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Convert a number of fifths from an improper fraction to mixed number 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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Dif- ferential role of adipose tissues in obesity and related metabolic and vas- cular complications. 2016;2016:1-15, 1216783. 6. Zwick RK, Guerrero-Juarez CF, Horsley V, Plikus MV. Anatomical, physiological, and functional diversity of adipose tissue. Cell Metab. 2018;27(1):68-83. 7. Gulyaeva O, Dempersmier J, Sul HS. Genetic and epigenetic control of adipose development. Biochimica et Biophysica Acta (BBA)— Molecular and Cell Biology of Lipids. 2019;1864:3-12. 8. Khan M, Joseph F. Adipose tissue and adipokines: the association with and application of adipokines in obesity. Forensic Sci. 2014;2014: 711-724, 328592. 9. Alotaibi MF. Physiology of puberty in boys and girls and pathological disorders affecting its onset. J Adolesc. 2019;71:63-71. 10. Cousminer DL, Stergiakouli E, Berry DJ, et al. Genome-wide associa- tion study of sexual maturation in males and females highlights a role for body mass and menarche loci in male puberty. Hum Mol Genet. 2014;23(16):4452-4464. 11. 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Ann Epidemiol. 2017;27(3):187-93.e2. 16. Glass NA, Torner JC, Letuchy EM, et al. The relationship between greater prepubertal adiposity, subsequent age of maturation, and bone strength during adolescence. Journal of bone and mineral research: the official journal of the American Society for Bone and Min- eral Research. 2016;31(7):1455-1465. 17. Holmgren A, Niklasson A, Nierop AF, et al. Pubertal height gain is inversely related to peak BMI in childhood. Pediatr Res. 2017;81(3): 448-454. 18. Kaplowitz PB, Slora EJ, Wasserman RC, Pedlow SE, Herman- Giddens ME. Earlier onset of puberty in girls: relation to increased body mass index and race. Pediatrics. 2001;108(2):347-353. 19. Kelly Y, Zilanawala A, Sacker A, Hiatt R, Viner R. Early puberty in 11-year-old girls: Millennium Cohort Study findings. Arch Dis Child. 2017;102(3):232-237. 20. Lazzeri G, Tosti C, Pammolli A, et al. Overweight and lower age at menarche: evidence from the Italian HBSC cross-sectional survey. 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. Selection criteria used were English language, longitudinal or cross-sectional studies assessing the onset of puberty, including menarche, thelarche, spermarche, or voice break, combined with high BMI or obesity/adiposity, and articles assessing or reviewing adipokines and its effects on the reproductive system. 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. 9 of 10 21. Lian Q, Mao Y, Luo S, et al. Puberty timing associated with obesity and central obesity in Chinese Han girls. BMC Pediatr. 2019; 19(1):1-7. 22. Deng Y, Liang J, Zong Y, et al. Timing of spermarche and menarche among urban students in Guangzhou, China: trends from 2005 to 2012 and association with Obesity. Sci Rep. 2018;8(1):263-270. 23. Li W, Liu Q. Association of prepubertal obesity with pubertal devel- opment in Chinese girls and boys: a longitudinal study. 2018;30: e23195. 24. Mendle J, Beltz AM, Carter R, Dorn LD. Understanding puberty and its measurement: ideas for research in a new generation. Journal of research on adolescence: the official journal of the Society for Research on Adolescence. 2019;29(1):82-95. 25. Pagani S, Meazza C, Gertosio C, Bozzola E, Bozzola M. Growth hor- mone receptor gene expression in puberty. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme. 2015;47:581-584. 26. Abreu AP, Kaiser UB. Pubertal development and regulation. Lancet Diabetes Endocrinol. 2016;4(3):254-264. 27. Aguirre RS, Eugster EA. Central precocious puberty: from genetics to treatment. Best Pract Res Clin Endocrinol Metab. 2018;32(4): 343-354. 28. Sultan C, Gaspari L, Maimoun L, Kalfa N, Paris F. Disorders of puberty. Best Pract Res Clin Obstet Gynaecol. 2018;48:62-89. 29. Skorupskaite K, George JT, Anderson RA. The kisspeptin-GnRH path- way in human reproductive health and disease. Hum Reprod Update. 2014;20(4):485-500. 30. Dahl SK, Amstalden M, Coolen L, Fitzgerald M, Lehman M. Dynorphin immunoreactive fibers contact GnRH neurons in the human hypothal- amus. Reprod Sci. 2009;16(8):781-787. 31. Navarro VM, Gottsch ML, Chavkin C, Okamura H, Clifton DK, Steiner RA. Regulation of gonadotropin-releasing hormone secretion by kisspeptin/dynorphin/neurokinin B neurons in the arcuate nucleus of the mouse. J Neurosci. 2009;29(38):11859-11866. 