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When Europeans met American Indians in the late 15th century, the people of two continents exchanged many beneficial customs and goods. Europeans received New World crops such as potatoes and corn. American Indians acquired cloth and horses. However, besides the beneficial exchanges, Europeans and American Indians often traded deadly germs–bacteria and viruses–for which they had no immunity. Smallpox and Indians Image 1: Smallpox epidemics helped Europeans conquer the Aztec and Incan Empires of Mexico and South America. North American Indians quickly concluded that contact with Europeans often resulted in devastating diseases that caused widespread death. This drawing, made in the 1500s in Mexico, shows how the disease was passed from a European to an American Indian through simple contact. Many of the diseases that were common in Europe were entirely new to the peoples of North America. Diseases such as tuberculosis and measles could be fatal, but Europeans had developed resistance to the disease, so many people survived. However, when European diseases infected American Indians with no previous exposure, the people suffered terribly. The most devastating of these diseases was smallpox which is caused by a virus (Variola major). Smallpox, like many other diseases, had a latent period of about one week between the time the person was exposed to the disease and the time when signs of the disease became apparent. During this time, the sick person might begin a journey and carry the germs along with him. Anyone the person met would be exposed to smallpox. Anything the victim touched including clothing, bedding, or unwashed dishes carried living germs of smallpox. Cotton Mather Image 2: Cotton Mather was a Boston minister. When smallpox threatened Boston, he remembered reading about how the Turks inoculated people with dried material from smallpox blisters. The inoculation usually gave the person a mild case of the disease and future immunity. The procedure was highly controversial, but it helped save the lives of 274 people who were inoculated during the Boston smallpox epidemic of 1721. Symptoms of the disease began with fever, chills, and aches. The fever might raise a person’s temperature from the normal 98.6o to a dangerous 106o. After four days of misery, the victim entered the second stage when large pustules (fluid-filled bumps) appeared on the body. The rash made the person feel as if their skin were on fire. After suffering with the rash for nine days, the victim entered a new stage-if he or she had survived this long. The pustules opened and dried up. Each pustule formed a scab that turned into a scar that marked the person’s face for the rest of his or her life. Complications of smallpox for those who survived might include loss of vision or damage to the lungs, heart, or liver. Waterhouse Image 3: Dr. Benjamin Waterhouse of Harvard University brought Jenner’s smallpox preventative to the United States. It was called vaccination and used cowpox as the infective material. This much milder form of pox gave immunity to smallpox with fewer complications. Dr. Waterhouse encouraged President-elect Thomas Jefferson to promote vaccination. Jefferson responded, “Every friend of humanity must look with pleasure on this discovery, by which one evil more is withdrawn from the condition of man.” (T. Jefferson 12/25/1800 to Benjamin Waterhouse, December 25, 1800) Historians have found evidence of smallpox as far back as 1157 B.C. when the Egyptian pharaoh Ramses V apparently died of smallpox. From Egypt, where scientists believe smallpox began, the disease spread to Asia. Europeans began to experience periodic epidemics of smallpox in the14th century when Crusaders returning from the Middle East brought smallpox to Europe. People who survived the disease were immune and could not get smallpox again. This fact explains why epidemics struck periodically and the disease was not a constant threat to European societies. Smallpox Vaccination 1803 Image 4: Dr. Edward Jenner’s new smallpox vaccination (from cowpox) was widely accepted. This medical image was published by a Spanish physician to teach colonial doctors how to apply the vaccine to native Mexicans. The scratches were supposed to go through several stages of development as evidence that the vaccine had given the patient immunity. Vaccination was very effective in preventing smallpox epidemics among those who received the vaccine. In 1520, while Cortés was trying to conquer the Aztecs, smallpox broke out among the Spaniards and was transferred to the Aztecs. By 1527, the disease had migrated through Central America to Peru where it helped Pizarro conquer the Incas. (See Image 1.) In 1633, smallpox infected American Indians living near the English colony of Plymouth, Massachusetts. The disease traveled very quickly to tribes living far inland from the English colonies. In 1721, a smallpox epidemic threatened the English colonists of Boston. (See Image 2.) Cotton Mather, a Boston minister, wanted to inoculate people against the disease. He knew that Turkish healers took material from a dried smallpox scab and injected it into the body of a healthy person by scratching the surface of the skin. The patients developed a mild form of the disease from which they recovered. The procedure was highly controversial in Boston where about 280 Bostonians accepted inoculation. The epidemic infected more than half of the people living in Boston at the time. About 15% of those who got sick died of the disease. Among those who were inoculated, only six (2%) died of smallpox. The practice of inoculation spread to other English colonies, but not to the American Indian tribes living near the colonies. Late