
Paris n'est pas toute la France
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âQuelle ville est mentionnĂ©e comme produisant beaucoup de soie ?
Paris
Lyon
Bordeaux
âComment les habitants de Lyon sont-ils dĂ©crits dans le texte?
Timides
Froids et distants
Accueillants et chaleureux
Quelle ville est mentionnée comme produisant beaucoup de soie ?
Comment les habitants de Lyon sont-ils décrits dans le texte?
Quel type d'accueil les visiteurs ont-ils reçu à Lyon ?
Quel roi a intégré l'Aquitaine au royaume en 507?
Qui a constitué l'Aquitaine en royaume en 781?
L'expulsion des Anglais de Bordeaux a eu lieu en 1453.
La lettre de Jean ĂȘtre dans lâembarras : ne pas savoir quelle dĂ©cision prendre, ĂȘtre gĂȘnĂ©. le dĂ©vouement : câest ce que fait une personne qui consacre son temps Ă aider les autres. Paris, le 18 fĂ©vrier 2005 Ma chĂšre Tatie, Je suis bien triste aujourdâhui. Maman est malade et le mĂ©decin que nous avons appelĂ© dit que ce nâest pas grave, mais quâil lui faut des soins constants. Elle doit rester au moins deux semaines au lit. Tu juges de notre embarras devant une telle situation. Qui va sâoccuper de nous, qui va soigner maman ? Papa nâest pas lĂ de la journĂ©e et moi je vais Ă lâĂ©cole ; le soir, jâai mes devoirs, mes leçons. Et puis on ne peut laisser maman seule pendant de longues heures. Aussi, ma chĂšre Tatie, je viens te demander si tu peux venir nous aider pendant la maladie de ta sĆur. Tu sais Ă quel point tu nous rendrais service. Nous nâavons pas hĂ©sitĂ© Ă te demander de venir car nous connaissons ton dĂ©vouement et ta gentillesse. Pour moi, ce sera une grande joie de tâavoir prĂšs de nous et je sais que tes bons soins permettront Ă maman de se rĂ©tablir rapidement. Excuse-nous de tout le dĂ©rangement que nous allons te causer. PrĂ©viens-nous de lâheure de ton arrivĂ©e afin que jâaille te chercher Ă la gare. Merci dâavance, ma chĂšre tante, pour tout ce que tu vas faire pour nous. Papa et maman se joignent Ă moi pour tâembrasser bien affectueusement. Ton neveu, Jean
Create 10 multiple choice questions from this tex : Un jour, ma grand-mĂšre poisson, Nukumi, m'a appelĂ©... GRAND-MĂRE : Kwis, petit poisson... Juwkalul ! Te voilĂ , Kwis. Je t'attendais. PETIT POISSON : Nikumi, vais-je grandir pour ĂȘtre aussi grand et fort que toi ? GRAND-MĂRE : Eh bien... Au commencement du temps, le Grand Esprit, Kisulkw, a créé toutes les choses de la nature Ă©galement. Le Soleil crĂ©e la vie et nous donne nos ombres. Les ombres reflĂštent les esprits de nos ancĂȘtres. Mâsit Nokomaq. PETIT POISSON : Nukumi, qu'est-ce que cela signifie ? GRAND-MĂRE : Cela signifie que nous sommes tous liĂ©s. Les gens de cette terre ont rĂ©alisĂ© que nous Ă©tions tous d'esprit, placĂ©s ici sur MĂšre Terre pour nous aider mutuellement. Kluscap nous a appelĂ©s, nous, les poissons, Nemeâjik, Ă venir Ă terre et Ă donner nos vies. Il ne prenait que ce qui Ă©tait nĂ©cessaire et rendait grĂące pour notre existence. Nous appelons cela Netukulimk. PETIT POISSON : Ensuite, que s'est-il passĂ©, Nukumi ? GRAND-MĂRE : Pendant des milliers d'annĂ©es, nous avons continuĂ© Ă compter sur nos frĂšres et sĆurs des bois et des eaux. Les Miâkmaq nous appelaient Peju, la morue. Ils utilisaient de petits bateaux appelĂ©s