Ukraine's president Volodymyr Zelenskyy in the meeting. But that didn't seem to worry Mr Trump who said the meeting was a success and Mr Putin even invited the US President to meet up again in Russia. DONALD TRUMP: We'll see you again very soon. Thank you very much, Vladimir. VLADIMIR PUTIN, RUSSIAN PRESIDENT: Next time in Moscow. DONALD TRUMP: Oh, that's an interesting one. No, no, no. I'll get a little heat on that one. Last week thousands of people marked the 80th anniversary of VJ Day. What does VJ Day commemorate? The victory of Allied forces in Europe, the surrender of Japan and the end of World War II or the dropping of the first atomic bomb? VJ Day or Victory over Japan day commemorates the surrender of Japan and the end of World War II on the 15th of August 1945. Around the world, and here in Australia, people marked the anniversary with ceremonies remembering those who fought in the war. REPORTER: Who will you be remembering today? VETERAN: Oh, a lot of fellows that I knew that never made it home. Scientists in the UK have created toothpaste that includes which of these ingredients? Hair, eye lashes or fingernails? Yeah, they're all a bit random and gross but the answer is hair. According to scientists from King's College in London, hair could be the key to good oral health because it contains a protein called Keratin which they say when mixed with saliva forms a crystal-like protective coating similar to enamel. And Swifties rejoice because Taylor Swift has announced her 12th Studio album. It's called life of a show what? Is it show pony, show girl or show bag? It's Life of a Showgirl and it'll be released October 3rd. Vincent Lingiari Reporter: Joseph Baronio INTRO: Now to this very famous photograph. It was taken 50 years ago and depicts a really significant moment in Australian history. Joe found out about the story behind it. On the 16th of August 1975, this famous photo was taken. It shows the former Prime Minister Gough Whitlam pouring sand into the hand of Aboriginal leader Vincent Lingiari. A simple gesture that symbolised handing the land at Wave Hill in the Northern Territory back to the Gurindji people. But the journey to get there was far from simple. It started back in the 1960s. At the time, Wave Hill was the biggest cattle station in the world, controlled by British landowner Lord Vestey. The Gurindji people, who had lived on the land for generations, worked for Vestey, but they weren't paid fairly, and conditions were tough. NEWS REPORTER: The station's 100 aboriginal stockmen, with their 100 dependents, are camped in the dry bed of the Victoria River with little shade from 90-degree heat, dust and flies. Eventually, Gurindji leader Vincent Lingiari said it was time to act. VINCENT LINGIARI: I said, "What was it before Lord Vestey born and I was born?" It was blackfella country. So, on August 23rd, 1966, Mr Lingiari and his fellow Aboriginal workers went on strike. It became known as the Wave Hill Walk Off. They moved their camp away from the Wave Hill station to a sacred site called Daguragu on Wattie Creek. They wanted to set up their own cattle station, and said they wouldn't move until their land was returned to them. For years, petitions and negotiations went on between the Gurindji people, the NT Administration, and the Australian Government in Canberra. CLAPPERS: 31. 32. 33. DAVID QUINN, ABSCOL: Well, it's basic justice that their land is recognised. PROTESTORS: Equal rights! As the news spread across the country, thousands of Aussies joined the campaign, including the leader of the Labor Party, Gough Whitlam, who made this promise during his 1972 election campaign. GOUGH WHITLAM: We will legislate to give Aborigines land rights. Not just because their case is beyond argument, but because all of us as Australians are diminished, while the Aborigines are denied their rightful place in this nation. Later that year, Gough Whitlam became Prime Minister. (Song From Little Things Big Things Grow, Song by Kev Carmody and Paul Kelly, 1993) From little things big things grow,from little things big things grow… But it wasn't until 1975, 9 years after the Wave Hill Walk Off started, that he followed through with his promise. Eight years went by, eight long years of waiting'Til one day a tall stranger appeared in the landAnd he came with lawyers and he came with great ceremony GOUGH WHITLAM: I solemnly hand to you these deeds as proof in Australian law that these lands belong to the Gurindji people. And through Vincent's fingers poured a handful of sandFrom little things big things grow 50 years on, and The Wave Hill Walk Off is seen as a pivotal moment in Australia's history. It led to significant legal and social changes for First Nations people, which is something many agree is worth celebrating. First Nations Seasons Reporter: Saskia Mortarotti INTRO: Recently, Melbourne's Lord Mayor suggested ditching the four-season calendar that most of us are familiar with and adopting a six-season Wurundjeri calendar instead saying it gives a better description of what the weather's actually like there. Sas found out more about the different seasonal calendars used by First Nations people. SASKIA MORTAROTTI, REPORTER: Right now, in most of the country, it's pretty cold. COLD GIRL: Think of somewhere warm. What? It's 32 degrees in Darwin in the middle of winter? But ah, yeah. There are some places where it's, well, quite warm. Which makes you wonder whether the weather actually matches the seasons. You see, Australia is pretty big, and we have lots of