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2018 Sci Chem N Level 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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Ann Epidemiol. 2017;27(3):187-93.e2. 16. Glass NA, Torner JC, Letuchy EM, et al. The relationship between greater prepubertal adiposity, subsequent age of maturation, and bone strength during adolescence. Journal of bone and mineral research: the official journal of the American Society for Bone and Min- eral Research. 2016;31(7):1455-1465. 17. Holmgren A, Niklasson A, Nierop AF, et al. Pubertal height gain is inversely related to peak BMI in childhood. Pediatr Res. 2017;81(3): 448-454. 18. Kaplowitz PB, Slora EJ, Wasserman RC, Pedlow SE, Herman- Giddens ME. Earlier onset of puberty in girls: relation to increased body mass index and race. Pediatrics. 2001;108(2):347-353. 19. Kelly Y, Zilanawala A, Sacker A, Hiatt R, Viner R. Early puberty in 11-year-old girls: Millennium Cohort Study findings. Arch Dis Child. 2017;102(3):232-237. 20. Lazzeri G, Tosti C, Pammolli A, et al. Overweight and lower age at menarche: evidence from the Italian HBSC cross-sectional survey. BMC Womens Health. 2018;18(1):168-174. thereby an early onset of obesity. leptin can inhibit the production of testosterone in boys and subse- quently inhibit the development of secondary sex characteristics affecting spermatogenesis. for other adipokines, like resistin and omentin, are present in the testes and ovaries suggesting a role in puberty or reproduction; 58, 71 however, their plausible function is still unknown. that adipokines may be key regulators in an early onset of puberty in both girls and boys with obesity, specifically by affecting the HPG axis during gonadarche. Future research should focus on assessing puberty onset by measuring consistent puberty markers and determine the percentage of body fat and its distribution and adipokines and hormone serum levels particularly involved in the HPG axis. CONFLICTS OF INTEREST The authors declare no conflict of interest. FUNDING INFORMATION This research was funded by Europees Fonds voor Regionale Ontwikkeling (EFRO), project BriteN 2016. ORCID Ilse A.C. Arnoldussen Amanda J. Kiliaan https://orcid.org/0000-0002-7395-5284 https://orcid.org/0000-0002-2158-6210 13, 14, 16-26, 29-32 Furthermore, several receptors Nevertheless, We conclude Search strategy We searched PubMed for articles published before Novem- ber 15th, 2019 using relevant keywords, including ‘onset of puberty and adiposity/obesity’, ‘onset of puberty’, ‘children with obesity’, ‘adipose tissue’, ‘childhood obesity’, ‘adiposity’, ‘obesity’, ‘adipokine(s)’, ‘HPG axis’, ‘adipokines ovary/ova- ries’, or ‘adipokines testes’, either alone or in combination. Selection criteria used were English language, longitudinal or cross-sectional studies assessing the onset of puberty, including menarche, thelarche, spermarche, or voice break, combined with high BMI or obesity/adiposity, and articles assessing or reviewing adipokines and its effects on the reproductive system. 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License NIEUWENHUIS ET AL. 9 of 10 21. Lian Q, Mao Y, Luo S, et al. Puberty timing associated with obesity and central obesity in Chinese Han girls. BMC Pediatr. 2019; 19(1):1-7. 22. Deng Y, Liang J, Zong Y, et al. Timing of spermarche and menarche among urban students in Guangzhou, China: trends from 2005 to 2012 and association with Obesity. 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Trends in menarcheal age between 1955 and 2009 in the Netherlands. PLoS ONE. 2013;8:e60056-e60056. 40. Kaplan HS, Lancaster JB. An evolutionary and ecological analysis of human fertility, mating patterns, and parental investment. Off- spring: Human fertility behavior in biodemographic perspective. 2003;1: 170-223. 41. Mitan LA. Menstrual dysfunction in anorexia nervosa. J Pediatr Adolesc Gynecol. 2004;17(2):81-85. 42. Xu H, Li P-H, Barrow TM, et al. Obesity as an effect modifier of the association between menstrual abnormalities and hypertension in young adult women: Results from Project ELEFANT. PLoS ONE. 2018; 13(11):e0207929-e0207929. 