in the 18th century, British doctor Edward Jenner recognized that people who milked cows never came down with smallpox. They had already been infected with cowpox, a similar, but much milder disease that gave them immunity to smallpox. In 1796, Jenner inoculated a young man with cowpox virus he had collected from a milkmaid. The young man had a mild infection for less than 24 hours and recovered. Jenner’s efforts resulted in a widespread acceptance of vaccination (vaccine comes from Latin words meaning “taken from a cow”). By 1800, many Americans were receiving smallpox vaccinations. (See Image 3.) President Thomas Jefferson supported and encouraged the vaccination program in major American cities. (See Image 4.) By the middle of the 19th century, smallpox was under control, but broke out from time to time among unvaccinated people. Bismarck, Dakota Territory, experienced a small outbreak of smallpox in 1882. American Indians, however, were still subject to the disease in its most dangerous form. Received: 26 November 2019 Revised: 10 January 2020 Accepted: 19 January 2020 DOI: 10.1111/obr.13005 PEDIATRICS/PHYSIOLOGY Adipokines: A gear shift in puberty Desirée Nieuwenhuis | Natàlia Pujol-Gualdo Amanda J. Kiliaan Department of Anatomy, Radboud university medical center, Donders Institute for Brain, Cognition and Behaviour, Preclinical Imaging Center PRIME, Nijmegen, The Netherlands Correspondence Amanda J. Kiliaan, PhD, Associate Professor, Department of Anatomy, Donders Institute for Brain, Cognition, and Behaviour, Preclinical Imaging Center PRIME, Radboud university medical center, 6500 HB Nijmegen, Geert Grooteplein 21N 6525 EZ Nijmegen, The Netherlands. Email: amanda.kiliaan@radboudumc.nl Funding information Europees Fonds voor Regionale Ontwikkeling (EFRO), Grant/Award Number: BriteN 2016 1 | INTRODUCTION The prevalence of obesity in adolescents and children is increasing in | Ilse A.C. Arnoldussen | Summary In this review, we discuss the role of adipokines in the onset of puberty in children with obesity during adrenarche and gonadarche and provide a clear and detailed overview of the biological processes of two major players, leptin and adiponectin. Adipokines, especially leptin and adiponectin, seem to induce an early onset of puberty in girls and boys with obesity by affecting the hypothalamic-pituitary- gonadal (HPG) axis. Moreover, adipokines and their receptors are expressed in the gonads, suggesting a role in sexual maturation and reproduction. All in all, adipokines may be a clue in understanding mechanisms underlying the onset of puberty in child- hood obesity and puberty onset variability. KEYWORDS adipokines, obesity, puberty 1,2 the age of 5 years were overweight or were with obesity in 2016, and 3 Obesity is defined by an excessive accumulation of white adipose tissue (WAT), and it is often indicated by a body mass index (BMI) 4 above 30. Two main types of adipose tissue were described: WAT and brown adipose tissue (BAT), which differ in morphology and func- 5-7 Ilse A.C. Arnoldussen and Amanda J. Kiliaan contributed equally to this work. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2020 The Authors. Obesity Reviews published by John Wiley & Sons Ltd on behalf of World Obesity Federation Obesity Reviews. 2020;21:e13005. wileyonlinelibrary.com/journal/obr 1 of 10 https://doi.org/10.1111/obr.13005 alarming rates. Specifically, worldwide, 41 million children below this number is expected to increase to 70 million in 2025. obesity is associated with various severe health complications, includ- ing increased risk of diabetes mellitus type 2, hypertension, heart dis- eases, and disturbances in sex hormone levels. 5,6 and mitochondria and plays a role in thermogenesis. Adipocytes in tion. BAT consists of adipocytes containing multiple lipid droplets WAT contain only a few mitochondria and a single lipid droplet. Adipose tissue has several functions including the storage of energy, thermogenesis, and the production and secretion of adipokines Generally, two physiological processes, adrenarche and gonadarche, 11,24 Childhood 5,7,8 a key role in puberty onset. Puberty is known as a period through which the body changes physically, being a physiological process resulting in the maturation of children, i.e. they develop sexual characteristics and obtain reproduc- 9,11 Adipokines are involved in a number of physiological processes including blood pressure, metabo- lism, glucose, and vascular homeostasis and may play amongst others 8-10 (hormones, cytokines, and peptides). tive functions. between obesity and puberty,2,12-23 the biological mechanisms under- lying obesity and puberty onset remain unclear. Hereafter, we review in detail the role of adipokines in the onset of puberty in childhood obesity. Although many studies have shown associations 2 | INITIATION OF PUBERTY PHYSIOLOGICAL PROCESSES IN THE interact to regulate the onset of puberty. During adrenarche, the adrenal cortex secretes steroid hormones (including 2 of 10 NIEUWENHUIS ET AL. androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate (DHEAS), androstenedione, and cortisol), insulin-like growth factor, and growth hormone, which contribute to the pubertal insights on new genetic loci (e.g. melanocortin-4 receptor, mitochon- drial carrier 2, and mitogen-activated protein kinase 13) and on sev- eral pathways that regulate the timing of puberty; however, it partly 34 9,24,25 Both adrenarche and gonadarche are involved in the development growth spurt, body odor, skin oiliness, and skeletal maturation. explains puberty timing variation. Thereby, defining the role of 25 adipokines is of importance in elucidating the variability in puberty as the expression of adipokines is sex-specific and is