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3.12 George Washington
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1. Battle of Lexington At the Battle of Lexington in 1775, British soldiers and colonial militia faced each other on the village green. A shot was fired, but no one knows for sure who fired first. Even so, this moment is often called the beginning of the American Revolution. Why is the Battle of Lexington still considered the start of the American Revolution, even though it is unclear who fired the first shot? A. It marked the first time colonists and British soldiers fought in open battle B. It proved that colonists planned the war long before the fighting began C. It showed that British soldiers were fully responsible for starting the war D. It confirmed that colonists had already declared independence from Britain 2. Battle of Concord After the fighting at Lexington, British troops marched to Concord to destroy colonial supplies. Instead, colonial militia gathered and fought back, forcing the British to retreat toward Boston. Why is the Battle of Concord considered an important turning point in the early American Revolution? A. It showed that colonial militias could organize and successfully push back British troops B. It proved that the British army had already lost control of all the colonies C. It confirmed that the colonies had officially declared independence from Britain D. It demonstrated that foreign countries were already helping the colonial forces 3. Second Continental Congress Much of the early violent conflict between colonists and British soldiers took place in Boston. After fighting broke out at Lexington and Concord near Boston, colonial leaders met at the Second Continental Congress in 1775 to decide what to do next. Which answer best describes the main actions taken by the Second Continental Congress? A. They created an army, chose a leader, and tried to avoid war with Britain B. They declared independence, wrote the Constitution, and ended the war C. They raised taxes, formed a monarchy, and supported British rule D. They ended slavery, gave women rights, and expanded voting laws 4. Olive Branch Petition In 1775, colonial leaders sent a letter called the Olive Branch Petition to King George III of Britain. Based on this situation, what was the main purpose of the Olive Branch Petition sent to the king? A. To ask the king to restore peace between both sides B. To declare independence from Britain and begin a new nation C. To request help from foreign countries in the war effort D. To organize protests against British taxes across the colonies 5. Battle of Bunker Hill On June 17, 1775, during the Battle of Bunker Hill in Boston, colonial forces fought against the British on a hill overlooking the city. The fighting was intense and led to heavy losses on both sides. Which statement best explains why the Battle of Bunker Hill was an important battle in the war? A. The colonists won the battle, showing they were stronger than British forces B. The colonists won the battle, showing the British that the war would be short and easy for the colonists C. The British won the battle, showing the war would be difficult and costly for both sides D. The British won the battle, showing British forces could defeat the colonists easily 6. Pamphlets During the American Revolution, pamphlets were short printed writings that were inexpensive to produce and often written in everyday language so many colonists could read them. How did these features of pamphlets most affect their role in the American Revolution? A. They helped spread ideas widely, allowing more colonists to form and share opinions B. They limited ideas to educated leaders, keeping most colonists uninvolved C. They replaced newspapers entirely, becoming the only source of information D. They prevented disagreement, causing most colonists to think the same way 7. Thomas Paineâs Common Sense In 1776, Thomas Paine published Common Sense, a widely read piece of writing about the relationship between the colonies and Britain. How did this pamphlet most influence colonial thinking during the American Revolution? A. It encouraged colonists to support independence from Britain B. It convinced colonists to remain loyal to the British government C. It explained how colonial armies should organize attacks D. It described laws colonists were expected to follow 8. Declaration of Independence In July 1776, the Declaration of Independence listed complaints against King George III and explained the colonistsâ ideas about government and rights. How do these parts of the Declaration of Independence work together to support the colonistsâ decision? A. They connect ideas about rights to real examples, justifying separation from Britain B. They describe past events in detail, showing how the war had already ended C. They list future plans for government, explaining how leaders would be chosen D. They organize military actions, showing how the colonies planned to win 9. Washington Crosses the Delaware and Battle of Trenton In December 1776, George Washington led his army across the Delaware River and launched a surprise attack on Hessian mercenaries in Trenton. Which statement best explains why Washingtonâs crossing of the Delaware and the attack on Trenton was an important turning point in the war? A. It defeated British forces completely, ending the war in a short time B. It boosted morale, helping discouraged soldiers choose to keep fighting C. It brought foreign allies into the war, adding support for the colonies D. It led to independence, allowing the colonies to form a new nation 10. Battle of Saratoga In 1777, American forces defeated the British at the Battle of Saratoga, a major event during the American Revolution. Which statement best explains why the Battle of Saratoga was an important turning point in the war? A. It brought French support, helping Americans gain a strong advantage in the war B. It ended the war quickly, forcing Britain to surrender all control in the colonies C. It improved army training, helping soldiers become more skilled in future battles D. It changed leadership roles, causing new generals to take control of the army 11. Battle of Yorktown In 1781, American forces surrounded British troops at Yorktown, leading to a major moment in the