32. Zhai L, Liu J, Zhao J, et al. Association of obesity with onset of puberty and sex hormones in chinese girls: a 4-year longitudinal study. PLoS ONE. 2015;10(8):1-12, e0134656. 33. Cizza G, Dorn LD, Lotsikas A, Sereika S, Rotenstein D, Chrousos GP. Circulating plasma leptin and IGF-1 levels in girls with premature adrenarche: potential implications of a preliminary study. Horm Metab Res. 2001;33(3):138-143. 34. Cousminer DL, Widén E, Palmert MR. The genetics of pubertal timing in the general population: recent advances and evidence for sex-spec- ificity. Curr Opin Endocrinol Diabetes Obes. 2016;23(1):57-65. 35. Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. Arch Dis Child. 1969;44(235):291-303. 36. Lacroix AE, Whitten R. Physiology. Treasure Island (FL): Menarche. StatPearls. StatPearls Publishing; 2018. 37. McDowell MA, Brody DJ, Hughes JP. Has Age at Menarche Chan- ged? Results from the National Health and Nutrition Examination Sur- vey (NHANES) 1999–2004. J Adolesc Health. 2007;40(3):227-231. 38. de Muinich Keizer SM, Mul D. Trends in pubertal development in Europe. Hum Reprod Update. 2001;7(3):287-291. 39. Talma H, Schönbeck Y, van Dommelen P, Bakker B, van Buuren S, Hirasing RA. Trends in menarcheal age between 1955 and 2009 in the Netherlands. PLoS ONE. 2013;8:e60056-e60056. 40. Kaplan HS, Lancaster JB. An evolutionary and ecological analysis of human fertility, mating patterns, and parental investment. Off- spring: Human fertility behavior in biodemographic perspective. 2003;1: 170-223. 41. Mitan LA. Menstrual dysfunction in anorexia nervosa. J Pediatr Adolesc Gynecol. 2004;17(2):81-85. 42. Xu H, Li P-H, Barrow TM, et al. Obesity as an effect modifier of the association between menstrual abnormalities and hypertension in young adult women: Results from Project ELEFANT. PLoS ONE. 2018; 13(11):e0207929-e0207929. 43. Tauqeer Z, Gomez G, Stanford FC. Obesity in women: insights for the clinician. J Womens Health (Larchmt). 2018;27(4):444-457. 44. de Ridder CM, Thijssen JH, Bruning PF, Van den Brande JL, Zonderland ML, Erich WB. Body fat mass, body fat distribution, and pubertal development: a longitudinal study of physical and hormonal sexual maturation of girls. J Clin Endocrinol Metab. 1992;75(2): 442-446. 45. Lassek W, Gaulin S. Brief communication: menarche is related to fat distribution. Am J Phys Anthropol. 2007;133(4):1147-1151. 46. Loomba-Albrecht LA, Styne DM. Effect of puberty on body composi- tion. Curr Opin Endocrinol Diabetes Obes. 2009;16:10-15. 47. Simonneaux V, Bahougne T. A multi-oscillatory circadian system times female reproduction. Front Endocrinol. 2015;6:1-15. 48. Marques P, Skorupskaite K, George JT, Anderson RA. Physiology of GNRH and gonadotropin secretion. In: Feingold KR, Anawalt B, Boyce A, et al., eds. Endotext. Endotext.org: South Dartmouth (MA); 2000. 49. Barcellos Gemelli IF, Farias EDS, Souza OF. Age at menarche and its association with excess weight and body fat percentage in girls in the Southwestern Region of the Brazilian Amazon. J Pediatr Adolesc Gynecol. 2016;29(5):482-488. 50. Aksglaede L, Juul A, Olsen LW, Sorensen TI. Age at puberty and the emerging obesity epidemic. PLoS ONE. 2009;4:1-6, e8450. 51. Ribeiro J, Santos P, Duarte J, Mota J. Association between over- weight and early sexual maturation in Portuguese boys and girls. Ann Hum Biol. 2006;33(1):55-63. 52. Budak E, Fernandez Sanchez M, Bellver J, Cervero A, Simon C, Pellicer A. Interactions of the hormones leptin, ghrelin, adiponectin, resistin, and PYY3-36 with the reproductive system. Fertil Steril. 2006;85(6):1563-1581. 53. Castellano JM, Tena-Sempere M. Metabolic control of female puberty: potential therapeutic targets. Expert Opin Ther Targets. 2016; 20(10):1181-1193. 54. Venancio JC, Margatho LO, Rorato R, et al. Short-term high-fat diet increases leptin activation of CART neurons and advances puberty in female mice. Endocrinology. 2017;158(11):3929-3942. 55. l'Allemand D, Schmidt S, Rousson V, Brabant G, Gasser T, Gruters A. Associations between body mass, leptin, IGF-I and circulating adrenal androgens in children with obesity and premature adrenarche. Eur J Endocrinol. 2002;146(4):537-543. 56. Böttner A, Jr K, Müller G, et al. Gender Differences of adiponectin levels develop during the progression of puberty and are related to serum androgen levels. J Clin Endocrinol Metabol. 2004;89(8):4053- 4061. 57. Unanue N, Bazaes R, Iñiguez G, Cortes F, Avila A, Mericq V. Adre- narche in Prader-Willi syndrome appears not related to insulin sensi- tivity and serum adiponectin. Horm Res. 2007;67(3):152-158. 