different weather patterns. Which is something First Nations people have tracked for thousands of years with their own seasonal calendars. KARL WINDA TELFER, CULTURAL CREATIVE KANYANYAPILLA: Why have we got four seasons when you know that don't make any sense here. It doesn't relate to the country here. This is Karl Telfer. He's an artist and storyteller who produced the Kuri Kurru exhibition at the Museum of Discovery in Adelaide that explores the 6 different seasons of the Kaurna Meyunna. SASKIA MORTAROTTI: So, how do you know when you're in one of those six seasons? KARL WINDA TELFER: Well, there are stars that rise. So, you know, there are certain stars, like in Parnatti, for example. There's a star called Parna, and we know what that star is. So, that talks to us about, okay, the time now is going to be cold on the ground. First Nations calendars like the Kaurna one don't just tell us what's happening with the weather; they're also used to track when certain plants and animals are around. KARL WINDA TELFER: It teaches you about what plants you can, you know, what you can eat what you can't and all that what is ready certain times a year and fruit everything, bird shows you the right time to eat the fruit, perfect time, if you try and go get them the next week they're gone. Karl says we can also use these calendars to see how the environment has changed over time. KARL WINDA TELFER: Kudlilla is the season we're in now and Kudlilla that talks about like the rain but we're not having enough rain these days, well, these times. And this is due to climate and the climate changing. There are many different First Nations seasonal calendars around the country. Like Ngan'gi calendar from the Northern Territory which has 13 seasons that follow the life cycle of the native spear grass. Or the Wurundjeri Calendar in Victoria which has 6 seasons. And recently, Melbourne's Lord Mayor, Nicholas Reece, said Melbourne, or Naarm, would be better off adopting the Wurundjeri calendar because it's more in tune to what's happening with the weather. Something many, including Karl, think we should be doing right across the country. KARL WINDA TELFER: I'm talking about the English four seasons. So, this is totally different systems that we're talking about and weather patterns and currents and all sorts of different things, because it's the sea country too. So, my question is, well, why do we have that? If that doesn't work, you know? Quiz How many seasons are there in the Tiwi Island Calendar? 1, 2 or 3? It's 3, although they also have 13 minor seasons. Book Week Reporter: Wren Gillett INTRO: This week, kids across Australia have been dressing up as their favourite characters to celebrate Book Week. Wren finds out why Book Week began 80 years ago and why it's still important today for getting young Aussies into reading. STUDENT: I read an hour every night, maybe even two hours some nights. STUDENT: My favourite book series are the Harry Potter series and the Keeper of the Lost City series. STUDENT: Probably Bad Guys and Weirdo. STUDENT: I like the Amulet, I've been reading that. STUDENT: I love reading Dork Diaries and Exploding Endings. Whether it's Fantasy, mystery, history — whatever you're into. Book week is a time to celebrate, well, books. STUDENT: Me and my friends are dressing up as Inside Out. STUDENT: I was thinking SpongeBob. STUDENT: I'm dressing up as Winnie the Pooh and it's just a fun way to express what kind of books you like. And guess what, book week has actually been a thing for many, many years. WREN GILLETT, REPORTER: Once upon a time, in a land not so far away, literacy lovers noticed a problem. The year was 1945. The second World War had just ended, and kids were mainly reading books from overseas, in particular the UK. Because, at the time, there weren't many Aussie authors writing books for children. WREN GILLETT: So, a group of passionate teachers, librarians, booksellers, publishers, and book-loving volunteers, decided to create what we now know as The Children's Book Council of Australia. Familiar logo, right? Together, they launched book week, all in an effort to get Aussie kids' reading more. And it seemed to work. The 1960s saw a boom in Australian children's books being published. REPORTER: How many books do you read a week? STUDENT: Well, it really depends on the week. If there's exams, I might read only one or two. But if there's no exams and if I've got plenty of time, I might read up to five or six. WREN GILLETT: But today, it's a slightly different story. Studies show that less than one in five eight to 18-year-olds are reading in their free time, and that only one in three actually enjoy reading for fun. WREN GILLETT: Why do you reckon we're seeing this trend? STUDENT: People are getting sucked into screens and they're like spending hours just scrolling through TikTok and stuff, and they're getting so attached to it that they don't feel the need to pick up books and read them. Yeah, there's a lot of different things competing for our attention these days, but many think books are still worth our time. PETER HELLIER, AUSSIE COMEDIAN AND AUTHOR: Books are the exact opposite of boring. And if you think they're boring, I'm sorry, but you're wrong. This is Peter Hellier, he's a pretty famous Aussie comedian, actor, and the author behind these books. And he's just released another one called Detective Galileo, about a trail horse who dreams of solving crimes. PETER HELLIER: He joins the police force and quickly finds out that the horses don't actually