canots, faits d'Ă©corce de bouleau, et de petits filets pour nous attraper. Ils nous utilisaient pour la nourriture et pour Ă©changer avec d'autres choses qu'ils n'avaient pas. Ils nous sĂ©chaient au soleil et utilisaient le sel de la mer pour nous conserver. Les Lânu, le peuple, Ă©taient reconnaissants pour l'aide et nous honoraient. Souviens-toi de Netukulimk ? Eux aussi ne prenaient que ce dont ils avaient besoin. Nous avons vĂ©cu en harmonie avec le peuple, la terre et toutes les choses. Nous remplissions la mer ! Et nous devenions grands et gras. Ton arriĂšre-arriĂšre-arriĂšre-grand-pĂšre Ă©tait de la taille d'un dauphin, ou d'un Mutch petch ! PETIT POISSON : Mais pourquoi n'ai-je jamais vu de morue si grande ? GRAND-MĂRE : Eh bien, il y a environ cinq cents ans, des gens de contrĂ©es lointaines sont arrivĂ©s. Ils sont venus pour nous, Ă©tonnĂ©s de ne pas pouvoir ramer Ă travers les eaux Ă cause de notre foule... Ils sont venus avec plus de bateaux et de filets plus grands. Et ils nous ont emmenĂ©s. Sans honneur. Sans remerciements... Ils en ont attrapĂ© trop de nous... Ils nous ont pris avant que nous puissions devenir grands et gras... Ils nous ont pris avant que nous puissions avoir des bĂ©bĂ©s. Ils ont dĂ©truit nos foyers. Ils n'ont pas appris Ă vivre en harmonie. Ils n'ont pas compris Netukulimk. PETIT POISSON : Que va-t-il advenir de nous maintenant ? GRAND-MĂRE : Cette histoire est encore en train d'ĂȘtre racontĂ©e, Kwis ! Pour que tu vives fort, pour que toi et tes enfants grandissiez aussi grands que ton arriĂšre-arriĂšre-arriĂšre-grand-pĂšre - niscamish - pour que nous remplissions de nouveau la mer... PETIT POISSON : ... pour cela, nous devons trouver Ă nouveau un moyen de vivre en harmonie avec nos frĂšres et sĆurs. Mâsit Nokomaq. Tous mes parents. GRAND-MĂRE : Et voilĂ la fin de l'histoire.
I Le contrat de vente classique 1. LâintĂ©rĂȘt pour la PMI de connaĂźtre la diversitĂ© des contrats commerciaux Les PME-PMI sont rĂ©guliĂšrement amenĂ©es Ă conclure des contrats commerciaux. Il est donc nĂ©cessaire pour lâassistant(e) de gestion de connaĂźtre les diffĂ©rents contrats et les rĂšgles qui les rĂ©gissent. 2. Le transfert de propriĂ©tĂ© DĂšs quâil y a accord entre le vendeur et lâacheteur, il y a transfert de propriĂ©tĂ©. Lâacheteur doit donc assumer les risques dĂšs le transfert de propriĂ©tĂ©. Pour pallier ce risque, il peut prĂ©voir dans le contrat une clause de rĂ©serve en propriĂ©tĂ©, qui a pour effet de diffĂ©rer le transfert de la propriĂ©tĂ© et des risques quâil entraine jusqu'Ă conclusion totale du contrat. 3. Les obligations des parties Les garanties dans le contrat de vente se dĂ©composent ainsi : ï Les garanties obligatoires : o la garantie lĂ©gale de conformitĂ© permettant au client dâobtenir la rĂ©paration, le remboursement ou le remplacement du produit dĂ©fectueux o la garantie contre les vices cachĂ©s : se sont des dĂ©fauts non visibles au moment de lâachat qui rendent le bien inutilisable ï Les garanties complĂ©mentaires ou commerciales : elles sont facultatives pour le client. Elles peuvent ĂȘtre gratuites (mise Ă disposition dâun produit au client durant une rĂ©paration) ou payantes (extension de garantie pour lâachat dâune machine Ă laver) Exercice