altered with body composition, adiposity, and during growth spurts. Moreover, adipokines and their receptors are expressed in gonads and several brain regions suggesting involvement in the onset of puberty and sex- ual maturation. Lastly, adipokines interfere in processes regulating timing and duration of puberty, for instance in the HPA and HPG axes which are both key players during adrenarche and gonadarche. Involvement of adipokines in the onset of puberty and specifically in individuals with obesity will be further reviewed in the next 2,24 3 | Puberty onset in girls is assessed using different markers, such as thelarche (breast development), menarche (the start of of pubic hair. pituitary-gonadal (HPG) axis is activated,2,26 and several hormones have been identified to participate in the activation of the HPG axis During gonadarche (Figure 1), the hypothalamic- 2,27 Kisspeptin, neurokinin B, and dynorphin are released by specialized including kisspeptin, neurokinin B, dynorphin, leptin, and ghrelin. 28 key regulator of the pulsatile secretion of gonadotropin releasing neurons, the KNDy neurons in the hypothalamus. Kisspeptin is a 29,30 B stimulates, and dynorphin inhibits the release of kisspeptin, which hormone (GnRH) from the hypothalamus. In addition, neurokinin implies that both coordinate a pulsatile release of kisspeptin. 31 Sub- sections. sequently, the activated HPG axis induces the pituitary gland to secrete luteinising hormone (LH) and follicle stimulating hormone (FSH). As a result, gametogenesis occurs, and the gonads will release sex hormones. Consequently, secondary sex characteristics develop including breast development in girls and an increased testicular vol- 2,26,32 is possibly due to differences in levels of body fat, hypothalamic-pitui- THE ONSET OF PUBERTY IN GIRLS ume in boys. The age at puberty onset varies greatly among individuals, which 19 35 menstruation), and pubic hair development. 33 genome-wide association studies have provided important new tary-adrenal (HPA) axis activity, and genetic background. Recent The average age of However, this age differs between cultures and ethnicities, and since 1980, age at menarche is girls at start of menarche is 12.4 years. 36 significantly decreasing. 36-39 F I G U R E 1 Hormonal regulation in the initiation of puberty in boys and girls. The secretion of kisspeptin, neurokinin B, and dynorphin from KNDy neurons initiate the release of gonadotropin releasing hormone (GnRH) from the hypothalamus. This activates the pituitary gland to produce and secrete luteinising hormone (LH) and follicle stimulating hormone (FSH), which in turn stimulate the gonads to produce estrogen and testosterone in girls and boys, respectively 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License NIEUWENHUIS ET AL. 3 of 10 T A B L E 1 Summary of included studies Authors Year Country Study Design Primary Outcome Sex Sample Size (n) Age (y) Data Collection Lian et al21 2019 China Cross-sectional Puberty starts earlier in Chinese Han girls with obesity compared with Chinese Han girls with normal weight. Girls 2996 9-19 2012 and 2013 Biro et al12 Lazzeri et al20 2018 USA 2018 Italy Longitudinal Cross-sectional Body mass index had a greater effect on age at menarche than did race and ethnicity. Girls 946 6-16 2004-2014 Li et al23 2018 China Longitudinal For both, boys and girls, a higher BMI (ie, overweight and obese) is associated with earlier onset of puberty Girls Girls Boys Girls 542 Deng et al22 Flom et al15 2017 China Cross-sectional Increased BMI is associated with early timing spermarche and menarche. Boys Girls Girls 1278258 9-15 2005-2012 He et al24 Holmgren et al17 2017 China 2017 Sweden Cross-sectional Longitudinal Onset of puberty is not related to obesity in boys. Boys Boys Girls Girls 782 7-17 972 929 5839 Kelly et al19 2017 UK 2016 Brazil 2016 USA Longitudinal prospective cohort Higher BMI in girls is associated with the onset of menstruation at an earlier age. 11 10-18 11-17 Barcellos Gemelli et al25 Cross-sectional Longitudinal Excess weight is associated with early age of menarche. Girls 727 2014 2003-2009 Glass et al16 Lee et al26 In girls, but not in boys, greater adiposity is associated with the earlier onset of puberty. Boys Girls 135 Cabrera et al27 Leonibus et al14 2014 USA 2013 Italy Cross-sectional Longitudinal Thelarche occurred earlier than recently reported, while age of menarche remained unchanged. Girls 610 3-17.9 2007 2005-2012 Currie et al13 2012 Europe, USA, Canada Cross-sectional Overweight/obesity during childhood predicts the early onset of puberty in girls. Girls 20410 11, 13, 15 2005-2006 2017 USA Prospective birth cohort Overweight/obese status at the age of 7 ye was associated with increased risk of early menarche 788 From birth to menarche occurred Pregnancies 1959-1966 2016 USA Cross-sectional Boys with overweight enter puberty earlier compared with boys with normal weight or obesity, while puberty starts later in boys with obesity compared with boys with normal weight and overweight. Boys 3872 6-16 2005-2010 Overweight during childhood shows a relation with the early onset of puberty in girls. 6535 4259 695 11 15 5.8-12.2 2009/2010 2013/2014 2014-2017 Higher BMI during childhood is associated with early puberty. 