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French 2: Lesson 12 practice (expressions of quantities for foods) Vocabulary (2): Practice 12 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. 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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 goverMultiple Choice Questions A6. You’ve hired a third-party to gather information about your company’s servers and data. The third-party will not have direct access to your internal network but can gather information from any other source. Which of the following would BEST describe this approach? ❍ A. Backdoor testing ❍ B. Passive footprinting ❍ C. OS fingerprinting ❍ D. Partially known environment A7. Which of these protocols use TLS to provide secure communication? (Select TWO) ❍ A. HTTPS ❍ B. SSH ❍ C. FTPS ❍ D. SNMPv2 ❍ E. DNSSEC ❍ F. SRTP A8. Which of these threat actors would be MOST likely to attack systems for direct financial gain? ❍ A. Organized crime ❍ B. Hacktivist ❍ C. Nation state ❍ D. Competitor A9. A security incident has occurred on a file server. Which of the following data sources should be gathered to address file storage volatility? (Select TWO) ❍ A. Partition data ❍ B. Kernel statistics ❍ C. ROM data ❍ D. Temporary file systems ❍ E. Process table Quick Answer: 33 The Details: 43 Quick Answer: 33 The Details: 44 Quick Answer: 33 The Details: 45 Quick Answer: 33 The Details: 46 6 Practice Exam A - Questions A10. An IPS at your company has found a sharp increase in traffic from all-in-one printers. After researching, your security team has found a vulnerability associated with these devices that allows the device to be remotely controlled by a third-party. Which category would BEST describe these devices? ❍ A. IoT ❍ B. RTOS ❍ C. MFD ❍ D. SoC A11. Which of the following standards provides information on privacy and managing PII? ❍ A. ISO 31000 ❍ B. ISO 27002 ❍ C. ISO 27701 ❍ D. ISO 27001 A12. Elizabeth, a security administrator, is concerned about the potential for data exfiltration using external storage drives. Which of the following would be the BEST way to prevent this method of data exfiltration? ❍ A. Create an operating system security policy to prevent the use of removable media ❍ B. Monitor removable media usage in host-based firewall logs ❍ C. Only allow applications that do not use removable media ❍ D. Define a removable media block rule in the UTM Quick Answer: 33 The Details: 47 Quick Answer: 33 The Details: 48 Quick Answer: 33 The Details: 49 Practice Exam A - Questions 7 A13. A CISO (Chief Information Security Officer) would like to decrease the response time when addressing security incidents. Unfortunately, the company does not have the budget to hire additional security engineers. Which of the following would assist the CISO with this requirement? ❍ A. ISO 27701 ❍ B. PKI ❍ C. IaaS ❍ D. SOAR A14. An insurance company has created a set of policies to handle data breaches. The security team has been given this set of requirements based on these policies: • Access records from all devices must be saved and archived • Any data access outside of normal working hours must be immediately reported • Data access must only occur inside of the country • Access logs and audit reports must be created from a single database Which of the following should be implemented by the security team to meet these requirements? (Select THREE) ❍ A. Restrict login access by IP address and GPS location ❍ B. Require government-issued identification during the onboarding process ❍ C. Add additional password complexity for accounts that access data ❍ D. Conduct monthly permission auditing ❍ E. Consolidate all logs on a SIEM ❍ F. Archive the encryption keys of all disabled accounts ❍ G. Enable time-of-day restrictions on the authentication server Quick Answer: 33 The Details: 50 Quick Answer: 33 The Details: 51 8 Practice Exam A - Questions A15. Rodney, a security engineer, is viewing this record from the firewall logs: UTC 04/05/2018 03:09:15809 AV Gateway Alert 136.127.92.171 80 -> 10.16.10.14 60818 Gateway Anti-Virus Alert: XPACK.A_7854 (Trojan) blocked. Which of the following can be observed from this log information? ❍ A. The victim's IP address is 136.127.92.171 ❍ B. A download was blocked from a web server ❍ C. A botnet DDoS attack was blocked ❍ D. The Trojan was blocked, but the file was not A16. A user connects to a third-party website and receives this message: Your connection is not private. NET::ERR_CERT_INVALID Which of the following attacks would be the MOST likely reason for this message? ❍ A. Brute force ❍ B. DoS ❍ C. On-path ❍ D. Disassociation A17. Which of the following would be the BEST way to provide a