58. Michalakis K, Mintziori G, Kaprara A, Tarlatzis BC, Goulis DG. The complex interaction between obesity, metabolic syndrome and repro- ductive axis: a narrative review. Metabolism: clinical and experimental. 2013;62(4):457-478. 59. Machinal-Quelin F, Dieudonne MN, Pecquery R, Leneveu MC, Giudicelli Y. Direct in vitro effects of androgens and estrogens on ob gene expression and leptin secretion in human adipose tissue. Endo- crine. 2002;18(2):179-184. 60. Dobrzyn K, Smolinska N, Kiezun M. Adiponectin: A new regulator of female reproductive system. Int J Endocrinol. 2018;2018:1-12, 7965071. 61. Martin LJ. Implications of adiponectin in linking metabolism to testic- ular function. Endocrine. 2014;46(1):16-28. 62. Mathew H, Castracane VD, Mantzoros C. Adipose tissue and repro- ductive health. Metabolism: clinical and experimental. 2018;86:18-32. 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 10 of 10 NIEUWENHUIS ET AL. 63. Sitticharoon C, Sukharomana M, Likitmaskul S, Churintaraphan M, Maikaew P. 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The usefulness of circulating levels of leptin, kisspeptin, and neurokinin B in obese girls with precocious puberty. 2018;34:627-630. 69. Lee J, Song J, Hootman JM, et al. Obesity and other modifiable fac- tors for physical inactivity measured by accelerometer in adults with knee osteoarthritis: data from the osteoarthritis initiative (OAI). Arthritis Care Res (Hoboken). 2012;53-61. 70. Bramswig J, Dubbers A. Disorders of pubertal development. Deutsches Arzteblatt international. 2009;106:295-303. quiz 04 71. Elias CF, Purohit D. Leptin signaling and circuits in puberty and fertil- ity. Cell Mol Life Sci. 2013;70(5):841-862. 72. Riumallo J, Durnin JV. Changes in body composition in adolescent boys. Eur J Clin Nutr. 1988;42(2):107-112. 73. Siervogel RM, Demerath EW, Schubert C, et al. Puberty and body composition. Horm Res. 2003;60(Suppl 1):36-45. 74. Zhang J. Gong M. Andrologia: Review of the role of leptin in the regu- lation of male reproductive function; 2018. 75. Kauffman AS, Gottsch ML, Roa J, et al. Sexual differentiation of Kiss1 gene expression in the brain of the rat. Endocrinology. 2007;148(4): 1774-1783. 76. Zeydabadi Nejad S, Ramezani Tehrani F, Zadeh-Vakili A. The role of kisspeptin in female reproduction. Int J Endocrinol Metab. 2017;15:1- 11, e44337. 77. Sorensen K, Aksglaede L, Petersen JH, Juul A. Recent changes in pubertal timing in healthy Danish boys: associations with body mass index. J Clin Endocrinol Metab. 2010;95(1):263-270. 78. Juul A, Magnusdottir S, Scheike T, Prytz S, Skakkebaek NE. Age at voice break in Danish boys: effects of pre-pubertal body mass index and secular trend. Int J Androl. 2007;30(6):537-542. 79. Lee JM, Wasserman R, Kaciroti N, et al. Timing of puberty in overweight versus obese boys. Pediatrics. 2016;137(2):137-146, e20150164. 80. He F, Guan P, Liu Q, Crabtree D, Peng L, Wang H. 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Secondary sexual characteristics in boys: data from the Pediatric Research in Office Settings Network. Pediatrics. 2012;130(5):e1058-e1068. 86. WHO. Physical status: the use and interpretation of anthropometry. Report of a WHO Expert Committee. World Health Organ Tech Rep Ser. 1995;854:1-452. 87. Akin I, Tolg R, Hochadel M, et al. No evidence of “obesity paradox” after treatment with drug-eluting stents in a routine clinical practice: results from the prospective multicenter German DES.DE (German Drug-Eluting Stent) Registry. JACC Cardiovasc Interv. 2012;5(2): 162-169. 88. Marcovecchio ML, Chiarelli F. Obesity and growth during childhood and puberty. World Rev Nutr Diet. 2013;106:135-141. How to cite this article: Nieuwenhuis D, Pujol-Gualdo N, Arnoldussen IAC, Kiliaan AJ. Adipokines: A gear shift in puberty. 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 goverAlign Panel: This panel allows you to align one or more objects the the artboard or other objects. Alignment: Formatting the appearance of text with the margins of the text box. Anchor Point Tool: Allows you to add or remove handles to create a curve on an anchor point. Anchor Points: A point on a path indicates a change of direction. Appearance Panel: This panel shows you the fill, strokes, graphic styles, and effects that have been applied to an object, group or layer and are able to modify theses from this panel directly. Area Type Tool: This occurs when using the type tool and you click and drag a text box, the text will automatically wrap inside the box. Blend Tool: This tool allows you to combine