2008 and 2009 2000-2002 Obesity during childhood is related to the earlier onset of puberty. Boys Girls 84 123 71 (Continues) 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 4 of 10 NIEUWENHUIS ET AL. 3.1 | Fat storage For the initiation of puberty, the timing of stimulation and/or inhibi- tion of different hormones is important, and additionally, a certain amount and distribution of body fat is needed in order to start menar- che, which emphasizes the importance of body fat. From an evolution- ary point of view, body fat increases in mammalian females during puberty onset, and it highlights the need to guarantee a healthy preg- 40 women with anorexia nervosa. particularly body fat localized predominantly on the gluteofemoral fat depots, is profoundly associated with start of menarche, more than nancy, offspring, and maternal survival. fat, sex-hormones, and neuroendocrine alterations can evolve in men- strual dysfunction, for instance, in women with severe obesity or in 41-43 44-46 to gluteofemoral fat depots suggesting that leptin may convey infor- amount of total body fat. mation on body fat distribution to the hypothalamus during puberty. An improper level of body Importantly, body fat distribution, Blood leptin levels are strongly related 45 3.2 | HPG axis The HPG axis is activated by the release of kisspeptin resulting in the release of GnRH from the hypothalamus, and LH and FSH from the pituitary gland. In girls, FSH is involved in the development of the folli- cles in the ovaries, and it promotes the secretion of estrogen. LH stim- ulates the production of androgen hormones and induces ovulation 48 9,47 the release of kisspeptin and neurokinin B, and kisspeptin thereby (Figure 1). The secretion of estrogen has an inhibitory effect on inhibits the GnRH release from the hypothalamus. pattern of GnRH is important for the regulation of the menstrual cycle. This roughly 28-day-cycle comprises several phases, including the follicular phase and luteal phase. During the follicular phase, increasing levels of FSH stimulate the maturation of follicles and the production of estrogen from the ovaries. This in turn inhibits the release of FSH from the pituitary gland. A high level of estrogen will induce the production of LH by the pituitary gland, resulting in ovula- tion. The matured follicle secretes progesterone thereby inhibiting the release of GnRH. When the corpus luteum is demolished, there is less 48 3.3 | Adipokines According to results from studies reported in Table 1, girls with obe- sity enter puberty earlier compared with girls with normal higher leptin concentrations inhibit the intake of food and increases inhibition of GnRH. As a consequence, the cycle will start again. whole process, starting from the activated HPG axis, results in the development of the secondary sex characteristics in girls including 9,47 thelarche and menarche. 13,14,16-23,49-51 weight. these girls might be found in the secretion of adipokines. For instance, leptin is positively associated with the amount of body fat. Generally, energy expenditure. 9,52-54 An explanation for the early onset of puberty in The expression This TABLE 1 (Continued) Authors Year Country Study Design Primary Outcome Sample Sex Size (n) Age (y) Data Collection Herman-Giddens et al28 2012 USA Cross-sectional Observed mean ages of beginning genital and pubic hair growth and early testicular volumes were earlier than in past studies, depending on the characteristic and race/ethnicity. Boys 4131 6-16 2005-2010 Sorensen et al29 Aksglaede et al30 2010 2009 Denmark Denmark Cross-sectional/longitudinal Longitudinal Puberty onset at earlier ages was associated with an increased BMI in boys. Boys 1528 5.8-19.9 1991-1993/2006-2008 1930-1969 Juul et al31 Ribeiro et al32 2007 2006 Denmark Portugal Retrospective cohort Cross-sectional Higher BMI is associated with early voice break. 11-15 10-15 1990-1999 Kaplowitz et al18 Abbreviation: BMI, body mass USA Cross-sectional The early onset of puberty in Caucasian girls is likely related to an increased BMI. 5-12 1992-1993 2001 index. The higher BMI in boys and girls at 7 y of age, the earlier they enter puberty. Boys 21 612 Girls 135 223 Boys 463 Boys 382 Girls 437 Girls 10 750 Early sexual maturation in boys and girls is associated with overweight. 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License NIEUWENHUIS ET AL. 5 of 10 Leptin may possibly play a role in adrenarche as its plasma level increases with higher levels of body fat and as it can modulate both girls. 33 ing adrenarche. In coherence, in children with obesity, the androgen These findings suggested that lower reproductive status was associated with higher total adiponectin concentrations and that a higher reproductive status was related to higher HMW adiponectin the HPA and HPG axes. These axes are functionally integrated dur- DHEAS was positively associated with leptin levels. Nevertheless, concentrations in girls. In addition, individuals with obesity often another study showed that enhanced adrenal androgen secretion in girls with premature adrenarche was not explained by leptin or BMI 55 ated with androgen levels in girls ; however, it was not related to levels. and IL-6. TNF-α alters, and IL-6 inhibits the expression of 56 8 In addition, the adipokine adiponectin was negatively associ- 57 differences of adiponectin seem to develop during the progression of 56 adiponectin (Figure 2). Thereby, a low level of total adiponectin and/or high levels of inflammatory cytokines in individuals with obe- sity can promote the onset of puberty. Many more adipokines are secreted by WAT including omentin, 52,65-67 9,36,62,68 adrenarche in girls with Prader-Willi syndrome. Interestingly, sex puberty. adrenarche; however, both are not required factors. Thus, leptin and adiponectin might be able to influence In gonadarche, leptin can stimulate the secretion of kisspeptin, and subsequently activation of the HPG axis, which eventually increases the expression of estrogen and androstenedione in the ova- 58 2,60 65-67 The expression of these ries (Figure 2). Ob gene in WAT, resulting in the synthesis and secretion of leptin. Thus, high levels of leptin promote onset of puberty in girls via secre- tion