American Revolution. Which statement best explains why the Battle of Yorktown was an important event in the war? A. French forces helped the Americans win, leading to the end of major fighting in the war B. Italian forces helped the British win, leading to a final victory over the American army C. German forces switched sides and helped the Americans win, leading to a final defeat for British troops D. French forces helped the British win, leading to a complete end of the war in the colonies 12. Treaty of Paris After the Battle of Yorktown, British public opinion turned against the war, and peace negotiations began. In 1783, American leaders signed the Treaty of Paris, which included agreements between the United States and Britain. Which statement best explains how the Treaty of Paris reflected the outcome of the American Revolution? A. Both sides made agreements, recognizing independence B. Americans gained independence, taking land without agreements C. British leaders kept control, ending the war with power D. Both sides refused compromise, continuing the war 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 DesirĂ©e Nieuwenhuis | NatĂ lia Pujol-Gualdo Amanda J. Kiliaan Department of Anatomy, Radboud university medical center, Donders Institute for Brain, Cognition and Behaviour, Preclinical Imaging Center PRIME, Nijmegen, The Netherlands Correspondence Amanda J. Kiliaan, PhD, Associate Professor, Department of Anatomy, Donders Institute for Brain, Cognition, and Behaviour, Preclinical Imaging Center PRIME, Radboud university medical center, 6500 HB Nijmegen, Geert Grooteplein 21N 6525 EZ Nijmegen, The Netherlands. Email: amanda.kiliaan@radboudumc.nl Funding information Europees Fonds voor Regionale Ontwikkeling (EFRO), Grant/Award Number: BriteN 2016 1 | INTRODUCTION The prevalence of obesity in adolescents and children is increasing in | Ilse A.C. Arnoldussen | Summary In this review, we discuss the role of adipokines in the onset of puberty in children with obesity during adrenarche and gonadarche and provide a clear and detailed overview of the biological processes of two major players, leptin and adiponectin. Adipokines, especially leptin and adiponectin, seem to induce an early onset of puberty in girls and boys with obesity by affecting the hypothalamic-pituitary- gonadal (HPG) axis. Moreover, adipokines and their receptors are expressed in the gonads, suggesting a role in sexual maturation and reproduction. All in all, adipokines may be a clue in understanding mechanisms underlying the onset of puberty in child- hood obesity and puberty onset variability. KEYWORDS adipokines, obesity, puberty 1,2 the age of 5 years were overweight or were with obesity in 2016, and 3 Obesity is defined by an excessive accumulation of white adipose tissue (WAT), and it is often indicated by a body mass index (BMI) 4 above 30. Two main types of adipose tissue were described: WAT and brown adipose tissue (BAT), which differ in morphology and func- 5-7 Ilse A.C. Arnoldussen and Amanda J. Kiliaan contributed equally to this work. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2020 The Authors. Obesity Reviews published by John Wiley & Sons Ltd on behalf of World Obesity Federation Obesity Reviews. 2020;21:e13005. wileyonlinelibrary.com/journal/obr 1 of 10 https://doi.org/10.1111/obr.13005 alarming rates. Specifically, worldwide, 41 million children below this number is expected to increase to 70 million in 2025. obesity is associated with various severe health complications, includ- ing increased risk of diabetes mellitus type 2, hypertension, heart dis- eases, and disturbances in sex hormone levels. 5,6 and mitochondria and plays a role in thermogenesis. Adipocytes in tion. BAT consists of adipocytes containing multiple lipid droplets WAT contain only a few mitochondria and a single lipid droplet. Adipose tissue has several functions including the storage of energy, thermogenesis, and the production and secretion of adipokines Generally, two physiological processes, adrenarche and gonadarche, 11,24 Childhood 5,7,8 a key role in puberty onset. Puberty is known as a period through which the body changes physically, being a physiological process resulting in the maturation of children, i.e. they develop sexual characteristics and obtain reproduc- 9,11 Adipokines are involved in a number of physiological processes including blood pressure, metabo- lism, glucose, and vascular homeostasis and may play amongst others 8-10 (hormones, cytokines, and peptides). tive functions. between obesity and puberty,2,12-23 the biological mechanisms under- lying obesity and puberty onset remain unclear. Hereafter, we review in detail the role of adipokines in the onset of puberty in childhood obesity. Although many studies have shown associations 2 | INITIATION OF PUBERTY PHYSIOLOGICAL PROCESSES IN THE interact to regulate the onset of puberty. During adrenarche, the adrenal cortex secretes steroid hormones (including 2 of 10 NIEUWENHUIS ET AL. androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate (DHEAS), androstenedione, and cortisol), insulin-like growth factor, and growth hormone, which contribute to the pubertal insights on new genetic loci (e.g. melanocortin-4 receptor, mitochon- drial carrier 2, and mitogen-activated protein kinase 13) and on sev- eral pathways that regulate the timing of puberty; however, it partly 34 9,24,25 Both adrenarche and gonadarche are involved in the development growth spurt, body odor, skin oiliness, and skeletal maturation. explains puberty timing variation. Thereby, defining the role of 25 adipokines is of importance in elucidating the variability in puberty as the expression of adipokines is sex-specific and is altered with body composition, adiposity, and during growth spurts. Moreover, adipokines and their receptors are expressed in gonads and several brain regions suggesting involvement in the onset of puberty and sex- ual maturation. Lastly, adipokines interfere in processes regulating timing and duration of puberty, for instance in the HPA and HPG axes which are both key players during adrenarche and gonadarche. Involvement of adipokines in the onset of puberty and specifically in individuals with obesity will be further reviewed in the next 2,24 3 | Puberty onset in girls is assessed using different markers, such as thelarche (breast development), menarche (the start of of pubic hair. pituitary-gonadal (HPG) axis is activated,2,26 and several hormones have been identified to participate in the activation of the HPG axis During gonadarche (Figure 1), the hypothalamic- 2,27 Kisspeptin, neurokinin B, and dynorphin are released by specialized including kisspeptin, neurokinin B, dynorphin, leptin, and ghrelin. 