website login using existing credentials from a third-party site? ❍ A. Federation ❍ B. 802.1X ❍ C. PEAP ❍ D. EAP-FAST Quick Answer: 33 The Details: 53 Quick Answer: 33 The Details: 54 Quick Answer: 33 The Details: 55 Practice Exam A - Questions 9 A18. A system administrator, Daniel, is working on a contract that will specify a minimum required uptime for a set of Internet-facing firewalls. Daniel needs to know how often the firewall hardware is expected to fail between repairs. Which of the following would BEST describe this information? ❍ A. MTBF ❍ B. RTO ❍ C. MTTR ❍ D. MTTF A19. An attacker calls into a company’s help desk and pretends to be the director of the company’s manufacturing department. The attacker states that they have forgotten their password and they need to have the password reset quickly for an important meeting. What kind of attack would BEST describe this phone call? ❍ A. Social engineering ❍ B. Tailgating ❍ C. Watering hole ❍ D. On-path A20. A security administrator has been using EAP-FAST wireless authentication since the migration from WEP to WPA2. The company’s network team now needs to support additional authentication protocols inside of an encrypted tunnel. Which of the following would meet the network team’s requirements? ❍ A. EAP-TLS ❍ B. PEAP ❍ C. EAP-TTLS ❍ D. EAP-MSCHAPv2 Quick Answer: 33 The Details: 56 Quick Answer: 33 The Details: 57 Quick Answer: 33 The Details: 58 10 Practice Exam A - Questions A21. Which of the following would be commonly provided by a CASB? (Select TWO) ❍ A. List of all internal Windows devices that have not installed the latest security patches ❍ B. List of applications in use ❍ C. Centralized log storage facility ❍ D. List of network outages for the previous month ❍ E. Verification of encrypted data transfers ❍ F. VPN connectivity for remote users A22. The embedded OS in a company’s time clock appliance is configured to reset the file system and reboot when a file system error occurs. On one of the time clocks, this file system error occurs during the startup process and causes the system to constantly reboot. Which of the following BEST describes this issue? ❍ A. DLL injection ❍ B. Resource exhaustion ❍ C. Race condition ❍ D. Weak configuration A23. A recent audit has found that existing password policies do not include any restrictions on password attempts, and users are not required to periodically change their passwords. Which of the following would correct these policy issues? (Select TWO) ❍ A. Password complexity ❍ B. Password expiration ❍ C. Password history ❍ D. Password lockout ❍ E. Password recovery Quick Answer: 33 The Details: 59 Quick Answer: 33 The Details: 60 Quick Answer: 33 The Details: 61 Practice Exam A - Questions 11 A24. What kind of security control is associated with a login banner? ❍ A. Preventive ❍ B. Deterrent ❍ C. Corrective ❍ D. Detective ❍ E. Compensating ❍ F. Physical A25. A security team has been provided with a noncredentialed vulnerability scan report created by a thirdparty. Which of the following would they expect to see on this report? ❍ A. A summary of all files with invalid group assignments ❍ B. A list of all unpatched operating system files ❍ C. The version of web server software in use ❍ D. A list of local user accounts A26. A business manager is documenting a set of steps for processing orders if the primary Internet connection fails. Which of these would BEST describe these steps? ❍ A. Communication plan ❍ B. Continuity of operations ❍ C. Stakeholder management ❍ D. Tabletop exercise A27. A security administrator is concerned about data exfiltration resulting from the use of malicious phone charging stations. Which of the following would be the BEST way to protect against this threat? ❍ A. USB data blocker ❍ B. Personal firewall ❍ C. MFA ❍ D. FDE Quick Answer: 33 The Details: 62 Quick Answer: 33 The Details: 63 Quick Answer: 33 The Details: 64 Quick Answer: 33 The Details: 65 12 Practice Exam A - Questions A28. A company would like to protect the data stored on laptops used in the field. Which of the following would be the BEST choice for this requirement? ❍ A. MAC ❍ B. SED ❍ C. CASB ❍ D. SOAR A29. A file server has a full backup performed each Monday at 1 AM. Incremental backups are performed at 1 AM on Tuesday, Wednesday, Thursday, and Friday. The system administrator needs to perform a full recovery of the file server on Thursday afternoon. How many backup sets would be required to complete the recovery? ❍ A. 2 ❍ B. 3 ❍ C. 4 ❍ D. 1GEOGRAPHY PRACTICE PAPER GRADE 12(2)12/2/25 RTI Prefix Suffix Work, Determine the meaning of the Figurative Phrase, Context Clues Practice12-1 Day 2 Practice: Mutually exclusive events1. How many pillars of Islam are there in total? A) Three B) Five (Correct) C) Six D) Seven Hint: Think about the famous Hadith of Gabriel where he asks about the basic practices of Islam. 