of kisspeptin, and estrogen stimulates leptin secretion addition- ally. Moreover, adiponectin can affect the HPG axis due to the expression of adiponectin receptors in the hypothalamus, pituitary In return, estrogen stimulates the expression of the 59 gland, and gonads. onset as it inhibits the secretion of kisspeptin and GnRH in the hypo- thalamus and the release of GH and LH in the pituitary gland, and 2,60-62 52,60 63 girls with central precocious puberty (CPP). Moreover, total adiponectin had negative correlations with progression of puberty in girls (defined by Tanner stages), whereas HMW adiponectin had FIGURE 2 Adipokinesaffectingthe initiation of puberty in girls. Leptin stimulates the release of kisspeptin in KNDy neurons, which activates the hypothalamus to produce gonadotropin releasing hormone (GnRH). In response to the release of GnRH, the pituitary gland secretes follicle stimulating hormone (FSH) and luteinising hormone (LH), which stimulates the ovaries to release estrogen resulting in the formation of secondary sex characteristics in girls. Estrogen stimulates the production of leptin. Adiponectin inhibits GnRH release resulting in reduced levels of GnRH and thereby a delayed onset of puberty. TNF- α and IL-6 inhibit the production of adiponectin and therefore stimulate the onset of puberty In detail, adiponectin is a regulator of puberty thereby inhibiting the onset of puberty (Figure 2). with obesity often have low levels of adiponectin. et al. showed that total adiponectin was significantly lower, whereas high molecular weight (HMW) adiponectin was significantly higher in ment. 55 63 develop a chronic low-grade inflammatory state, which can be indi- cated by a high level of circulating inflammatory cytokines like TNF-α 64 Individuals Sitticharoon positive associations with LH levels and the progression of puberty in 63 visfatin, resistin, and chemerin. and visfatin are expressed in the ovaries. adipokines in the ovaries suggests a role within the reproductive sys- tem; however, the exact biological processes have to be examined. Thus, specifically leptin, adiponectin, and inflammatory cytokines pro- duced by WAT could be permissive key players during an early onset of puberty in girls with obesity. As an exception, HMW adiponectin seems to have a stimulatory effect on peripheral repro- ductive function as HMW is not able to cross the blood brain 63 barrier. 4 | Markers that are used to assess puberty onset in boys are THE ONSET OF PUBERTY IN BOYS spermarche, voice break, testicular volume, and pubic hair develop- 35 spermarche develop in the early stages of puberty onset, voice In women, omentin, chemerin, While pubic hair development, larger testicular volume, and 69 testicular volume increases, which occurs at an average age of break usually appears in later stages of puberty. Generally, first 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 6 of 10 NIEUWENHUIS ET AL. 11.9 years, followed by the development of pubic hair at 12.2 years of average, and lastly, boys experience spermarche around an aver- 55 related with leptin levels. Thereby, leptin plausibly has a minor impact in adrenarche in boys. Since leptin receptors are found in the hypothalamus, pituitary gland, and testes, they might be involved in the onset of puberty by affecting the HPG axis during gonadarche. Leptin stimulates the release of kisspeptin and GnRH, and as a consequence, it accelerates the onset of puberty (Table 1, Figure 3). In contrast, adiponectin inhibits the secretion of GnRH, GH, LH, and FSH therewith delaying the onset of puberty. However, adiponectin levels are generally lower in men compared with women and even lower in men with obe- age age of 13.4 years. 70 4.1 | Fat storage Many aspects of the reproductive physiology are energetically demanding,71 and therefore, an adequate energy level is necessary. In boys, a dynamic change in body composition occurs around the age of 10 to 13 years, in which they gain approximately 40% of sity. culating inflammatory cytokines. levels can stimulate the HPG axis and therewith an early onset of puberty in boys. Nevertheless, leptin can inhibit the production of tes- 72 mostly consisting of lean mass, which causes exhaustion of most of fat. Subsequently, a growth spurt follows in which they gain tissue 72 in boys, an adequate amount of body fat is important in the onset of their body fat. These alterations in amount of body fat indicate that 4.2 | Puberty in boys is initiated by the release of kisspeptin. As mentioned before, this activates the HPG axis, resulting in the release of GnRH from the hypothalamus, and consequently the release of LH and FSH 9,74 puberty. tosterone from the testes, to estrogen (Figure 3). of the development of secondary sex characteristics in boys. Additionally, leptin can affect fertility in men as it can modulate the nutritional support of spermatogenesis, and moreover, dysfunction of spermatogenesis is associated with an increased leptin level and 73 58 2,60-62 HPG axis from the pituitary gland (Figure 1). and LH stimulates the secretion of testosterone from the testes, which inhibits the release of kisspeptin from the KNDy neurons and 9,48 in men, the release of kisspeptin is more consistent, causing a con- 29,48 subsequently GnRH from the hypothalamus. receptors expressed on KNDy neurons. In humans, KNDy neurons Contrarily to women, LH-induced testosterone levels lead to the stant release of LH. development of secondary sex characteristics in boys. differences between sexes in kisspeptin release are related to a sex- specific and sex steroid-dependent kisspeptin system as estrogen and progesterone modulate kisspeptin activity through the sex-steroid 48 in the infundibular nucleus are involved in negative