43. Tauqeer Z, Gomez G, Stanford FC. Obesity in women: insights for the clinician. J Womens Health (Larchmt). 2018;27(4):444-457. 44. de Ridder CM, Thijssen JH, Bruning PF, Van den Brande JL, Zonderland ML, Erich WB. Body fat mass, body fat distribution, and pubertal development: a longitudinal study of physical and hormonal sexual maturation of girls. J Clin Endocrinol Metab. 1992;75(2): 442-446. 45. Lassek W, Gaulin S. Brief communication: menarche is related to fat distribution. Am J Phys Anthropol. 2007;133(4):1147-1151. 46. Loomba-Albrecht LA, Styne DM. Effect of puberty on body composi- tion. Curr Opin Endocrinol Diabetes Obes. 2009;16:10-15. 47. Simonneaux V, Bahougne T. A multi-oscillatory circadian system times female reproduction. Front Endocrinol. 2015;6:1-15. 48. Marques P, Skorupskaite K, George JT, Anderson RA. Physiology of GNRH and gonadotropin secretion. In: Feingold KR, Anawalt B, Boyce A, et al., eds. Endotext. Endotext.org: South Dartmouth (MA); 2000. 49. Barcellos Gemelli IF, Farias EDS, Souza OF. Age at menarche and its association with excess weight and body fat percentage in girls in the Southwestern Region of the Brazilian Amazon. 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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 goverGenerate all of these 25 questions Part A: Each correct answer is worth 5. 1. The regular pentagon shown has a side length of 2 cm. The perimeter of the pentagon is (A) 2 cm (B) 4 cm (C) 6 cm (D) 8 cm (E) 10 cm 2 cm 2. The faces of a cube are labelled with 1, 2, 3, 4, 5, and 6 dots. Three of the faces are shown. What is the total number of dots on the other three faces? (A) 6 (B) 8 (C) 10 (D) 12 (E) 15 3. The equation that best represents \a number increased by _ve equals 15" is (A) n 5 = 15 (B) n _ 5 = 15 (C) n + 5 = 15 (D) n + 15 = 5 (E) n _ 5 = 15 4. The line graph shows the number of bobbleheads sold at a store each year. The sale of bobbleheads increased the most between (A) 2016 and 2017 (B) 2017 and 2018 (C) 2018 and 2019 (D) 2019 and 2020 (E) 2020 and 2021 Number of 2016 2017 2018 2019 2020 Year Sale of Bobbleheads 2021 Bobbleheads 20 40 60 80 5. Starting at 72, Aryana counts down by 11s: 72; 61; 50; : : : . What is the last number greater than 0 that Aryana will count? (A) 4 (B) 5 (C) 6 (D) 7 (E) 8 6. In the diagram, \ABC = 90_. The value of x is (A) 68 (B) 23 (C) 56 (D) 28 (E) 26 Day of the Week 44° x° A B C x° 7. Which of the following values is closest to zero? (A) 1 (B) 5 4 (C) 12 (D) 4 5 (E) 0:9 Grade 8 8. A jar contains 267 quarters. One quarter is worth $0.25. How many quarters must be added to the jar so that the total value of the quarters is $100.00? (A) 33 (B) 53 (C) 103 (D) 133 (E) 153 9. A package of 8 greeting cards comes with 10 envelopes. Kirra has 7 cards but no envelopes. What is the smallest number of packages that Kirra needs to buy to have more envelopes than cards? (A) 3 (B) 4 (C) 5 (D) 6 (E) 7 10. For the points in the diagram, which statement is true? (A) e > c (B) b < d (C) f > b (D) a < e (E) a > c y x (e, f ) (a, b) (c, d ) Part B: Each correct answer is worth 6. 11. The 26 letters of the English alphabet are listed in an in_nite, repeating loop: ABCDEFGHIJKLMNOPQRSTUVWXY ZABC : : : What is the 258th letter in this sequence? (A) V (B) W (C) X (D) Y (E) Z 12. A public holiday is always celebrated on the third Wednesday of a certain month. In that month, the holiday cannot occur on which of the following days? (A) 16th (B) 22nd (C) 18th (D) 19th (E) 21st 13. A circular spinner is divided into three sections. An arrow is attached to the centre of the spinner. The arrow is spun once. The probability that the arrow stops on the largest section is 50%. The probability it stops on the next largest section is 1 in 3. The probability it stops on the smallest section is (A) 1 4 (B) 2 5 (C) 1 6 (D) 2 7 (E) 3 10 14. A positive number is divisible by both 3 and 4. The tens digit is greater than the ones digit. How many positive two-digit numbers have this property? (A) 4 (B) 5 (C) 6 (D) 7 (E) 8 15. A rectangular pool measures 20 m by 8 m. There is a 1 m wide walkway around the outside of the pool, as shown by the shaded region. The area of the walkway is (A) 56 m2 (B) 60 m2 (C) 29 m2 (D) 52 m2 (E) 50 m2 20 m 8 m 1 m Grade 8 16. The results of asking 50 students if they participate in music or sports are shown in the Venn diagram. What percentage of the 50 students do not participate in music and do not participate in sports? (A) 0% (B) 80% (C) 20% (D) 70% (E) 40% Music Sports 15 5 20 17. There are 2 3 as many golf balls in Bin F as in Bin G. If there are a total of 150 golf balls, how many fewer golf balls are in Bin F than in Bin G? (A) 15 (B) 30 (C) 50 (D) 60 (E) 90 18. In the sequence shown, Figure 1 is formed using 7 squares. Each _gure after Figure 1 has 5 more squares than the previous _gure. What _gure has 2022 squares? (A) Figure 400 (B) Figure 402 (C) Figure 404 (D) Figure 406 (E) Figure 408 Figure 1 Figure 2 Figure 3 19. Mateo's 300 km trip from Edmonton to Calgary passed through Red Deer. Mateo started in Edmonton at 7 a.m. and drove until stopping for a 40 minute break in Red Deer. Mateo arrived in Calgary at 11 a.m. Not including the break, what was his average speed for the trip? (A) 83 km/h (B) 94 km/h (C) 90 km/h (D) 95 km/h (E) 64 km/h 20. Equilateral triangle ABC has sides of length 4. The midpoint of BC is D, and the midpoint of AD is E. The value of EC2 is (A) 7 (B) 6 (C) 6:25 (D) 8 (E) 10 Part C: Each correct answer is worth 8. 21. The positive factors of 6 are 1, 2, 3, and 6. There are two perfect squares less than 100 that have exactly _ve positive factors. What is the sum of these two perfect squares? (A) 177 (B) 80 (C) 145 (D) 52 (E) 97 22. In the list p; q; r; s; t; u; v, each letter represents a positive integer. The sum of the values of each group of three consecutive letters in the list is 35. If q + u = 15, then p + q + r + s + t + u + v is (A) 85 (B) 70 (C) 80 (D) 90 (E) 75 Grade 8 23. The net shown is folded to form a cube. An ant walks from face to face on the cube, visiting each face exactly once. For example, ABCFED and ABCEFD are two possible orders of faces the ant visits. If the ant starts at A, how many possible orders are there? (A) 24 (B) 48 (C) 32 (D) 30 (E) 40 A D B C E F 24. The number 385 is an example of a three-digit number for which one of the digits is the sum of the other two digits. How many numbers between 100 and 999 have this property? (A) 144 (B) 126 (C) 108 (D) 234 (E) 64 25. Student A, Student B, and Student C have been hired to help scientists develop a new avour of juice. There are 4200 samples to test. Each sample either contains blueberry or does not. Each student is asked to taste each sample and report whether or not they think it contains blueberry. Student A reports correctly on exactly 90% of the samples containing blueberry and reports correctly on exactly 88% of the samples that do not contain blueberry. The results for all three students are shown below. Student A Student B Student C Percentage correct on samples 90% 98% (2m)% containing blueberry Percentage correct on samples 88% 86% (4m)% not containing blueberry Student B reports 315 more samples as containing blueberry than Student A. For some positive integers m, the total number of samples that the three students report as containing blueberry is equal to a multiple of 5 between 8000 and 9000. The sum of all such values of m is (A) 45 (B) 36 (C) 24 (D) 27 (E) 29Dès le début de vos recherches, vous allez collecter, produire et exploiter des données. La gestion des données (Research Data Management - RDM) fait partie du processus de recherche. Elle concerne l'ensemble des opérations de collecte, description, stockage, traitement, analyse, archivage et mise en accès des données. (extrait de : Passeport pour la Science Ouverte. Guide pratique pour les doctorants ) "La science ouverte est la diffusion sans entrave des publications et des données de la recherche. Elle s’appuie sur l’opportunité que représente la mutation numérique pour développer l’accès ouvert aux publications et – autant que