shapes/colors between two or more objects to create a new object between the original, blending the colors and shapes by inserting the middle steps to get from one object to the next. Blob Brush Tool: This tool is used to create free-form objects that can have a more hand-drawn feel. Brushes: Allows you to set the appearance/style of a path, can be applied to existing paths or used to create new paths. Clipping Masks: This command allows you to mask objects to a shape so that only areas that lie within the shape are visible, the mask and objects that are masked are called a clipping set. Closed Path: A path that has the same beginning and ending point. It forms a complete shape that can be filled with color or text. Create Outlines: This command converts text to closed paths and can be found in the Type Menu. Curvature Pen Tool: Allows you to simply create paths with curved anchor points. Curves: Can be applied to an anchor point using handles to create an arched line. Direct Select Tool: Allows you to select individual points of any path. Effects: These can be added to objects to create quick dynamic characteristics. Eraser Tool: This tool allows you to remove anchor points and cut through paths. Expand Objects: This allows you to divide a single object into multiple objects that make up its appearance. Eyedropper Tool: This tool allows you to sample the color or text from an existing part of the artwork. Global Swatches: This is a color swatches that will be automatically updated throughout your artwork when you change them, indicated with a white triangle in the corner of the swatch. Graphic Styles: A set of reusable appearance attributes that allow you to quickly change the look of an object. Grouping: This command allows you to link objects together so that they can be moved, scaled, rotator, or copy. Groups can be nested inside other groups. Hierarchy: To create visual order in design, controlling what the viewer looks at in order using size, color, contrast, etc… Image Trace: This command allows you to convert a raster image into a vector artwork. Isolation Mode: This mode allows you to adjust single objects/groups inside a group without ungrouping the group. Join Tool: This tool joins paths and anchor points together quickly. Kerning: This is the adjustment of the space between two individual letters. Knife Tool: This tool allows you to split an object into 2 pieces along a freehand path you draw. Leading: This is the adjustment of the space between lines of text. Live Corners: This widget appears when using the Direct Select tool and a corner is selected, when used this will create a rounded corner. Live Paint: This command allows you to quickly apply colors to objects in a complex design. Open Path: A path that does not end, not connected back to the original anchor point. Overflow Text: This occurs when the text box is too small to house all the text and is indicated by a small red plus sign in the bottom right corner of the text box. Paintbrush Tool: This tool is used to create free-form paths that can have a more hand-drawn feel. Paragraph Spacing: The space that occurs between lines of text. Pathfinder Panel: This panel allows you to create complex shapes by selecting 2 or more objects and using the buttons in the panel to cut, combine, or divide the objects. Paths: These are created when 2 or more points are connected, these are created using the pen tool. Pen Tool: It allows you to create and edit anchor points and paths. Pencil Tool: This tool is used to create free-form shapes or lines, the accuracy of the lines can be adjusted. Perspective Tool: This tool allows you to place elements on a perspective grid to adjust objects on a different perspective, automatically snapping to the perspective grid. Placeholder Text: Text that is placed in a text box that "holds a place" in a design to allow for creating a layout or adjust the text design. Point Type Tool: This occurs when when using the type tool and you click once, the text will continue without wrapping. Readability: The characteristics of fonts and styles that make test easy to identify and read. Scale, Shear, Distort Objects: This set of commands allows you to adjust the size and perspective of objects. Scissors Tool: This tool allows you to split a path into 2 pieces. Selection Tool: Allows you to select paths, objects or groups by click or dragging over them. Shape Builder Tool: This interactive tool allows you to create complex shapes by merging and erasing simpler objects. Shapes Tools: A group of tools to create basic