dâapplication 4. Les recours possibles Lorsquâune procĂ©dure est engagĂ©e, la juridiction compĂ©tente pour statuer lâaffaire est le tribunal de commerce du dĂ©fendeur si le client et lâentreprise sont des commerçants. Les sanctions les plus courantes sont : - infliger des pĂ©nalitĂ©s de retard - obtenir une rĂ©duction de prix - faire exĂ©cuter le contrat par une autre entreprise - obtenir des dommages et intĂ©rĂȘts II Les particularitĂ©s du contrat de vente commerciale Le contrat prĂ©sente certaines particularitĂ©s que la PME doit connaitre : On peut donc considĂ©rer quâun bon de commande est un contrat de vente commerciale, dans la mesure oĂč il rĂ©unit ses clauses. Enfin, il existe des situations ou les engagements peuvent diffĂ©rĂ©s. Câest le cas : - de la vente Ă distance : le client dispose dâun dĂ©lai de rĂ©tractation de 14 jours - la vente avec arrhes : si le client verse des arrhes, il pourra annuler le contrat mais perdra le montant versĂ© Ă lâentreprise. III Les contrats de maintenance et de sous6traitance 1. Le contrat de maintenance Câest un contrat par lequel une entreprise se charge de vĂ©rifier, dâentretenir ou de rĂ©parer un appareil technique ou une installation complexe. Il doit donc spĂ©cifier : - la dĂ©finition de la prestation et le lieu de rĂ©alisation - la durĂ©e du contrat - le prix unitaire ou forfaitaire 2. Le contrat de sous-traitance Il permet Ă une entreprise appelĂ©e « donneur dâordre » de confier la rĂ©alisation dâune prestation Ă une autre entreprise appelĂ©e « sous traitant ». Lâentreprise sâengage Ă payer le sous traitant selon les modalitĂ©s prĂ©vues dans le contrat et reste donc responsable de la rĂ©alisation de la prestation devant le client. Avantages et inconvĂ©nients de la sous-traitance : IV CrĂ©er un contrat via un rĂ©seau de franchise Afin de dĂ©velopper son activitĂ©, lâassistant(e) de gestion peut conclure des contrats commerciaux avec des partenaires Ă©trangers La franchise est une mĂ©thode de collaboration entre, dâune part, une entreprise, le franchiseur, et, dâautre part, une ou plusieurs entreprises, les franchisĂ©s. Son objet est dâexploiter un concept de franchise mis au point par le franchiseur. Tous sont porteurs de la mĂȘme enseigne, symbole de lâidentitĂ© et de la rĂ©putation du rĂ©seau. La garantie de qualitĂ© est assurĂ©e par la transmission et le contrĂŽle du respect du savoir-faire et par la mise Ă disposition dâune gamme homogĂšne de produits, de services et/ou de technologies. a. Le franchiseur Câest un entrepreneur indĂ©pendant qui a mis au point et exploitĂ© avec succĂšs un concept original dans plusieurs unitĂ©s pilotes. Il apporte Ă ses franchisĂ©s une formation initiale et permanente pour leur permettre dâappliquer son concept et consacre Ă la promotion de sa marque, Ă la recherche et Ă lâinnovation, les moyens humains et financiers permettant dâassurer le dĂ©veloppement et la pĂ©rennitĂ© de son concept. b. Le franchisĂ© Câest un entrepreneur indĂ©pendant sĂ©lectionnĂ© par le franchiseur. Il doit avoir la volontĂ© de collaborer loyalement Ă la rĂ©ussite du rĂ©seau de franchise en adhĂ©rant au principe dâhomogĂ©nĂ©itĂ© de ce rĂ©seau, tel que dĂ©fini par le franchiseur. Il engage des moyens financiers, afin de rĂ©tribuer le franchiseur