solve the crimes, it's the police officers who solve the crime. So he promptly gets thrown out of the force and begins his own detective agency, which I'm reliably told is the only detective agency in the world run by a horse. Peter actually started writing books when he was a kid. PETER HELLIER: I started writing when I was six, seven, eight years old. In fact, I started my own publishing company called Better Books. And I would write these books, and then I would get a parent or one of my parents or teachers to type them up. And I would read them in front of the class. And, you see, each has the logo, the Better Books logo, there it is — the famous Better Books logo. WREN GILLETT: You weren't mucking around. PETER HELLIER: There all on all of them. There we go. There we go. Many, Including Peter, say there's plenty to get from a good book. They help us learn new words and phrases, get a better understanding of the world around us, and strengthen our imaginations. PETER HELLIER: Books can take you absolutely anywhere. They can take you to countries that you never dreamed about going. Countries that exist, countries that don't exist. Reading just makes the world a much bigger place. It's why for the past 80 years, schools around the country have been taking part in book week. STUDENT: Reading is a place where you can have your own world just to yourself. STUDENT: It's like watching a movie inside your head, but you can choose how it goes. STUDENT: Picking up a book is a good idea, maybe you should start with something that you're interested with and then you can start exploring from there. Quiz What is the title of the book that took out this year's Book of the year Award for younger readers? It's Laughter is the Best Endingby Maryam Master. Some other winners included I'm not really here by Gary Loneborough which took out book of the year for older readers and best picture book went to The Truck Cat, by Deborah Frenkel. Sport Australia's men's national basketball team — the Boomers — have won their third Asia Cup in a row, with an epically narrow victory over China. COMMENTATOR: It is Australia who are celebrating! China started strong, leading 25-17 at quarter time. But Aussie Xavier Cooks led a fierce comeback, shooting 30 points and collecting nine rebounds, earning him the title of MVP. And there seriously couldn't have been a tighter finish. Just as the final buzzer went off, China missed a shot that would have won them the game, leaving Australia with a 90-89 victory. COMMENTATOR: An unbelievable finish. The 2025 AFLW season kicked off last week, and so did a new trick. Yeah, 19-year-old Ash Centra from Collingwood, pulled out this move in the warm-up before their season-opener to Carlton, and since then, a lot of people have been trying to do it, with some success, kind of? FOOTY PLAYER: No, I'm not doing it on camera. But despite the epic warmup, Carlton did end up beating Collingwood by 24 points. Now, the moves from these athletes in China weren't quite so graceful but give 'em a break, okay, they're robots. For the first time ever, humanoid robots from all over the world, competed in their very own games, which featured, soccer, boxing, running, and ahh, lots of falling over. Lots. Luckily though, they did bring their own cheer squad. Young Rapper Reporter: Rylie INTRO: Finally, we're going to meet another winner of this year's Heywire competition — which asks young people in regional areas to share their stories. Rylie's going to tell us how music helped to transform his life. Check it out. Mum and I were homeless. We lived at a caravan park, in motels and tents around Warrnambool. It wasn't pretty. I'm First Nations, and I remember feeling like, my own country is failing me right now. So, we camped right along here. I remember pitching a tent right here and this was actually around the same time I started to get into music which was a good way for me to have something to look forward to. I was raised by the SoundCloud era, listening to a lot of trap music. When I was in school, I'd rap along to songs by Juice World, then I started to make my own. My first track was recorded on my phone. It was bad but a lot of fun to make. Some kids in my school heard it and shamed me. That put me off music for the next couple of years, until a friend of mine bought a microphone and encouraged me to give it another go. There was something about that mic and the energy of the crew around me that gave me confidence. It lit a fire in me. Over time, I was able to focus my flow. My songs are about escapism, living the life, being a success. I rap about stuff that takes me to a better place in my head. I'm manifesting my future. My stage name is Hundo Milli, it's short for hundreds of millions. Money's not really the end goal; it's more about having the freedom to dream big. Mum taught me to never stop believing. Even when times were tough, she kept pushing for us to get housing and eventually we did. We're some of the lucky ones. Today, I'm in a Melbourne studio recording my next single. I remember living in my tent dreaming about this very moment and now I'm here, doing what I love. Ain't nothing going to stop me. Closer Well, that's all we've got for you today, but we'll be back before you know it. In the meantime, you can head to our website, there's plenty to see and do. You can also catch Newsbreak every weeknight and there's BTN High for all you highschoolers out there. Have an awesome week and I'll see you next time. 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