possible – aux données de la recherche. "Les données de la recherche sont la matière première de la connaissance. Les partager, c'est ouvrir de nouvelles perspectives scientifiques" Source : Plan national pour la Science ouverte - Ministère ESR - Juillet 2018 Source image : https://bibliotheques.univ-tlse3.fr/file/composantes-science-ouverte Cette page est une introduction à la gestion des données de recherche. Elle présente quelques concepts et étapes clés pour vous engager dans cette démarche. Consultez les liens pour approfondir vos connaissances. • What are data ? Définition des données de recherche de l’OCDE (2007) « Enregistrements factuels (chiffres, textes, images, sons) utilisés comme source principale pour la recherche scientifique et généralement reconnus par la communauté scientifique comme nécessaires pour valider les résultats de la recherche. Un ensemble de données de recherche constitue une représentation systématique et partielle du sujet faisant l’objet de la recherche ». Exemples • les images d’une ville préhistorique deviennent des données pour un chercheur qui étudie l’histoire de cette ville; • les « données » d’un linguiste peuvent être des écrits ou des discours, des enregistrements de locuteurs ; • les « données » d’un médiéviste sont des sources archivistiques, archéologiques, épigraphiques, iconographiques, littéraires ; • les « données » d’un géologue rassemblent des coupes et observations de terrain consignées sur un carnet, des résultats de carottage, des analyses d’échantillons, des données sismographiques… • • Pourquoi partager ses données ? "La science ouverte vise à construire un écosystème dans lequel la science est plus cumulative, plus fortement étayée par des données, plus transparente, plus rapide et d’accès plus universel.La science ouverte favorise également les avancées scientifiques, particulièrement les avancées imprévues, ainsi que l’innovation, les progrès économiques et sociaux, en France, dans les pays développés et dans les pays en développement. Enfin, la science ouverte constitue un levier pour l’intégrité scientifique et favorise la confiance des citoyens dans la science. Elle constitue un progrès scientifique et un progrès de société." Source : Plan national pour la Science Ouverte (2018) Les enjeux de l'Open Data • enjeux patrimoniaux o preuve et mémoire (éviter les pertes de données) • enjeux économiques o valeur économique de la donnée o réutilisation gratuite ou payante des données, exploitation des résultats de recherches antérieures (éviter de refaire ce qui a déjà été validé), o accélération de l'innovation et le retour sur investissement dans la R&D • enjeux scientifiques o de "hypothesis-driven" à "data-driven" o plus de visibilité pour le scientifique • enjeux sociétaux o participation des citoyens et de la société civile : "Citizen science" o confiance en la recherche Pour aller plus loin • Site Doranum : https://doranum.fr/enjeux-benefices/fiche-synthetique/ • Adopter de bonnes pratiques tout au long du cycle de vie des données De bonnes pratiques de gestion à toutes les étapes du cycle de vie de la donnée sont un préalable indispensable à l’ouverture des données et à leur réutilisation. • Rechercher des données Pour identifier des jeux de données (datasets) pertinents pour votre thèse, des outils de recherche sont disponibles. Suivez ces liens pour les découvrir : • Site Doranum : https://doranum.fr/acces-visualisation/rechercher-donnees/ • Site DataCC - Vos besoins, trouver des données : https://www.datacc.org/vos-besoins/trouver-des-donnees/ • Fiche CoopIST : Trouver des jeux de données via des bases pluridisciplinaires et des moteurs de recherche Pensez-aussi à consulter l'entrepôt institutionnel Data INRAE Page de présentation du portail • Choisir les bons formats et bien organiser vos données Choisir des formats de fichier : https://www6.inrae.fr/datapartage/Gerer/Choisir-des-formats-de-fichier Nommer et organiser vos fichiers de données : https://www6.inrae.fr/datapartage/Gerer/Nommer-et-organiser-ses-fichiers-de-donnees Pour aller plus loin • Jaouen, G.