pour ses apports (paiement dâun droit dâentrĂ©e et dâun pourcentage sur le chiffre dâaffaires). c. Les avantages et les inconvĂ©nients du contrat de franchise pour le franchiseur et pour le franchisĂ©. Avantages InconvĂ©nients Franchiseur â DĂ©velopper son rĂ©seau Ă moindres frais. â Faire des Ă©conomies dâĂ©chelle. â MaĂźtriser le dĂ©veloppement de son concept. â DĂ©velopper son image, sa notoriĂ©tĂ©. â Augmenter ses parts de marchĂ©. â AccroĂźtre son chiffre dâaffaires. â Organiser des campagnes publicitaires Ă lâĂ©chelon national. â Transmettre son savoir-faire Ă des commerçants indĂ©pendants. â Assurer une assistance technique et des formations. â Avoir des franchisĂ©s qui dĂ©prĂ©cient lâimage de lâentreprise. FranchisĂ© â Avoir une notoriĂ©tĂ© dĂšs lâouverture du commerce. â Rester un commerçant indĂ©pendant et ĂȘtre responsable de son entreprise. â BĂ©nĂ©ficier du savoir-faire du franchiseur. â BĂ©nĂ©ficier dâune assistance technique, de formations, dâune logistique dâapprovisionnements, etc. â Respecter la charte et les normes du franchiseur, ce qui limite sa libertĂ© de commerçant indĂ©pendant. â Sâacquitter des droits dâentrĂ©e et de redevance. â Avoir une obligation dâapprovisionnement exclusif chez le franchiseur. d. Les clĂ©s de la rĂ©ussite de cette forme de commerce Les clĂ©s de la rĂ©ussite sont : â la collaboration commerciale et technique ; â lâassociation du savoir-faire du franchiseur et de lâesprit entrepreneurial du franchisĂ© ; â les structures organisationnelles sont plus simples et plus Ă©conomiques quâen succursalisme car un bon franchisĂ© est motivĂ© et nâa pas besoin dâĂȘtre poussĂ© ; â câest un systĂšme rapide et Ă©volutif pour couvrir un marchĂ© car investissements et compĂ©tences sont partagĂ©es. e. Les chiffres clĂ©s de la franchise en 2019 f. La typologie des franchisĂ©s âą 60% des franchisĂ©s sont des hommes âą 50% des franchisĂ©s ont entre 35 et 49 ans âą 66% des franchisĂ©s sont dâanciens salariĂ©s du privĂ© âą Chaque franchisĂ© emploie en moyenne 7 salariĂ©s âą 84% des rĂ©seaux sont toujours la propriĂ©tĂ© de leur fondateur âą Chaque rĂ©seau crĂ©e en moyenne 8 nouveaux points de vente par an âą 29% des rĂ©seaux ont des points de vente Ă lâĂ©tranger
I Suivre les ventes et les livraisons La plupart du temps, les commandes des clients vont dĂ©clencher les rĂšglements. RĂ©ceptionner les commandes et les traiter rigoureusement est donc une activitĂ© essentielle pour la PME. 1. La rĂ©ception de la commande Avant de traiter la commande, il est important quâelle soit vĂ©rifiĂ©e pour optimiser la relation client et Ă©viter les erreurs. Les points de contrĂŽle sont : 2. Le traitement de la commande Les documents Ă gĂ©nĂ©rer sur le PGI sont : 3. Le suivi de la commande Le suivi permet Ă lâentreprise de surveiller la progression de lâensemble des commandes. Lâentreprise peut ainsi crĂ©er un tableau de suivi visuel lui permettant dâanticiper les problĂšmes de livraison. Voici un exemple : 4. Lâorganisation et le suivi des livraisons Livrer, câest mettre Ă la disposition du client les produits commandĂ©s Ă la date prĂ©vue et au lieu convenu. Lâentreprise peut dĂ©cider de livrer elle-mĂȘme out de faire appel Ă un transporteur : âą La prise en charge de la livraison par