2. What is the first pillar of Islam? A) Salah (Prayer) B) Zakat (Charity) C) Shahadah (Declaration of faith) (Correct) D) Sawm (Fasting) Hint: It is the declaration that there is no god but Allah and Muhammad is His messenger. 3. How many times a day must a Muslim perform Salah (prayer)? A) Three times B) Five times (Correct) C) Four times D) Six times Hint: Count Fajr, Dhuhr, Asr, Maghrib, and Isha. 4. What does the word 'Zakat' mean in terms of practice? A) Fasting all day B) Giving charity to the poor (Correct) C) Traveling to Makkah D) Reading the Quran Hint: It involves sharing a small part of your saved wealth to purify the rest of it. 5. During which Islamic month do Muslims fast (Sawm)? A) Muharram B) Ramadan (Correct) C) Shawwal D) Dhul-Hijjah Hint: It is the month in which the Quran was first revealed. 6. Where must a Muslim go to perform Hajj? A) Madinah B) Jerusalem C) Makkah (Correct) D) Cairo Hint: This city contains the Kaaba, the direction Muslims face during prayer. 7. Which pillar of Islam directly trains a Muslim in patience and feeling the hunger of the poor? A) Shahadah B) Sawm (Fasting) (Correct) C) Salah D) Hajj Hint: It is done during the daylight hours of Ramadan. Part 2: Pillars of Iman (أركان الإيمان) 8. How many pillars of Iman (faith) are there? A) Five B) Six (Correct) C) Four D) Eight Hint: It is one more than the number of pillars of Islam. 9. What is the first and most important pillar of Iman? A) Belief in Angels B) Belief in Allah (Correct) C) Belief in the Books D) Belief in the Last Day Hint: This is the belief in Monotheism (Tawhid). 10. Muslims believe that angels are created from what? A) Fire B) Clay C) Light (Correct) D) Water Hint: Think of a bright source that illuminates the dark, which matches their pure and luminous nature. 11. Which angel was responsible for bringing the revelation (Quran) to the Prophet Muhammad? A) Angel Mikaeel (Michael) B) Angel Jibreel (Gabriel) (Correct) C) Angel Israfeel D) Angel Malak al-Mawt Hint: He is the leader of all angels and visited the Prophet in the cave of Hira. 12. Belief in the Holy Books is a pillar of Iman. Which book was given to Prophet Isa (Jesus)? A) The Torah B) The Zabur C) The Injeel (Correct) D) The Quran Hint: The English translation often links this word closely to the 'Gospel'. 13. Who is the final Prophet and Messenger sent by Allah to mankind? A) Prophet Ibrahim (Abraham) B) Prophet Musa (Moses) C) Prophet Muhammad (Correct) D) Prophet Nuh (Noah) Hint: He was born in Makkah and received the Quran. 14. What does 'Belief in the Last Day' mean? A) Belief in the last day of Ramadan B) Belief in the Day of Judgment (Correct) C) Belief in the weekend D) Belief that the sun will never set Hint: It is the day when people will be rewarded with Paradise or punished based on their deeds. 15. What is the sixth pillar of Iman? A) Belief in Qadar (Divine Decree/Fate) (Correct) B) Belief in Hellfire C) Belief in the Companions D) Belief in Charity Hint: It relates to destiny and accepting whatever Allah has written for us. 16. What is the Arabic word for the 'Divine Decree' or destiny in the pillars of Iman? A) Zakat B) Qadar (Correct) C) Injeel D) Tawhid Hint: It sounds like 'Al-Qadr', as in the night of decree (Laylat al-Qadr). 17. Belief in Prophets includes believing in messengers mentioned in other scriptures. Who did Allah speak to directly? A) Prophet Musa (Moses) (Correct) B) Prophet Nuh (Noah) C) Prophet Yusuf (Joseph) D) Prophet Yunus (Jonah) Hint: He is the prophet associated with Mount Sinai and parting the sea. Part 3: Ihsan (الإحسان) 18. What is the meaning of 'Ihsan' according to the famous Hadith? A) To give all your money away B) To worship Allah as if you see Him (Correct) C) To memorize the whole Quran D) To fast twice a week Hint: It is the highest level of religion, focusing on absolute perfection and sincerity in worship. 19. If you cannot see Allah during worship, what must you always remember according to Ihsan? A) That other people are watching you B) That Allah sees you (Correct) C) That you should finish quickly D) That the angels will pray for you Hint: Allah is All-Seeing (Al-Baseer) and All-Knowing (Al-Aleem). 20. Which of the following represents the correct order of levels in religion from lowest to highest? A) Ihsan, then Iman, then Islam B) Islam, then Iman, then Ihsan (Correct) C) Iman, then Islam, then Ihsan D) Islam, then Ihsan, then Iman Hint: Every Muhsin (person of Ihsan) is a Mu'min (person of Iman) and a Muslim, but not vice versa.