28 key regulator of the pulsatile secretion of gonadotropin releasing neurons, the KNDy neurons in the hypothalamus. Kisspeptin is a 29,30 B stimulates, and dynorphin inhibits the release of kisspeptin, which hormone (GnRH) from the hypothalamus. In addition, neurokinin implies that both coordinate a pulsatile release of kisspeptin. 31 Sub- sections. sequently, the activated HPG axis induces the pituitary gland to secrete luteinising hormone (LH) and follicle stimulating hormone (FSH). As a result, gametogenesis occurs, and the gonads will release sex hormones. Consequently, secondary sex characteristics develop including breast development in girls and an increased testicular vol- 2,26,32 is possibly due to differences in levels of body fat, hypothalamic-pitui- THE ONSET OF PUBERTY IN GIRLS ume in boys. The age at puberty onset varies greatly among individuals, which 19 35 menstruation), and pubic hair development. 33 genome-wide association studies have provided important new tary-adrenal (HPA) axis activity, and genetic background. Recent The average age of However, this age differs between cultures and ethnicities, and since 1980, age at menarche is girls at start of menarche is 12.4 years. 36 significantly decreasing. 36-39 F I G U R E 1 Hormonal regulation in the initiation of puberty in boys and girls. The secretion of kisspeptin, neurokinin B, and dynorphin from KNDy neurons initiate the release of gonadotropin releasing hormone (GnRH) from the hypothalamus. This activates the pituitary gland to produce and secrete luteinising hormone (LH) and follicle stimulating hormone (FSH), which in turn stimulate the gonads to produce estrogen and testosterone in girls and boys, respectively 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License NIEUWENHUIS ET AL. 3 of 10 T A B L E 1 Summary of included studies Authors Year Country Study Design Primary Outcome Sex Sample Size (n) Age (y) Data Collection Lian et al21 2019 China Cross-sectional Puberty starts earlier in Chinese Han girls with obesity compared with Chinese Han girls with normal weight. Girls 2996 9-19 2012 and 2013 Biro et al12 Lazzeri et al20 2018 USA 2018 Italy Longitudinal Cross-sectional Body mass index had a greater effect on age at menarche than did race and ethnicity. Girls 946 6-16 2004-2014 Li et al23 2018 China Longitudinal For both, boys and girls, a higher BMI (ie, overweight and obese) is associated with earlier onset of puberty Girls Girls Boys Girls 542 Deng et al22 Flom et al15 2017 China Cross-sectional Increased BMI is associated with early timing spermarche and menarche. Boys Girls Girls 1278258 9-15 2005-2012 He et al24 Holmgren et al17 2017 China 2017 Sweden Cross-sectional Longitudinal Onset of puberty is not related to obesity in boys. Boys Boys Girls Girls 782 7-17 972 929 5839 Kelly et al19 2017 UK 2016 Brazil 2016 USA Longitudinal prospective cohort Higher BMI in girls is associated with the onset of menstruation at an earlier age. 11 10-18 11-17 Barcellos Gemelli et al25 Cross-sectional Longitudinal Excess weight is associated with early age of menarche. Girls 727 2014 2003-2009 Glass et al16 Lee et al26 In girls, but not in boys, greater adiposity is associated with the earlier onset of puberty. Boys Girls 135 Cabrera et al27 Leonibus et al14 2014 USA 2013 Italy Cross-sectional Longitudinal Thelarche occurred earlier than recently reported, while age of menarche remained unchanged. Girls 610 3-17.9 2007 2005-2012 Currie et al13 2012 Europe, USA, Canada Cross-sectional Overweight/obesity during childhood predicts the early onset of puberty in girls. Girls 20410 11, 13, 15 2005-2006 2017 USA Prospective birth cohort Overweight/obese status at the age of 7 ye was associated with increased risk of early menarche 788 From birth to menarche occurred Pregnancies 1959-1966 2016 USA Cross-sectional Boys with overweight enter puberty earlier compared with boys with normal weight or obesity, while puberty starts later in boys with obesity compared with boys with normal weight and overweight. Boys 3872 6-16 2005-2010 Overweight during childhood shows a relation with the early onset of puberty in girls. 6535 4259 695 11 15 5.8-12.2 2009/2010 2013/2014 2014-2017 Higher BMI during childhood is associated with early puberty. 2008 and 2009 2000-2002 Obesity during childhood is related to the earlier onset of puberty. Boys Girls 84 123 71 (Continues) 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 4 of 10 NIEUWENHUIS ET AL. 3.1 | Fat storage For the initiation of puberty, the timing of stimulation and/or inhibi- tion of different hormones is important, and additionally, a certain amount and distribution of body fat is needed in order to start menar- che, which emphasizes the importance of body fat. From an evolution- ary point of view, body fat increases in mammalian females during puberty onset, and it highlights the need to guarantee a healthy preg- 40 women with anorexia nervosa. particularly body fat localized predominantly on the gluteofemoral fat depots, is profoundly associated with start of menarche, more than nancy, offspring, and maternal survival. fat, sex-hormones, and neuroendocrine alterations can evolve in men- strual dysfunction, for instance, in women with severe obesity or in 41-43 44-46 to gluteofemoral fat depots suggesting that leptin may convey infor- amount of total body fat. mation on body fat distribution to the hypothalamus during puberty. An improper level of body Importantly, body fat distribution, Blood leptin levels are strongly related 45 3.2 | HPG axis The HPG axis is activated by the release of kisspeptin resulting in the release of GnRH from the hypothalamus, and LH and FSH from the pituitary gland. In girls, FSH is involved in the development of the folli- cles in the ovaries, and it promotes the secretion of estrogen. LH stim- ulates the production of androgen hormones and induces ovulation 48 9,47 the release of kisspeptin and neurokinin