shapes without using the pen tool (rectangle, ellipse, polygon, star, etc…). Smooth Tool: This tool will smooth a complex path and reduce the number of anchor points. Swatches: This is a saved color that can be applied in a design via the swatches panel and can be grouped, these can include gradients and patterns. Text Wrapping: This is when the text in a text box automatically wraps to the next line when it reaches the edge of the box. Threading Text: This is the ability to create 2 or more text boxes that are linked, when text is added/adjusted in one box, it will affect the other(s). Touch Type Tool: This tool allows you to adjust individual letter in a previously created text box. Tracking: This is the adjustment of the overall spacing between letters. Transform Objects: This allows you to change the size of objects. Type on a Path Tool: This tool allows you to add text along any previously created path. Type Tool: This tool allows you to create text in a design. View Modes: Ability to view projects and adjust the display on the screen. Modes include Outlines, Presentation, & Full Screen.What is a Plant Cell? Plant cells are eukaryotic cells that vary in several fundamental factors from other eukaryotic organisms. Both plant and animal cells contain a nucleus along with similar organelles. One of the distinctive aspects of a plant cell is the presence of a cell wall outside the cell membrane. Plant Cell Structure Just like different organs within the body, plant cell structure includes various components known as cell organelles that perform different functions to sustain itself. These organelles include: Cell Wall It is a rigid layer which is composed of polysaccharides cellulose, pectin and hemicellulose. It is located outside the cell membrane. It also comprises glycoproteins and polymers such as lignin, cutin, or suberin. The primary function of the cell wall is to protect and provide structural support to the cell. The plant cell wall is also involved in protecting the cell against mechanical stress and providing form and structure to the cell. It also filters the molecules passing in and out of it. The formation of the cell wall is guided by microtubules. It consists of three layers, namely, primary, secondary and the middle lamella. The primary cell wall is formed by cellulose laid down by enzymes. Cell membrane It is the semi-permeable membrane that is present within the cell wall. It is composed of a thin layer of protein and fat. The cell membrane plays an important role in regulating the entry and exit of specific substances within the cell. For instance, cell membrane keeps toxins from entering inside, while nutrients and essential minerals are transported across. Nucleus The nucleus is a membrane-bound structure that is present only in eukaryotic cells. The vital function of a nucleus is to store DNA or hereditary information required for cell division, metabolism and growth. 1. Nucleolus: It manufactures cells’ protein-producing structures and ribosomes. 2. Nucleopore: Nuclear membrane is perforated with holes called nucleopore that allow proteins and nucleic acids to pass through. Plastids They are membrane-bound organelles that have their own DNA. They are necessary to store starch and to carry out the process of photosynthesis. It is also used in the synthesis of many molecules, which form the building blocks of the cell. Some of the vital types of plastids and their functions are stated below: Leucoplasts They are found in the non-photosynthetic tissue of plants. They are used for the storage of protein, lipid and starch. Chromoplasts They are heterogeneous, colored plastid which is responsible for pigment synthesis and for storage in photosynthetic eukaryotic organisms. Chromoplasts have red-, orange- and yellow-colored pigments which provide color to all ripe fruits and flowers. Central Vacuole It occupies around 30% of the cell’s volume in a mature plant cell. Tonoplast is a membrane that surrounds the central vacuole. The vital function of the central vacuole apart from storage is to sustain turgor pressure against the cell wall. The central vacuole consists of cell sap. It is a mixture of salts, enzymes and other substances. Golgi Apparatus They are found in all eukaryotic cells, which are involved in distributing synthesized macromolecules to various parts of the cell. Ribosomes They are the smallest membrane-bound organelles which comprise RNA and protein. They are the sites for protein synthesis, hence, also referred to as the protein factories of the