- Gérer ses données. Pourquoi, Comment ? Séminaire - Guadeloupe, du 25 au 27 Novembre 2019 – CRAG INRA • Bien décrire et documenter ses données La description d’un jeu de données se fait à l’aide de métadonnées (*) qui doivent apporter suffisamment d'éléments (sur la collecte des données, les unités de mesure employées...) pour chercher et trouver le jeu de données, juger de sa qualité/fiabilité, et pouvoir le comprendre ou le réutiliser dans un autre contexte. (*) Définition des métadonnées : Ensemble d’informations structurées qui décrit, explicite, localise une ressource informationnelle, dans le but d’en faciliter la recherche, l’usage, et la gestion. Source : NISO. Understanding Metadata. 2004. Quelques liens utiles : • Site Doranum : https://doranum.fr/metadonnees-standards-formats/ • DataCC : https://www.datacc.org/vos-besoins/documenter-ses-donnees/metadonnees/ • Site DataPartage INRAE : https://www6.inrae.fr/datapartage/Gerer/Documenter-les-donnees En complément des métadonnées, la rédaction d'un fichier READ ME.txt est également recommandée. • Stocker, sécuriser, préserver ses données Bien différencier les notions de stockage et d'archivage. Anticiper pour déterminer les données à éliminer et celles qui doivent être préservées à long terme. • Dans l'environnement INRAE : https://www6.inrae.fr/datapartage/Gerer/Stocker-les-donnees • Site Doranum : https://doranum.fr/stockage-archivage/ • Site DataCC : https://www.datacc.org/vos-besoins/conserver-ses-donnees/ • Partager, ne pas partager ses données ? Dans le cadre de la Science Ouverte, il y a de plus en plus d'incitations voire d'exigences pour rendre accessibles les données, en particulier les données liées aux publications : • de l'édition scientifique : de plus en plus de revues adoptent une "data policy" (à consulter dans les instructions aux auteurs) et exigent des auteurs qu'ils fournissent les données associées aux publications, • des organismes de financement (ANR, Commission Européenne ...), • des politiques nationale (Plan national pour la Science ouverte - Ministère ESR - Juillet 2018) et institutionnelle. Mais attention, toutes les données ne sont pas partageables : assurez-vous que vos données sont bien diffusables au regard du droit et des conditions d'exercice de votre thèse et de son mode de financement (se reporter à votre contrat de thèse). Les données produites dans les organismes de recherche publics sont communicables à tous si elles n'entrent pas dans le cadre d'exceptions légales (sécurité défense, sécurité des populations, patrimoine scientifique et technique, données personnelles, données liées au secret, statistique, etc.) Liens utiles : • sur le site Data Partage, la page Partager-Publier ou la page : "Données de la recherche : qui a les droits, qui doit partager ?" • le site INRAE dédié à la protection des données personnelles et l'application du RGPD (Règlement général sur la protection des données) : https://intranet.inrae.fr/cil-dpo • Valoriser ses données Voici les principales voies de diffusion • Partager ses données en les déposant dans un entrepôt Choisir un entrepôt Déposer dans Data INRAE Partager ses données comme matériel supplémentaire d'un article (à la demande de l'éditeur) Publier un Data Paper (article de données) : la meilleure voie en terme de visibilité des données, et pour faciliter leur réutilisation. Pour aller plus loin • Site Doranum o Dépôts et entrepôts. Comment et où déposer mes données ? o Data papers et Data journals. Comment publier mes données comme un article scientifique ? • Site DataCC o Valoriser ses données • Site CoopIST o Déposer des données de recherche dans un entrepôt o Rédiger et publier un data paper dans une revue scientifique A télécharger : Synthèse du processus de rédaction d'un article avec des données associées • Pourquoi ne pas rédiger un plan de gestion de données (PGD) pour votre thèse ? La thèse peut être assimilée à un projet et certaines universités au Royaume Uni, aux Pays-Bas et plus récemment en France préconisent la rédaction d'un plan de gestion associé à la thèse. Le PGD (ou DMP = Data Management