B, and kisspeptin thereby (Figure 1). The secretion of estrogen has an inhibitory effect on inhibits the GnRH release from the hypothalamus. pattern of GnRH is important for the regulation of the menstrual cycle. This roughly 28-day-cycle comprises several phases, including the follicular phase and luteal phase. During the follicular phase, increasing levels of FSH stimulate the maturation of follicles and the production of estrogen from the ovaries. This in turn inhibits the release of FSH from the pituitary gland. A high level of estrogen will induce the production of LH by the pituitary gland, resulting in ovula- tion. The matured follicle secretes progesterone thereby inhibiting the release of GnRH. When the corpus luteum is demolished, there is less 48 3.3 | Adipokines According to results from studies reported in Table 1, girls with obe- sity enter puberty earlier compared with girls with normal higher leptin concentrations inhibit the intake of food and increases inhibition of GnRH. As a consequence, the cycle will start again. whole process, starting from the activated HPG axis, results in the development of the secondary sex characteristics in girls including 9,47 thelarche and menarche. 13,14,16-23,49-51 weight. these girls might be found in the secretion of adipokines. For instance, leptin is positively associated with the amount of body fat. Generally, energy expenditure. 9,52-54 An explanation for the early onset of puberty in The expression This TABLE 1 (Continued) Authors Year Country Study Design Primary Outcome Sample Sex Size (n) Age (y) Data Collection Herman-Giddens et al28 2012 USA Cross-sectional Observed mean ages of beginning genital and pubic hair growth and early testicular volumes were earlier than in past studies, depending on the characteristic and race/ethnicity. Boys 4131 6-16 2005-2010 Sorensen et al29 Aksglaede et al30 2010 2009 Denmark Denmark Cross-sectional/longitudinal Longitudinal Puberty onset at earlier ages was associated with an increased BMI in boys. Boys 1528 5.8-19.9 1991-1993/2006-2008 1930-1969 Juul et al31 Ribeiro et al32 2007 2006 Denmark Portugal Retrospective cohort Cross-sectional Higher BMI is associated with early voice break. 11-15 10-15 1990-1999 Kaplowitz et al18 Abbreviation: BMI, body mass USA Cross-sectional The early onset of puberty in Caucasian girls is likely related to an increased BMI. 5-12 1992-1993 2001 index. The higher BMI in boys and girls at 7 y of age, the earlier they enter puberty. Boys 21 612 Girls 135 223 Boys 463 Boys 382 Girls 437 Girls 10 750 Early sexual maturation in boys and girls is associated with overweight. 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License NIEUWENHUIS ET AL. 5 of 10 Leptin may possibly play a role in adrenarche as its plasma level increases with higher levels of body fat and as it can modulate both girls. 33 ing adrenarche. In coherence, in children with obesity, the androgen These findings suggested that lower reproductive status was associated with higher total adiponectin concentrations and that a higher reproductive status was related to higher HMW adiponectin the HPA and HPG axes. These axes are functionally integrated dur- DHEAS was positively associated with leptin levels. Nevertheless, concentrations in girls. In addition, individuals with obesity often another study showed that enhanced adrenal androgen secretion in girls with premature adrenarche was not explained by leptin or BMI 55 ated with androgen levels in girls ; however, it was not related to levels. and IL-6. TNF-α alters, and IL-6 inhibits the expression of 56 8 In addition, the adipokine adiponectin was negatively associ- 57 differences of adiponectin seem to develop during the progression of 56 adiponectin (Figure 2). Thereby, a low level of total adiponectin and/or high levels of inflammatory cytokines in individuals with obe- sity can promote the onset of puberty. Many more adipokines are secreted by WAT including omentin, 52,65-67 9,36,62,68 adrenarche in girls with Prader-Willi syndrome. Interestingly, sex puberty. adrenarche; however, both are not required factors. Thus, leptin and adiponectin might be able to influence In gonadarche, leptin can stimulate the secretion of kisspeptin, and subsequently activation of the HPG axis, which eventually increases the expression of estrogen and androstenedione in the ova- 58 2,60 65-67 The expression of these ries (Figure 2). Ob gene in WAT, resulting in the synthesis and secretion of leptin. Thus, high levels of leptin promote onset of puberty in girls via secre- tion of kisspeptin, and estrogen stimulates leptin secretion addition- ally. Moreover, adiponectin can affect the HPG axis due to the expression of adiponectin receptors in the hypothalamus, pituitary In return, estrogen stimulates the expression of the 59 gland, and gonads. onset as it inhibits the secretion of kisspeptin and GnRH in the hypo- thalamus and the release of GH and LH in the pituitary gland, and 2,60-62 52,60 63 girls with central precocious puberty (CPP). Moreover, total adiponectin had negative correlations with progression of puberty in girls (defined by Tanner stages), whereas HMW adiponectin had FIGURE 2 Adipokinesaffectingthe initiation of puberty in girls. Leptin stimulates the release of kisspeptin in KNDy neurons, which activates the hypothalamus to produce gonadotropin releasing hormone (GnRH). In response to the release of GnRH, the pituitary gland secretes follicle stimulating hormone (FSH) and luteinising hormone (LH), which stimulates the ovaries to release estrogen resulting in the formation of secondary sex characteristics in girls. Estrogen stimulates the production of leptin. Adiponectin inhibits GnRH release resulting in reduced levels of GnRH and thereby a delayed onset of puberty. TNF- α and IL-6 inhibit the production of adiponectin and therefore stimulate the onset of puberty In detail, adiponectin is a regulator of puberty thereby inhibiting the onset of puberty (Figure 2). with obesity often have low levels of adiponectin. et al. showed that total adiponectin was significantly lower, whereas high molecular weight (HMW) adiponectin was significantly higher in ment. 55 63 develop a chronic low-grade inflammatory state, which can be indi- cated by a high level of circulating inflammatory cytokines like TNF-α 64 Individuals Sitticharoon positive associations with LH levels and the progression of puberty in 63 visfatin, resistin, and chemerin. and visfatin are expressed in the ovaries. adipokines in the ovaries suggests a role within the reproductive sys- tem; however, the exact biological processes have to be examined. Thus, specifically leptin, adiponectin, and inflammatory cytokines pro- duced by WAT could be permissive key players during an early onset of puberty in girls with obesity. As an exception, HMW adiponectin seems to have a stimulatory effect on peripheral repro- ductive function as HMW is not able to cross the blood brain 63 barrier. 