cell. Mitochondria They are the double-membraned organelles found in the cytoplasm of all eukaryotic cells. They provide energy by breaking down carbohydrate and sugar molecules, hence they are also referred to as the “Powerhouse of the cell.” Lysosome Lysosomes are called suicidal bags as they hold digestive enzymes in an enclosed membrane. They perform the function of cellular waste disposal by digesting worn-out organelles, food particles and foreign bodies in the cell. In plants, the role of lysosomes is undertaken by the vacuoles. Chloroplasts It is an elongated organelle enclosed by phospholipid membrane. The chloroplast is shaped like a disc and the stroma is the fluid within the chloroplast that comprises a circular DNA. Each chloroplast contains a green colored pigment called chlorophyll required for the process of photosynthesis. The chlorophyll absorbs light energy from the sun and uses it to transform carbon dioxide and water into glucose. Structure of Chloroplast Chloroplasts are found in all higher plants. It is oval or biconvex, found within the mesophyll of the plant cell. The size of the chloroplast usually varies between 4-6 µm in diameter and 1-3 µm in thickness. They are double-membrane organelle with the presence of outer, inner and intermembrane space. There are two distinct regions present inside a chloroplast known as the grana and stroma. • Grana are made up of stacks of disc-shaped structures known as thylakoids or lamellae. The granum of the chloroplast consists of chlorophyll pigments and are the functional units of chloroplasts. • Stroma is the homogenous matrix which contains grana and is similar to the cytoplasm in cells in which all the organelles are embedded. Stroma also contains various enzymes, DNA, ribosomes, and other substances. Stroma lamellae function by connecting the stacks of thylakoid sacs or grana. The chloroplast structure consists of the following parts: Membrane Envelope It comprises inner and outer lipid bilayer membranes. The inner membrane separates the stroma from the intermembrane space. Intermembrane Space The space between inner and outer membranes. Thylakoid System (Lamellae) The system is suspended in the stroma. It is a collection of membranous sacs called thylakoids or lamellae. The green colored pigments called chlorophyll are found in the thylakoid membranes. It is the sight for the process of light-dependent reactions of the photosynthesis process. The thylakoids are arranged in stacks known as grana and each granum contains around 10-20 thylakoids. Stroma It is a colorless, alkaline, aqueous, protein-rich fluid present within the inner membrane of the chloroplast present surrounding the grana. Grana Stack of lamellae in plastids is known as grana. These are the sites of conversion of light energy into chemical energy. Chlorophyll It is a green photosynthetic pigment that helps in the process of photosynthesis. Functions of Chloroplast Following are the important chloroplast functions: • The most important function of the chloroplast is to synthesize food by the process of photosynthesis. • Absorbs light energy and converts it into chemical energy. • Chloroplast has a structure called chlorophyll which functions by trapping the solar energy and is used for the synthesis of food in all green plants. • Produces NADPH and molecular oxygen (O 2 ) by photolysis of water. • Produces ATP – Adenosine triphosphate by the process of photosynthesis. • The carbon dioxide (CO2) obtained from the air is used to generate carbon and sugar during the Calvin Cycle or dark reaction of photosynthesis. Mitochondria “Mitochondria are membrane-bound organelles present in the cytoplasm of all eukaryotic cells, that produce adenosine triphosphate (ATP), the main energy molecule used by the cell.” What are Mitochondria? Popularly known as the “Powerhouse of the cell,” mitochondria (singular: mitochondrion) are a double membrane-bound organelle found in most eukaryotic organisms. They are found inside the cytoplasm and essentially function as the cell’s “digestive system.” They play a major role in breaking down nutrients and generating energy-rich molecules for the cell. Many of the biochemical reactions involved in cellular respiration take place within the mitochondria. The term ‘mitochondrion’ is derived from the Greek words “mitos” and “chondrion” which means “thread” and “granules-like”, respectively. It was first described by a German pathologist named Richard Altmann in the year 1890. Structure of Mitochondria • The mitochondrion is a double-membraned, rod-shaped