and positive sex- 48 tal exposure to sex steroids and result in sex-specific differences in steroid feedbacks. kisspeptin release. These sexual dimorphisms are induced by perina- 75,76 4.3 | Adipokines The association between obesity and puberty onset in boys is rather controversial compared with findings in girls. Most studies reported an early onset of puberty in boys associated with increased ate adipose tissue from actual breast tissue. stages are more difficult to assess than female stages as boys lack a more determined marker such as menarche. Thirdly, puberty onset can be indicated by the activation of the HPG axis, and the presence of these secondary sex characteristics is the result of hormonal 2 14,17,22,23,50,51,77,78 BMI, 20,49 all while others reported no associations at Current markers used 79 16,80 or a delayed onset of puberty (Table 1). The presence of excessive adipose tissue can be involved in puberty onset in boys as the secretion of adipokines can modulate both adrenarche and gonadarche. Leptin can affect adrenarche by modulating both the HPG and HPA axes,33 and moreover, androgen levels were positively 55 nal androgen secretion in boys with premature adrenarche was not associated with plasma leptin levels. Nevertheless, enhanced adre- 9 In more detail, 61,62 adiponectin, and individuals with obesity often have high levels of cir- Moreover, inflammatory cytokines, TNF-α, and IL-6, inhibit expression of the leptin receptor in the testis. FSH induces spermatogenesis, too. function and role still have to be examined. 64 High leptin and low adiponectin and fat tissue can convert testosterone Both processes might result in the delay 29,61,79 81,82 In men, other adipokines like chemerin are found in the gonads 65 Thus, particularly high leptin and low adiponectin levels stimulate the HPG axis and thereby accelerate the onset of puberty in boys. Additionally, leptin can dysregulate the development of secondary sex characteristics and spermatogenesis by affecting testosterone levels and nutritional sup- port of spermatogenesis. 5 | LIMITATIONS AND FUTURE RESEARCH DIRECTIONS Even though multiple epidemiological studies have shown the link between puberty onset and obesity, there are some important limita- tions. Firstly, determining both the onset and stage of puberty is rather difficult. For instance, assessing the stage of breast develop- ment in girls with obesity is complicated as clinicians should differenti- 2 changes in response to the activated HPG axis. to determine the onset of puberty refer to secondary sex characteris- tics, such as testicular volume in boys and breast development in girls. A more accurate measurement of puberty onset would be to combine secondary sex characteristics with plasma or serum hormone level measurements such as LH, FSH, adipokines, e.g. leptin. Thereby, differences in puberty measurements could explain variations in the age of puberty onset between boys and girls within different Thereby, resistin is expressed in the testes of rats, but its exact 83 Secondly, male pubertal 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License NIEUWENHUIS ET AL. 7 of 10 FIGURE 3 Adipokines affecting the initiation of puberty in boys. Leptin activates kisspeptin secretion in KNDy neurons, this activates the production of gonadotropin releasing hormone (GnRH) from the hypothalamus. GnRH stimulates the pituitary gland to secrete follicle stimulating hormone (FSH) and luteinising hormone (LH), activating the production of testosterone from the testes allowing the development of secondary sex characteristics. Leptin also inhibits the production of testosterone, which may cause a delayed onset of puberty. Adiponectin inhibits GnRH release. Low levels of adiponectin, as a result of TNF-α and IL-6 expression, lead to a reduced inhibition of GnRH. In response to GnRH release, the pituitary gland will secrete FSH and LH, and the testes will produce testosterone resulting in the development of secondary sex characteristics in boys countries, and In addition, the inclusion of a of puberty. ferent time points is complicated, as subjects examined several decades ago presented pronounced differences concerning lifestyle patterns such as nutrition and exercise habits. Lastly, obesity or over- weight is often determined by BMI, a classification based on weight and height measurements. Additionally, it is important that all studies studies or across continents, ethnicities proper age range (8-16 years) is important when assessing the onset (Figure 4). 12-15,17,20-23,49,77-79,84,85 30,47 Furthermore, comparison between studies from dif- 86 Specifically in children, BMI is often dependent on age and growth use the same anthropometric standards and sex-specific cut-offs. 13,14,16-23,49-51,77-80 fat and would represent a more accurate measurement in its regard. Based on this review, several suggestions can be made for further research. Firstly, the roles of adipokines like resistin, chemerin, visfatin, and omentin in puberty onset, fertility, and sexual maturation should be examined in detail. Secondly, future research examining the onset of puberty should combine indicators of puberty onset (e.g. breast development or testicular volume) with plasma or serum hor- mone measurements such as LH, FSH, sex-steroids, adipokines (e.g. spurts. ment in case of growth spurts. distribution of body fat should be taken into account in determining puberty and obesity in children. For instance, the body adiposity index (BAI), which was introduced in 2011 by Bergman et al.,87 uses hip cir- cumference and height in order to estimate the percentage of body 87 Thereby, BMI is a less accurate measure- F I G U R E 4 87,88 Therefore, both percentage and Average age of puberty onset in Europe, China, and the United States according to several studies from Table 1. Age of puberty onset ranges from 8.47 to 13.33 years in girls and from 8.63 leptin), and body fat distribution (e.g. BAI,87 waist-hip ratio's and/or dual-energy X-ray absorptiometry (DXA)2). Additionally, defining con- sistent and general measurements of puberty in both boys and girls, combined with a proper age range (8-16 years), would facilitate the comparisons between different studies and their results. 