4 | Markers that are used to assess puberty onset in boys are THE ONSET OF PUBERTY IN BOYS spermarche, voice break, testicular volume, and pubic hair develop- 35 spermarche develop in the early stages of puberty onset, voice In women, omentin, chemerin, While pubic hair development, larger testicular volume, and 69 testicular volume increases, which occurs at an average age of break usually appears in later stages of puberty. Generally, first 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 6 of 10 NIEUWENHUIS ET AL. 11.9 years, followed by the development of pubic hair at 12.2 years of average, and lastly, boys experience spermarche around an aver- 55 related with leptin levels. Thereby, leptin plausibly has a minor impact in adrenarche in boys. Since leptin receptors are found in the hypothalamus, pituitary gland, and testes, they might be involved in the onset of puberty by affecting the HPG axis during gonadarche. Leptin stimulates the release of kisspeptin and GnRH, and as a consequence, it accelerates the onset of puberty (Table 1, Figure 3). In contrast, adiponectin inhibits the secretion of GnRH, GH, LH, and FSH therewith delaying the onset of puberty. However, adiponectin levels are generally lower in men compared with women and even lower in men with obe- age age of 13.4 years. 70 4.1 | Fat storage Many aspects of the reproductive physiology are energetically demanding,71 and therefore, an adequate energy level is necessary. In boys, a dynamic change in body composition occurs around the age of 10 to 13 years, in which they gain approximately 40% of sity. culating inflammatory cytokines. levels can stimulate the HPG axis and therewith an early onset of puberty in boys. Nevertheless, leptin can inhibit the production of tes- 72 mostly consisting of lean mass, which causes exhaustion of most of fat. Subsequently, a growth spurt follows in which they gain tissue 72 in boys, an adequate amount of body fat is important in the onset of their body fat. These alterations in amount of body fat indicate that 4.2 | Puberty in boys is initiated by the release of kisspeptin. As mentioned before, this activates the HPG axis, resulting in the release of GnRH from the hypothalamus, and consequently the release of LH and FSH 9,74 puberty. tosterone from the testes, to estrogen (Figure 3). of the development of secondary sex characteristics in boys. Additionally, leptin can affect fertility in men as it can modulate the nutritional support of spermatogenesis, and moreover, dysfunction of spermatogenesis is associated with an increased leptin level and 73 58 2,60-62 HPG axis from the pituitary gland (Figure 1). and LH stimulates the secretion of testosterone from the testes, which inhibits the release of kisspeptin from the KNDy neurons and 9,48 in men, the release of kisspeptin is more consistent, causing a con- 29,48 subsequently GnRH from the hypothalamus. receptors expressed on KNDy neurons. In humans, KNDy neurons Contrarily to women, LH-induced testosterone levels lead to the stant release of LH. development of secondary sex characteristics in boys. differences between sexes in kisspeptin release are related to a sex- specific and sex steroid-dependent kisspeptin system as estrogen and progesterone modulate kisspeptin activity through the sex-steroid 48 in the infundibular nucleus are involved in negative and positive sex- 48 tal exposure to sex steroids and result in sex-specific differences in steroid feedbacks. kisspeptin release. These sexual dimorphisms are induced by perina- 75,76 4.3 | Adipokines The association between obesity and puberty onset in boys is rather controversial compared with findings in girls. Most studies reported an early onset of puberty in boys associated with increased ate adipose tissue from actual breast tissue. stages are more difficult to assess than female stages as boys lack a more determined marker such as menarche. Thirdly, puberty onset can be indicated by the activation of the HPG axis, and the presence of these secondary sex characteristics is the result of hormonal 2 14,17,22,23,50,51,77,78 BMI, 20,49 all while others reported no associations at Current markers used 79 16,80 or a delayed onset of puberty (Table 1). The presence of excessive adipose tissue can be involved in puberty onset in boys as the secretion of adipokines can modulate both adrenarche and gonadarche. Leptin can affect adrenarche by modulating both the HPG and HPA axes,33 and moreover, androgen levels were positively 55 nal androgen secretion in boys with premature adrenarche was not associated with plasma leptin levels. Nevertheless, enhanced adre- 9 In more detail, 61,62 adiponectin, and individuals with obesity often have high levels of cir- Moreover, inflammatory cytokines, TNF-α, and IL-6, inhibit expression of the leptin receptor in the testis. FSH induces spermatogenesis, too. function and role still have to be examined. 64 High leptin and low adiponectin and fat tissue can convert testosterone Both processes might result in the delay 29,61,79 81,82 In men, other adipokines like chemerin are found in the gonads 65 Thus, particularly high leptin and low adiponectin levels stimulate the HPG axis and thereby accelerate the onset of puberty in boys. Additionally, leptin can dysregulate the development of secondary sex characteristics and spermatogenesis by affecting testosterone levels and nutritional sup- port of spermatogenesis. 