structure found in both plant and animal cell. • Its size ranges from 0.5 to 1.0 micrometers in diameter. • The structure comprises an outer membrane, an inner membrane, and a gel-like material called the matrix. • The outer membrane and the inner membrane are made of proteins and phospholipid layers separated by the intermembrane space. • The outer membrane covers the surface of the mitochondrion and has a large number of special proteins known as porins. Cristae The inner membrane of mitochondria is rather complex in structure. It has many folds that form a layered structure called cristae, and this helps in increasing the surface area inside the organelle. The cristae and the proteins of the inner membrane aid in the production of ATP molecules. The inner mitochondrial membrane is strictly permeable only to oxygen and ATP molecules. A number of chemical reactions take place within the inner membrane of mitochondria. Mitochondrial Matrix The mitochondrial matrix is a viscous fluid that contains a mixture of enzymes and proteins. It also comprises ribosomes, inorganic ions, mitochondrial DNA, nucleotide cofactors, and organic molecules. The enzymes present in the matrix play an important role in the synthesis of ATP molecules. Functions of Mitochondria The most important function of mitochondria is to produce energy through the process of oxidative phosphorylation. It is also involved in the following process: 1. Regulates the metabolic activity of the cell 2. Promotes the growth of new cells and cell multiplication 3. Helps in detoxifying ammonia in the liver cells 4. Plays an important role in apoptosis or programmed cell death 5. Responsible for building certain parts of the blood and various hormones like testosterone and estrogen 6. Helps in maintaining an adequate concentration of calcium ions within the compartments of the cell 7. It is also involved in various cellular activities like cellular differentiation, cell signaling, cell senescence, controlling the cell cycle and in cell growth. Disorders Associated with Mitochondria Any irregularity in the way mitochondria function can directly affect human health, but often, it is difficult to identify because symptoms differ from person to person. Disorders of the mitochondria can be quite severe; in some cases, they can even cause an organ to fail.They've Got the Beat! Some students in New York really sing their hearts out! That's because they are in the school chorus at Public School 22. These students from Staten Island had a concert at the White House. They sang at a Hollywood awards show. Audiences have clapped and cheered them on. These kids are always asked to return. How does it feel to sing on stage? "I get nervous singing for a big audience," Brianna Crispino recalls. "But when I see the joy on their faces, I get excited." Sounds Good. The P.S.22 chorus is divided into two groups. The sopranos sing high notes. The altos sing lower sounds. Instruments like drums sometimes keep the beat. It's important to keep the rhythm so they make the right sounds together. Most adult choruses have four groups of voices. Here's a look at the number of each type of voice in one adult chorus from Pennsylvania. Musical Expression. Being part of the chorus is hard work. The chorus members won't disagree. They practice for three hours each week. Gregg Breinberg, their teacher, encourages the chorus to use movements. They move their hands to show how the songs make them feel. "They have their own movements because nobody feels music the same way," he explains. The chorus members understand that singing in a chorus is a big job. "We just want to give it our best!" one student says.Got it ✅ I’ll create 4 simple sections of assignments based on these two pages (1.1 What is a network? and 1.2 Network connections). Total marks = 25. Suitable for Oxford International Primary Computing Grade 5. --- Assignment – Computer Networks Grade 5 – Total Marks: 25 --- Section A: Choose the Correct Answer (6 marks) Circle the correct option. Each question = 2 marks. 1. A group of computers connected together is called a: a) Website b) Network c) Software 2. Which type of network connects computers inside a school? a) LAN b) WAN c) Wi-Fi 3. To use a network safely, you need: a) A strong password b) A printer c) A hotspot --- Section B: Fill in the Blanks (6 marks) Each correct answer = 2 marks. 1. We can use a network to share files and ________. 2. A wireless connection is also called ________. 