12-15, 17, 20-23, 25-29, 31 to 13.7 years in boys. included if average age of markers used to assess puberty was not reported. Pink: girls. Blue: boys Studies (Table 1) were not 39, 56 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 8 of 10 NIEUWENHUIS ET AL. 6 | CONCLUSION In conclusion, epidemiological data regarding obesity and puberty onset in girls show similar outcomes as adiposity results in the early onset of puberty in girls. The majority of the studies examining boys with obesity indicate an early onset of puberty, while not all reported an earlier onset of puberty. In detail, high leptin, TNF-α, and IL-6 levels combined with low adiponectin levels stimulate the activation of the HPG axis in girls and boys with obesity, and 5, 45, 50, 51 REFERENCES 1. Kumar S, Kelly AS. Review of childhood obesity: from epidemiology, etiology, and comorbidities to clinical assessment and treatment. May- o Clin Proc. 2017;92(2):251-265. 2. Reinehr T, Roth CL. Is there a causal relationship between obesity and puberty? The Lancet Child & adolescent health. 2019;3(1):44-54. 3. WorldHealthOrganization. Facts and figures on childhood obesity. 2017. 4. Guglielmi V, Sbraccia P. Obesity phenotypes: depot-differences in adipose tissue and their clinical implications. Eat Weight Disord. 2018; 23(1):3-14. 5. Gomez-Hernandez A, Beneit N, Diaz-Castroverde S. Escribano O. 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FUNDING INFORMATION This research was funded by Europees Fonds voor Regionale Ontwikkeling (EFRO), project BriteN 2016. ORCID Ilse A.C. Arnoldussen Amanda J. Kiliaan https://orcid.org/0000-0002-7395-5284 https://orcid.org/0000-0002-2158-6210 13, 14, 16-26, 29-32 Furthermore, several receptors Nevertheless, We conclude Search strategy We searched PubMed for articles published before Novem- ber 15th, 2019 using relevant keywords, including ‘onset of puberty and adiposity/obesity’, ‘onset of puberty’, ‘children with obesity’, ‘adipose tissue’, ‘childhood obesity’, ‘adiposity’, ‘obesity’, ‘adipokine(s)’, ‘HPG axis’, ‘adipokines ovary/ova- ries’, or ‘adipokines testes’, either alone or in combination. 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Obesity Reviews. 2020;21:e13005. https://doi.org/ 10.1111/obr.13005 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are gover 1. What is the name of the three-legged shark wearing Nike sneakers? A) Bombardino Crocodilo B) Tralalero Tralala C) Sahur Sharko D) Boneca Ambalabu [Answer: B] 2. Which character has a crocodile head and the body of a bomber plane? A) Tralalero Tralala B) Sahur Sahur C) Bombardino Crocodilo D) Cappuccina Bomberina [Answer: C] 3. What phrase is often repeated in videos featuring Tralalero Tralala? A) “Tung tung tung sahur!” B) “Tralalero tralala!” C) “Boom boom bomba!” D) “Larila lirili!” [Answer: B] 4. Who created the character Tung Tung Tung Sahur? A) @italianobrain B) @bomberfrog C) @noxaasht D) @sahur_vibes [Answer: C] 5. What does “Tung Tung Tung Sahur” refer to? A) A traditional Italian chant B) Indonesian suhur drum-beating C) A type of military code D) Frog mating sounds [Answer: B] 6. What is Boneca Ambalabu’s body made of? A) A cactus and flip-flops B) A traffic cone and pizza C) A tree frog and car tire D) A jellyfish and megaphone [Answer: C] 7. Which character is a cactus-elephant hybrid wearing sandals? A) Lirili Larila B) Ballerina Cappuccina C) Boneca Ambalabu D) Crocoelephanto [Answer: A] 8. What object is used as the head of Ballerina Cappuccina? A) A shoe B) A clock C) A cappuccino mug D) A music box [Answer: C] 9. How is the voiceover for Lirili Larila typically described? A) Robotic and glitchy B) Deep and demonic C) Poetic and chant-like D) Sarcastic and fast [Answer: C] 10. Which two characters have been accused of being Islamophobic? A) Lirili Larila and Cappuccina B) Boneca Ambalabu and Sahur C) Tralalero Tralala and Bombardino Crocodilo D) Sahur and Crocodilo [Answer: C] 11. What controversy surrounds Bombardino Crocodilo? A) It mocks Christianity B) It jokes about bombings in Gaza C) It promotes military propaganda D) It insults Italian cuisine [Answer: B] 12. How have some Italian users responded to blasphemy accusations? A) By apologizing B) By deleting the content C) By denying the claims D) By brushing it off as general blasphemy [Answer: D] 13. What term best describes the genre featuring these absurd characters? A) MemeCore B) AI Junk C) Italian Brainrot D) Surreal Punk [Answer: C] 14. Which character’s name contains an onomatopoeia? A) Bombardino Crocodilo B) Lirili Larila C) Tung Tung Tung Sahur D) Tralalero Tralala [Answer: C] 15. Where did most Italian Brainrot characters and memes gain popularity? A) YouTube B) Reddit C) Instagram D) TikTok [Answer: D]Mediul wireless transportă semnale electromagnetice care reprezintă cifre binare pentru comunicațiile de date care folosesc frecvențe radio sau de microunde. Ca și mediu de rețea, wireless nu este restricționat la conductori sau căi de acces, așa cum sunt mediile din fibră sau cupru. Mediul wireless asigură cele mai bune opțiuni de mobilitate dintre toate mediile. Astfel, numărul de echipamente wireless este în continuă creștere. Din aceste motive, wireless a devenit o opțiune pentru toate rețelele de domiciliu. Pe măsură ce