Plan) est un outil de planification qui peut vous aider à anticiper et bien gérer toutes les étapes du cycle de vie de vos données, à limiter les risques de perte ou corruption de données, à adopter de bonnes pratiques de gestion, pour in fine produire des données respectueuses des principes FAIR, adoptés aujourd'hui par l'ensemble des acteurs de la recherche. Il est désormais exigé par la plupart des financeurs de la recherche (Commission Européenne et ANR ...) dans le cadre de projets financés. Rédiger un PGD pour votre thèse, peut être un bon exercice pour vous préparer à la future rédaction de réponses à des appels d'offre. Comment faire en pratique ? • Site DataPartage : Pourquoi et comment rédiger un plan de gestion de données ? • Site Doranum : https://doranum.fr/plan-gestion-donnees-dmp/, La minute vidéo PGD • Site DataCC : https://www.datacc.org/bonnes-pratiques/adopter-un-plan-de-gestion-des-donnees/ • Suivre une classe virtuelle INRAE : Open Class "Rédaction d'un PGD" • Produire des données FAIR ! Favoriser la production de données FAIR (Findable - Accessible - Interoperable - Reusable) est aujourd'hui un objectif soutenu par l'ensemble des acteurs de la recherche. Source : https://open-science-training-handbook.gitbook.io/book/ Si vous suivez les conseils et recommandations de cette page, vous avez toutes les chances d'avoir produit des données de qualité. Si vous préférez une version illustrée : "Pensez FAIR" - https://datapartage.inrae.fr/Gerer/Cycle-de-la-donnee Affiche cycle de vie des données réalisée dans le cadre des Missions QualiNous & RGPD, INRAE-ACT Vous pouvez tester le niveau de "Fairification" de vos données grâce à ces outils : ARDC : https://ardc.edu.au/resources/working-with-data/fair-data/fair-self-assessment-tool • D'autres ressources pour se former ou s'autoformer En interne INRAE • Formation à la science ouverte OSCAR - Module "Gestion et partage des données" • Le site "Gestion et partage des données" • Des classes virtuelles d'environ 2h (Open Class) sont régulièrement proposées sur : o la rédaction des plans de gestion de données, o le dépôt et la description d'un jeu de données dans Data INRAE, o la rédaction et la publication de data papers, Sites externes • Le site DORANUM (Données de la Recherche : Apprentissage NUMérique à la gestion et au partage) propose un dispositif de formation à distance intégrant de nombreuses ressources d’auto-formation déclinées sur différents supports (textes, infographies, vidéos) et sur 9 thématiques. o Parcours interactif sur la gestion des données de la recherche (2020) o • Le site DataCC. Accompagnement à la gestion des données de recherche en physique et en chimie : https://www.datacc.org/ o Data Stories : https://www.datacc.org/reseau-datacc/data-stories/ o • Le dossier "Open Access & Open Data" réalisé par l'Ecole des Ponts - ParisTech • • The Open Science Training Handbook : https://www.ouvrirlascience.fr/the-open-science-training-handbook/I. Définition L'appel d'offres est donc une procédure par laquelle un acheteur public choisit l'offre économiquement la plus avantageuse, sans négociation, sur la base de critères objectifs préalablement définis Son but est de mettre en concurrence plusieurs entreprises privées pour obtenir la meilleure offre possible. Les caractéristiques principales sont les suivantes : • Absence de négociation : L'acheteur sélectionne l'offre uniquement sur la base des propositions reçues, sans négociation avec les candidats • Critères objectifs : La sélection se fait selon des critères définis à l'avance et communiqués aux candidats • Transparence : Les appels d'offres publics sont soumis à des règles strictes de publicité et de transparence Ce principe d’appel d’offre garantie donc l’égalité de traitement des entreprises privées candidates et une certaine transparence. II. Les différentes formes d’appel d’offres Il existe deux formes principales d'appels d'offres dans les marchés publics : • Appel d'offres ouvert : Toute entreprise intéressée peut répondre à l’appel d’offre • Appel d'offres restreint : Seuls les candidats