3. Network ________ help devices work together. --- Section C: Short Answer Questions (7 marks) 1. Write two advantages of using a network. (2 marks) 2. What is the difference between a wired connection and a wireless connection? (2 marks) 3. Write one rule to keep your password safe. (1 mark) 4. Create a strong password example using numbers and symbols. (2 marks) --- Section D: Activity / Problem Solving (6 marks) 1. Web Valley School has 60 network connections. Each cable is 50 meters long. How many meters of cable are used in total? (2 marks) 2. Convert your answer into kilometers. (2 marks) 3. Why is it important to hide or lock network equipment? (2 marks) --- ✅ Total = 25 marks --- Would you like me to also make a teacher’s marking guide with answers and mark distribution?Q1. A teacher designs a lesson where students compute real-life percentages such as discounts and savings. 👉 A student calculates 15% of 200 to determine savings in a purchase. What is the correct result? A. 20 B. 25 C. 30 D. 35 Q2. In a classroom activity, learners compare numbers to find the highest common factor for grouping materials evenly. 👉 What is the GCF of 24 and 36? A. 6 B. 8 C. 12 D. 18 📘 FRACTIONS, DECIMALS, AND POWERS Q3. A learner converts fractions into percentages for data interpretation. 👉 What is 3/4 expressed as a percentage? A. 50% B. 60% C. 75% D. 80% Q4. A student models exponential growth using repeated multiplication. 👉 What is the value of 252^525? A. 25 B. 30 C. 32 D. 64 📘 ALGEBRA (EQUATIONS AND EXPRESSIONS) Q5. A teacher guides students to solve equations that represent real-life situations. 👉 Solve: 2x+8=202x + 8 = 202x+8=20 A. x = 4 B. x = 6 C. x = 8 D. x = 10 Q6. Students simplify expressions to understand relationships between quantities. 👉 Simplify: 3(x+4)−2x3(x + 4) - 2x3(x+4)−2x A. x + 12 B. x + 4 C. 5x + 4 D. 5x + 12 📘 FUNCTIONS AND GRAPHING Q7. A student analyzes a linear equation to determine its rate of change. 👉 What is the slope of y=3x−5y = 3x - 5y=3x−5? A. -5 B. -3 C. 3 D. 5 Q8. A learner evaluates functions to predict outcomes. 👉 If f(x)=2x+3f(x) = 2x + 3f(x)=2x+3, what is f(4)f(4)f(4)? A. 7 B. 9 C. 11 D. 14 📘 GEOMETRY Q9. Students explore geometric shapes and their properties through visual models. 👉 What is the sum of interior angles of a triangle? A. 90° B. 180° C. 270° D. 360° Q10. A student calculates the area of a classroom table with dimensions 8 cm by 5 cm. 👉 What is the area? A. 26 sq cm B. 30 sq cm C. 40 sq cm D. 48 sq cm 📘 MEASUREMENT AND FIGURES Q11. A learner determines the volume of a cube used in a science experiment. 👉 What is the volume of a cube with side 4 cm? A. 16 cubic cm B. 32 cubic cm C. 48 cubic cm D. 64 cubic cm Q12. Students identify shapes used in design projects. 👉 How many sides does a hexagon have? A. 5 B. 6 C. 7 D. 8 📘 STATISTICS AND PROBABILITY Q13. A teacher helps students interpret data sets using measures of central tendency. 👉 What is the mean of 4, 6, 8, 10, 12? A. 6 B. 8 C. 10 D. 12 Q14. A class experiment involves flipping a fair coin. 👉 What is the probability of getting heads? A. 1/4 B. 1/3 C. 1/2 D. 2/3 📘 WORD PROBLEMS (APPLICATION) Q15. A car travels 180 km in 3 hours during a learning task on speed. 👉 What is its average speed? A. 45 km/h B. 60 km/h C. 75 km/h D. 90 km/h Q16. Students analyze work efficiency in a project. 👉 If 5 workers complete a task in 12 days, how long will 10 workers take? A. 3 days B. 6 days C. 8 days D. 12 days Q17. A student solves a problem involving ratios in a classroom population. 👉 If the ratio of boys to girls is 3:2 and there are 30 students, how many boys are there? A. 12 B. 15 C. 18 D. 20 Q18. A learner determines the duration of a scheduled trip. 👉 A journey starts at 8:30 AM and ends at 11:15 AM. How long is the trip? A. 2 hrs 15 mins B. 2 hrs 30 mins C. 2 hrs 45 mins D. 3 hrs 15 mins Q19. A student computes simple interest for financial literacy. 👉 What is the simple interest on ₱1000 at 5% for 2 years? A. ₱50 B. ₱75 C. ₱100 D. ₱150 Q20. A learner solves a perimeter problem involving a rectangle. 👉 A rectangle has a length of 12 cm and perimeter of 34 cm. What is the width? A. 5 cm B. 7 cm C. 10 cm D. 11 cm ✅ ANSWER KEY (BASED ON YOUR REVIEWER) (All verified from your uploaded file) [ilide.info...002acd4e5a | PDF] QAnswer1C2C3C4C5B6A7C8C9B10C11D12B13B14C15B16B17C18C19C20ACould you give me a fifth grade math practice test based on the following items… quiz on adding fractions with unlike denominators. Students will need to know how to create a least common denominator, add, regroup, convert between improper fractions and mixed numbers, as well as simplify.