5 | LIMITATIONS AND FUTURE RESEARCH DIRECTIONS Even though multiple epidemiological studies have shown the link between puberty onset and obesity, there are some important limita- tions. Firstly, determining both the onset and stage of puberty is rather difficult. For instance, assessing the stage of breast develop- ment in girls with obesity is complicated as clinicians should differenti- 2 changes in response to the activated HPG axis. to determine the onset of puberty refer to secondary sex characteris- tics, such as testicular volume in boys and breast development in girls. A more accurate measurement of puberty onset would be to combine secondary sex characteristics with plasma or serum hormone level measurements such as LH, FSH, adipokines, e.g. leptin. Thereby, differences in puberty measurements could explain variations in the age of puberty onset between boys and girls within different Thereby, resistin is expressed in the testes of rats, but its exact 83 Secondly, male pubertal 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License NIEUWENHUIS ET AL. 7 of 10 FIGURE 3 Adipokines affecting the initiation of puberty in boys. Leptin activates kisspeptin secretion in KNDy neurons, this activates the production of gonadotropin releasing hormone (GnRH) from the hypothalamus. GnRH stimulates the pituitary gland to secrete follicle stimulating hormone (FSH) and luteinising hormone (LH), activating the production of testosterone from the testes allowing the development of secondary sex characteristics. Leptin also inhibits the production of testosterone, which may cause a delayed onset of puberty. Adiponectin inhibits GnRH release. Low levels of adiponectin, as a result of TNF-α and IL-6 expression, lead to a reduced inhibition of GnRH. In response to GnRH release, the pituitary gland will secrete FSH and LH, and the testes will produce testosterone resulting in the development of secondary sex characteristics in boys countries, and In addition, the inclusion of a of puberty. ferent time points is complicated, as subjects examined several decades ago presented pronounced differences concerning lifestyle patterns such as nutrition and exercise habits. Lastly, obesity or over- weight is often determined by BMI, a classification based on weight and height measurements. Additionally, it is important that all studies studies or across continents, ethnicities proper age range (8-16 years) is important when assessing the onset (Figure 4). 12-15,17,20-23,49,77-79,84,85 30,47 Furthermore, comparison between studies from dif- 86 Specifically in children, BMI is often dependent on age and growth use the same anthropometric standards and sex-specific cut-offs. 13,14,16-23,49-51,77-80 fat and would represent a more accurate measurement in its regard. Based on this review, several suggestions can be made for further research. Firstly, the roles of adipokines like resistin, chemerin, visfatin, and omentin in puberty onset, fertility, and sexual maturation should be examined in detail. Secondly, future research examining the onset of puberty should combine indicators of puberty onset (e.g. breast development or testicular volume) with plasma or serum hor- mone measurements such as LH, FSH, sex-steroids, adipokines (e.g. spurts. ment in case of growth spurts. distribution of body fat should be taken into account in determining puberty and obesity in children. For instance, the body adiposity index (BAI), which was introduced in 2011 by Bergman et al.,87 uses hip cir- cumference and height in order to estimate the percentage of body 87 Thereby, BMI is a less accurate measure- F I G U R E 4 87,88 Therefore, both percentage and Average age of puberty onset in Europe, China, and the United States according to several studies from Table 1. Age of puberty onset ranges from 8.47 to 13.33 years in girls and from 8.63 leptin), and body fat distribution (e.g. BAI,87 waist-hip ratio's and/or dual-energy X-ray absorptiometry (DXA)2). Additionally, defining con- sistent and general measurements of puberty in both boys and girls, combined with a proper age range (8-16 years), would facilitate the comparisons between different studies and their results. 12-15, 17, 20-23, 25-29, 31 to 13.7 years in boys. included if average age of markers used to assess puberty was not reported. Pink: girls. Blue: boys Studies (Table 1) were not 39, 56 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 8 of 10 NIEUWENHUIS ET AL. 6 | CONCLUSION In conclusion, epidemiological data regarding obesity and puberty onset in girls show similar outcomes as adiposity results in the early onset of puberty in girls. The majority of the studies examining boys with obesity indicate an early onset of puberty, while not all reported an earlier onset of puberty. In detail, high leptin, TNF-α, and IL-6 levels combined with low adiponectin levels stimulate the activation of the HPG axis in girls and boys with obesity, and 5, 45, 50, 51 REFERENCES 1. Kumar S, Kelly AS. Review of childhood obesity: from epidemiology, etiology, and comorbidities to clinical assessment and treatment. May- o Clin Proc. 2017;92(2):251-265. 2. Reinehr T, Roth CL. Is there a causal relationship between obesity and puberty? The Lancet Child & adolescent health. 2019;3(1):44-54. 3. WorldHealthOrganization. Facts and figures on childhood obesity. 2017. 4. Guglielmi V, Sbraccia P. Obesity phenotypes: depot-differences in adipose tissue and their clinical implications. Eat Weight Disord. 2018; 23(1):3-14. 5. Gomez-Hernandez A, Beneit N, Diaz-Castroverde S. Escribano O. 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BMC Womens Health. 2018;18(1):168-174. thereby an early onset of obesity. leptin can inhibit the production of testosterone in boys and subse- quently inhibit the development of secondary sex characteristics affecting spermatogenesis. for other adipokines, like resistin and omentin, are present in the testes and ovaries suggesting a role in puberty or reproduction; 58, 71 however, their plausible function is still unknown. that adipokines may be key regulators in an early onset of puberty in both girls and boys with obesity, specifically by affecting the HPG axis during gonadarche. Future research should focus on assessing puberty onset by measuring consistent puberty markers and determine the percentage of body fat and its distribution and adipokines and hormone serum levels particularly involved in the HPG axis. CONFLICTS OF INTEREST The authors declare no conflict of interest. FUNDING INFORMATION This research was funded by Europees Fonds voor Regionale Ontwikkeling (EFRO), project