présélectionnés par l'acheteur sont autorisés à soumettre une offre. Cette procédure est particulièrement adaptée aux marchés complexes ou spécialisés, où l'acheteur souhaite présélectionner les entreprises les plus qualifiées avant d'examiner leurs offres en détail. III. Les objectifs pour une PME de prospecter des nouveaux marchés via les appels d’offres Il y a plusieurs objectifs pour une entreprise de prospecter de nouveaux marchés : – trouver de nouveaux clients ; – garantir le développement de l’activité de l’entreprise ; – compenser l’érosion du portefeuille clients existant ou remplacer les clients peu ou pas rentables Ainsi, au-delà du simple gain commercial, les appels d'offres représentent un véritable levier stratégique de développement pour les entreprises, quelle que soit leur taille. IV. La procédure de réponse aux appels d’offre 1. Les étapes principales Voici les principales étapes pour répondre efficacement à un appel d'offres : • Identifiez les appels d'offres pertinents • Activez des alertes automatiques sur les plateformes dédiées • Téléchargez le Dossier de Consultation des Entreprises (DCE) • Analysez minutieusement le cahier des charges et le règlement de consultation • Préparer la réponse soit constituez le dossier de candidature avec les documents administratifs requis • Transmettre la réponse soit déposer le dossier complet sur la plateforme de dématérialisation avant la date limite • Suivre la réponse : en cas de rejet, demandez un retour pour identifier les points d'amélioration 2. La consultation des appels d’offre Les PME doivent d’abord identifier les appels d'offres pertinents. Cela peut se faire par : • Les réseaux professionnels : Participer à des salons, des conférences et des événements réseaux aide à découvrir des opportunités. • La veille : S'abonner à des bulletins d'information et des alertes sur les marchés pertinents. • La consultation de plateformes en ligne : De nombreux sites web répertorient les appels d'offres publics, utilisateur aux PME de filtre par secteur et localisation. L’assistant(e) de gestion dispose de plusieurs sites de marché publics Voici les principaux sites français pour consulter les appels d'offres publics : Les Sites officiels : BOAMP (Bulletin Officiel des Annonces des Marchés Publics) : C'est le site officiel qui publie les appels d'offres de l'État, des collectivités territoriales et des établissements publics PLACE (Plateforme des Achats de l'État) : C'est la plateforme de dématérialisation des marchés publics de l'État. La publication y est obligatoire pour les marchés de l'État à partir de 40 000 € HT JOUE (Journal Officiel de l'Union Européenne) : Il publie les appels d'offres européens Les plateformes privées : France Marchés : Ce portail agrège les appels d'offres de plus de 300 journaux régionaux, du BOAMP, du JOUE et de plus de 1000 sites d'acheteurs publics Marchés Online : Cette plateforme donne accès à l'ensemble des appels d'offres publiés, quel que soit le secteur d'activité E-marchespublics : Ce site permet d'accéder aux appels d'offres publiés sur diverses sources comme le BOAMP, le JOUE, la presse et les profils d'acheteurs Les Autres sources : Journaux d'Annonces Légales (JAL) : Environ 540 journaux en France sont habilités à publier des annonces légales, dont les appels d'offres Sites internet des administrations publiques : La plupart des administrations publient leurs appels d'offres directement sur leur site internet Presse spécialisée : Certaines revues sont spécialisées dans les appels d'offres de leur département ou région Pour une veille efficace, il est recommandé d'utiliser des outils de veille électronique ou de s'abonner aux alertes proposées par ces différentes plateformes. Cela permet de recevoir automatiquement les appels d'offres correspondant à vos critères de recherche 3. Les candidatures d’appels d’offre Pour concourir à un marché public, il est possible de se présenter seul, de présenter une candidature groupée avec plusieurs entreprises : • La candidature seule : l'entreprise se présente pour exécuter personnellement le marché. Elle a la capacité technique et financière d’exécuter seule et dans son entier le marché. • Le groupement : le groupement conjoint (l’entreprise n'est responsable que de la part du marché qu'elle exécute) ou le groupement solidaire : (chaque membre du groupement est engagé financièrement pour la totalité du marché. Cela signifie que tous les membres sont collectivement responsables de l'exécution complète du contrat). 