opțiunile lățimii de bandă cresc, wireless crește în popularitate în rețelele companiilor. Figura evidențiază câteva simboluri cu privire la wireless. În orice caz, wireless-ul are câteva zone de preocupare precum: • Aria de acoperireTehnologiile de comunicare a datelor wireless funcționează bine în mediile deschise. În orice caz, unele materiale de construcție folosite în structuri și clădiri și terenul local vor limita aria de acoperire. • InterferențaWireless-ul este predispus la interferențe și poate fi întrerupt de echipamente obișnuite cum ar fi telefoane fără fir, unele tipuri de lumină fluorescentă, cuptoare cu microunde și alte comunicații wireless. • SecuritateaAcoperirea comunicației wireless nu necesită acces fizic la mediu. Așadar, echipamentele și utilizatorii care nu au autorizație pentru a accesa rețeaua pot obține accesul la transmisie. În consecință, securitatea rețelei este o componentă principală pentru administrarea rețelei wireless. Deși wireless-ul crește în popularite pentru conectivitatea calculatoarelor, fibra și cuprul sunt cele mai populare medii ale layer-ului fizic pentru dezvoltarea rețelelor. Tipuri de Mediu Wireless IEEE și standardele industriei de telecomunicații pentru comunicarea wireless a datelor acoperă atât layer-ului fizic, cât și layer-ul data link. Există patru standarde uzuale de comunicare a datelor care se aplică mediului wireless: • Standard IEEE 802.11Tehnologia WLAN (Wireless LAN), denumită și Wi-Fi, folosește un sistem nedeterminist sau controversat cu un proces de acces la mediu CSMA/CA (Carrier Sense Multiple Access/Collision Avoidance). • Standard IEEE 802.15Standardul WPAN (Wireless Personal Area Network), cunoscut și ca "Bluetooth", folosește un proces de împerechere a echipamentelor pentru a comunica pe distanțe cuprinse între 1 și 100 metri. • Standard IEEE 802.16Cunoscută de obicei ca WiMAX (Worldwide Interoperability for Microwave Access), folosește o topologie de tip point-to-multipoint pentru a furniza acces broadband de tip wireless. Figura evidențiază câteva diferențe ale mediilor wireless. Notă:Celelalte tehnologii wireless cum ar fi comunicațiile prin satelit și celulare pot asigura și ele conectivitatea rețelei de date. În orice caz, aceste tehnologii wireless depășesc scopul acestui capitol. În fiecare din exemplele de mai sus, specificațiile layer-ului fizic sunt aplicate zonelor care includ: • Codificarea semnalului radio sau de date • Frecvența sau puterea de transmisie • Recepția semnalului sau cerințele de decodificare • Construcția și design-ul antenei Notă:Wi-Fi este marcă înregistrată Wi-Fi Alliance. Wi-Fi este utilizat împreună cu produse certificate care aparțin echipamentelor din WLAN bazate pe standardele IEEE 802.11. LAN Wireless O implementare uzuală wireless a datelor este permiterea echipamentelor să se conecteze prin wireless la un LAN. În general, un LAN wireless necesită următoarele echipamente de rețea: • Puncte de Acces Wireless (AP)Concentrează semnalele wireless de la utilizatori și se conectează, de obicei printr-un cablu de cupru la infrastructura de rețea existentă bazată pe cupru, cum ar fi Ethernet. Routerele wireless din companiile mici sau de domiciliu integrează funcțiile unui router, switch și punct de acces într-un echipament, așa cum se arată în figură. • Plăcile de rețea wirelessAsigură capacitatea de comunicare wireless la fiecare host de rețea. Având în vedere că tehnologia s-a dezvoltat, a apărut un număr de standarde WLAN bazate pe Ethernet. Este necesară atenția atunci când se achiziționează echipamentele wireless pentru a asigura compatibilitatea și interoperabilitatea. Beneficiile tehnologiilor de comunicare a datelor wireless sunt evidente, în special conveniența ce reiese din mobilitatea hostului și reducerea costurilor necesare cablării. În orice caz, administratorii de rețea trebuie să dezvolte și să aplice politici de securitate și procese pentru a proteja LAN-urile wireless împotriva accesului neautorizat și a defecțiunilor. Standardele 802.11 Wi-Fi În ultimii ani au fost dezvoltate mai multe standarde 802.11. Standardele includ: • IEEE 802.11aFuncționează pe banda de frecvență de 5 GHz și oferă viteze de până la 54 Mb/s. Deoarece acest standard funcționează la frecvențe înalte, are o arie de acoperire mică și este mai puțin eficientă la penetrarea structurilor construcțiilor. Echipamentele care funcționează în cadrul acestui standard nu sunt interoperabile cu standardele 802.11b și 802.11g descrise mai jos. • IEEE 802.11bFuncționează pe banda de frecvență de 2.4 GHz și oferă viteze de până la 11 Mb/s. Echipamentele care implementează acest standard au o arie mai mare și pot pătrunde mai bine în structurile clădirilor decât echipamentele bazate pe 802.11a. • IEEE 802.11gFuncționează pe banda de frecvență de 2.4 GHz și oferă viteze de până la 54 Mb/s. Echipamentele care implementează acest standard funcționează la aceeași frecvență de radio și arie ca și 802.11b dar cu lățimea de bandă de la 802.11a • IEEE 802.11nFuncționează pe benzile de frecvență de 2.4 GHz sau 5 GHz. Rata așteptată a datelor este cuprinsă între 100 Mb/s și 600 Mb/s cu o distanță care poate ajunge până la 70 metri. Este compatibil cu echipamentele 802.11a/b/g. • IEEE 802.11acPoate funcționa simultan pe benzile de frecvență 2.4 GHz și 5.5 GHz și asigură rate de până la 450 Mb/s și 1.3 Gb/s (1300 Mb/s). Este compatibil cu echipamentele 802.11a/b/g/n. • IEEE 802.11adCunoscut și ca "WiGig". Folosește o soluție Wi-Fi pe trei benzi folosind 2.4 GHz, 5 GHz și 60 GHz și oferă viteze teoretice de până la 7 Gb/s. Figura evidențiază câteva din aceste diferențe.controversia a.Why is fracking controversial?Physical Appearance – ConTroVerSiaL BbCluBsBen Tillman: A Controversial Figure in South Carolina History