BriteN 2016. ORCID Ilse A.C. Arnoldussen Amanda J. Kiliaan https://orcid.org/0000-0002-7395-5284 https://orcid.org/0000-0002-2158-6210 13, 14, 16-26, 29-32 Furthermore, several receptors Nevertheless, We conclude Search strategy We searched PubMed for articles published before Novem- ber 15th, 2019 using relevant keywords, including âonset of puberty and adiposity/obesityâ, âonset of pubertyâ, âchildren with obesityâ, âadipose tissueâ, âchildhood obesityâ, âadiposityâ, âobesityâ, âadipokine(s)â, âHPG axisâ, âadipokines ovary/ova- riesâ, or âadipokines testesâ, 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 gover 1. Imperialism â 2. Alfred Mahan â 3. Sanford B. Dole â 4. Yellow Journalism â 5. U.S.S. Maine â 6. George Dewey â 7. Rough Riders â 8. Protectorate â 9. Foraker Act â 10. William Randolph Hearst â 11. Emilio Aguinaldo â 12. Open Door Notes (policy) â 13. Boxer Rebellion â 14. Panama Canal â 15. Roosevelt Corollary - 16. San Juan Hill - Understanding Quantum Theory of Electrons in Atoms The goal of this section is to understand the electron orbitals (location of electrons in atoms), their different energies, and other properties. The use of quantum theory provides the best understanding to these topics. This knowledge is a precursor to chemical bonding. As was described previously, electrons in atoms can exist only on discrete energy levels but not between them. It is said that the energy of an electron in an atom is quantized, that is, it can be equal only to certain specific values and can jump from one energy level to another but not transition smoothly or stay between these levels. The energy levels are labeled with an n value, where n = 1, 2, 3, âŠ. Generally speaking, the energy of an electron in an atom is greater for greater values of n. This number, n, is referred to as the principal quantum number. The principal quantum number defines the location of the energy level. It is essentially the same concept as the n in the Bohr atom description. Another name for the principal quantum number is the shell number. The shells of an atom can be thought of concentric circles radiating out from the nucleus. The electrons that belong to a specific shell are most likely to be found within the corresponding circular area. The further we proceed from the nucleus, the higher the shell number, and so the higher the energy level (Figure 9.4.1). The positively charged protons in the nucleus stabilize the electronic orbitals by electrostatic attraction between the positive charges of the protons and the negative charges of the electrons. So the further away the electron is from the nucleus, the greater the energy it has. This quantum mechanical model for where electrons reside in an atom can be used to look at electronic transitions, the events when an electron moves from one energy level to another. If the transition is to a higher energy level, energy is absorbed, and the energy change has a positive value. To obtain the amount of energy necessary for the transition to a higher energy level, a photon is absorbed by the atom. A transition to a lower energy level involves a release of energy, and the energy change is negative. This process is accompanied by emission of a photon by the atom. The following equation summarizes these relationships and is based on the hydrogen atom: The values nf and ni are the final and initial energy states of the electron. The principal quantum number is one of three quantum numbers used to characterize an orbital. An atomic orbital, which is distinct from an orbit, is a general region in an atom within which an electron is most probable to reside. The quantum mechanical model specifies the probability of finding an electron in the three-dimensional space around the nucleus and is based on solutions of the Schrödinger equation. In addition, the principal quantum number defines the energy of an electron in a hydrogen or hydrogen-like atom or an ion (an atom or an ion with only one electron) and the general region in which discrete energy levels of electrons in a multi-electron atoms and ions are located. Another quantum number is l, the angular momentum quantum number. It is an integer that defines the shape of the orbital, and takes on the values, l = 0, 1, 2, âŠ, n â 1. This means that an orbital with n = 1 can have only one value of l, l = 0, whereas n = 2 permits l = 0 and l = 1, and so on. The principal quantum number defines the general size and energy of the orbital. The l value specifies the shape of the orbital. Orbitals with the same value of l form a subshell. In addition, the greater the angular momentum quantum number, the greater is the angular momentum of an electron at this orbital. Orbitals with l = 0 are called s orbitals (or the s subshells). The value l = 1 corresponds to the p orbitals. For a given n, p orbitals constitute a p subshell (e.g., 3p if n = 3). The orbitals with l = 2 are called the d orbitals, followed by the f-, g-, and h-orbitals for l = 3, 4, 5, and there are higher values we will not consider. There are certain distances from the nucleus at which the probability density of finding an electron located at a particular orbital is zero. In other words, the value of the wavefunction Ï is zero at this distance for this orbital. Such a value of radius r is called a radial node. The number of radial nodes in an orbital is n â l â 1. Consider the examples in Figure 9.4.2. The orbitals depicted are of the s type, thus l = 0 for all of them. It can be seen from the graphs of the probability densities that there are 1 â 0 â 1 = 0 places where the density is zero (nodes) for 1s (n = 1), 2 â 0 â 1 = 1 node for 2s, and 3 â 0 â 1 = 2 nodes for the 3s orbitals. The s subshell electron density distribution is spherical and the p subshell has a dumbbell shape. The d and f orbitals are more complex. These shapes represent the three-dimensional regions within which the electron is likely to be found. Principal quantum number (n) & Orbital angular momentum (l): The Orbital Subshell: https://youtu.be/ms7WR149fAY If an electron has an angular momentum (l â 0), then this vector can point in different directions. In addition, the z component of the angular momentum can have more than one value. This means that if a magnetic field is applied in the z direction, orbitals with different values of