4. La réponse à l’appel d’offre La réponse à un appel d'offres doit contenir les éléments suivants : • une lettre de présentation : Présenter brièvement l'entreprise et son intérêt pour le projet. • une proposition technique : Détails sur la façon dont le projet sera réalisé soient les méthodes et leurs chronologies. • Une proposition financière : faire une estimation des coûts et des conditions de paiement Le dossier de réponse étant l’interface entre la PME et le donneur d’ordre, il convient de lui apporter le plus grand soin. Il faut donc préparer le dossier de réponse et remplir le document unique de marché européen appelé DUME : déclaration sur l'honneur standardisée et électronique utilisée dans les procédures de marchés publics Le certificat électronique est un élément essentiel pour répondre aux appels d'offres publics dématérialisés. Voici les principaux points à retenir : Depuis le 1er octobre 2018, la dématérialisation est obligatoire pour les marchés publics supérieurs à 40 000 € HT Dans ce cadre, une signature électronique valide est requise pour signer les documents de réponse aux appels d'offres. L'utilisation d'un certificat électronique pour les appels d'offres présente plusieurs avantages : Gain de temps dans les échanges avec les acheteurs publics Économies sur les frais d'impression et d'envoi Sécurisation accrue des documents transmis Possibilité de signer à distance Les certificats électroniques pour répondre aux appels d'offres sont délivrés par des prestataires de services de confiance qualifiés, conformes au règlement européen eIDAS et au Référentiel Général de Sécurité (RGS) français. Les principaux émetteurs de ces certificats sont : CertEurope ChamberSign France Certigna (filiale de Docaposte) Dhimyotis Universign La date limite de réception des offres (DLRO) est un élément crucial dans le processus des appels d'offres pour les marchés publics. La DLRO, également appelée date limite de remise des offres ou des plis, correspond à la date et l'heure limites auxquelles les candidatures ou offres doivent être reçues par l'acheteur public1 Le délai commence le lendemain de la date d'envoi de l'avis d'appel à la concurrence par l'acheteur. Dans cette démarche, l’entreprise peut réaliser un tableau de suivi des appels d’offres dont voici un exemple : 5. La réponse à l’appel d’offre Une fois la décision prise, l'acheteur doit envoyer une notification officielle à l'entreprise retenue. Cette communication doit être faite par écrit, généralement par lettre recommandée avec accusé de réception ou par voie électronique sécurisée. Tout candidat évincé peut demander par écrit des informations complémentaires sur les motifs du rejet de son offre. L'acheteur doit alors répondre dans un délai de 15 jours en fournissant : • Les motifs détaillés du rejet de la candidature ou de l'offre • Les caractéristiques et avantages de l'offre retenue • Le nom de l'attributaire V. Le paiement des marchés en appel d’offres Le délai maximal de paiement est généralement de 30 jours. Ce délai est porté à 50 jours pour les hôpitaux et 60 jours pour les entreprises publiques. . Le paiement intervient après constatation du "service fait", c'est-à-dire une fois que la prestation a été réalisée et vérifiée conforme par l'acheteur public Des avances et acomptes peuvent être versés : L'avance est obligatoire pour les PME sur les marchés de plus de 50 000 € HT et d'une durée supérieure à 2 mois. Elle représente 20% du montant pour l'État, 10% pour les autres acheteurs publics Les acomptes sont versés tous les 3 mois maximum, ou tous les mois pour les marchés de travaux avec des PME20182018년_중3_비상(이석재)_8과_단원별기출문제_Reading32018-2019مراجعة