the z component of the angular momentum will have different energies resulting from interacting with the field. The magnetic quantum number, called ml, specifies the z component of the angular momentum for a particular orbital. For example, for an s orbital, l = 0, and the only value of ml is zero. For p orbitals, l = 1, and ml can be equal to â1, 0, or +1. Generally speaking, ml can be equal to âl, â(l â 1), âŠ, â1, 0, +1, âŠ, (l â 1), l. The total number of possible orbitals with the same value of l (a subshell) is 2l + 1. Thus, there is one s-orbital for ml = 0, there are three p-orbitals for ml = 1, five d-orbitals for ml = 2, seven f-orbitals for ml = 3, and so forth. The principal quantum number defines the general value of the electronic energy. The angular momentum quantum number determines the shape of the orbital. And the magnetic quantum number specifies orientation of the orbital in space, as can be seen in Figure 9.4.3. Figure 9.4.4 illustrates the energy levels for various orbitals. The number before the orbital name (such as 2s, 3p, and so forth) stands for the principal quantum number, n. The letter in the orbital name defines the subshell with a specific angular momentum quantum number l = 0 for s orbitals, 1 for p orbitals, 2 for d orbitals. Finally, there are more than one possible orbitals for l â„ 1, each corresponding to a specific value of ml. In the case of a hydrogen atom or a one-electron ion (such as He+, Li2+, and so on), energies of all the orbitals with the same n are the same. This is called a degeneracy, and the energy levels for the same principal quantum number, n, are called degenerate energy levels. However, in atoms with more than one electron, this degeneracy is eliminated by the electronâelectron interactions, and orbitals that belong to different subshells have different energies. Orbitals within the same subshell (for example ns, np, nd, nf, such as 2p, 3s) are still degenerate and have the same energy. While the three quantum numbers discussed in the previous paragraphs work well for describing electron orbitals, some experiments showed that they were not sufficient to explain all observed results. It was demonstrated in the 1920s that when hydrogen-line spectra are examined at extremely high resolution, some lines are actually not single peaks but, rather, pairs of closely spaced lines. This is the so-called fine structure of the spectrum, and it implies that there are additional small differences in energies of electrons even when they are located in the same orbital. These observations led Samuel Goudsmit and George Uhlenbeck to propose that electrons have a fourth quantum number. They called this the spin quantum number, or ms. The other three quantum numbers, n, l, and ml, are properties of specific atomic orbitals that also define in what part of the space an electron is most likely to be located. Orbitals are a result of solving the Schrödinger equation for electrons in atoms. The electron spin is a different kind of property. It is a completely quantum phenomenon with no analogues in the classical realm. In addition, it cannot be derived from solving the Schrödinger equation and is not related to the normal spatial coordinates (such as the Cartesian x, y, and z). Electron spin describes an intrinsic electron ârotationâ or âspinning.â Each electron acts as a tiny magnet or a tiny rotating object with an angular momentum, even though this rotation cannot be observed in terms of the spatial coordinates. The magnitude of the overall electron spin can only have one value, and an electron can only âspinâ in one of two quantized states. One is termed the α state, with the z component of the spin being in the positive direction of the z axis. This corresponds to the spin quantum number ms=12. The other is called the ÎČ state, with the z component of the spin being negative and ms=â12. Any electron, regardless of the atomic orbital it is located in, can only have one of those two values of the spin quantum number. The energies of electrons having ms=â12 and ms=12 are different if an external magnetic field is applied. Figure 9.4.5 illustrates this phenomenon. An electron acts like a tiny magnet. Its moment is directed up (in the positive direction of the z axis) for the 12 spin quantum number and down (in the negative z direction) for the spin quantum number of â12. A magnet has a lower energy if its magnetic moment is aligned with the external magnetic field (the left electron) and a higher energy for the magnetic moment being opposite to the applied field. This is why an electron with ms=12 has a slightly lower energy in an external field in the positive z direction, and an electron with ms=â12 has a slightly higher energy in the same field. This is true even for an electron occupying the same orbital in an atom. A spectral line corresponding to a transition for electrons from the same orbital but with different spin quantum numbers has two possible values of energy; thus, the line in the spectrum will show a fine structure splitting. The Pauli Exclusion Principle An electron in an atom is completely described by four quantum numbers: n, l, ml, and ms. The first three quantum numbers define the orbital and the fourth quantum number describes the intrinsic electron property called spin. An Austrian physicist Wolfgang Pauli formulated a general principle that gives the last piece of information that we need to understand the general behavior of electrons in atoms. The Pauli exclusion principle can be formulated as follows: No two electrons in the same atom can have exactly the same set of all the four quantum numbers. What this means is that electrons can share the same orbital (the same set of the quantum numbers n, l, and ml), but only if their spin quantum numbers ms have different values. Since the spin quantum number can only have two values (±12), no more than two electrons can occupy the same orbital (and if two electrons are located in the same orbital, they must have opposite spins). Therefore, any atomic orbital can be populated by only zero, one, or two electrons. The properties and meaning of the quantum numbers of electrons in atoms are briefly3.123.12 Identify the topic and locate the author's stated purposes in writing the text3.12 Landmark Supreme Court Cases3-12 Genetics Chapter Review