le fournisseur La PME organise le planning et la tournĂ©e des livreurs en tenant compte des attentes du client, du temps de trajet et du volume Ă livrer. Elle utilise pour chaque Ă©tape le bon de livraison. Un exemplaire est conservĂ© par lâentreprise et un exemplaire sera laissĂ© au client lors de la livraison. âą La prise en charge de la livraison via un transporteur Le suivi de la livraison : Le contrat gĂ©nĂ©ral de vente permet dâanticiper les problĂšmes et de limiter les contestations (retards de livraison). Les frais de transport doivent donc figurer sur le bon de livraison. Trois type de frais existent : âȘ franco de port : âȘ port dĂ» : Certains transporteurs offrent la possibilitĂ© de suivre les expĂ©ditions sur leur site Web. II Facturer, suivre les rĂšglements et les relances clients 1. La facture A chaque Ă©tape du processus de vente, divers documents sont créés. Le dernier document du processus est la facture. Elle indique le paiement Ă faire au client et prouve la vente : facture de doit. Chaque facture portant une date et un numĂ©ro unique, une fois Ă©mise, il nâest donc plus possible de lâannuler ou la modifier .Sâil se passe un Ă©vĂšnement aprĂšs lâĂ©dition, on devra alors Ă©mettre un avoir. Le processus peut se schĂ©matiser ainsi : 2. La prĂ©sentation dâune facture La facture est Ă©tablit en double exemplaire et doit ĂȘtre conservĂ©e pendant 10 ans. Elle rĂ©sulte dâune obligation lĂ©gale et se matĂ©rialise par un enregistrement comptable. Quelques rĂšgles sont Ă respecter : 3. Les Ă©lĂ©ments Ă contrĂŽler sur la facture Il est nĂ©cessaire de vĂ©rifier les mentions obligatoires afin dâĂ©viter les rĂ©clamations clients. Si elle est conforme, elle est envoyĂ©e au client et transmise au service comptabilitĂ© pour lâenregistrement. Les Ă©lĂ©ments Ă vĂ©rifier sont : 4. Les aspects fiscaux liĂ©s aux ventes : le mĂ©canisme de TVA Lâenregistrement des ventes doit se faire dans le respect des rĂšgles fiscales relatives Ă la TVA (taxe sur la valeur ajoutĂ©e) Il existe 4 taux principaux de TVA en France : Certaines activitĂ©s et certains territoires sont exonĂ©rĂ©s de TVA. âą Le taux de TVA intermĂ©diaire de 10 % sâapplique pour les activitĂ©s suivantes : Restauration (pour consommation immĂ©diate) Aide Ă la personne HĂ©bergement et transport Produits agricoles non transformĂ©s et bois de chauffage MĂ©dicaments non remboursĂ©s Travaux et rĂ©paration pour les logements anciens (plus de deux ans) MusĂ©es et zoos âą Le taux de TVA rĂ©duit Ă 5.5 % sâapplique pour les activitĂ©s et produits suivants : Produits alimentaires de premiĂšre nĂ©cessitĂ© Fourniture de chaleur produite Ă partir dâĂ©nergies renouvelables Livres (y compris numĂ©riques) Billetterie de spectacle vivant Restauration pour les cantines scolaire Ăquipements pour personnes handicapĂ©es Travaux dâamĂ©lioration Ă©nergĂ©tique des logements de plus de 2 ans âą Le taux de TVA spĂ©cifique Ă 2,1% sâapplique pour les activitĂ©s suivantes : MĂ©dicaments remboursĂ©s par la SĂ©curitĂ© sociale Publications de presse Billetterie de certains spectacles et cinĂ©mas Animaux vivants de boucherie et de charcuterie vendus Ă des non-assujettis âą Les activitĂ©s suivantes sont exonĂ©rĂ©es de TVA (0%) : PĂȘche en mer Certaines Ćuvres non lucratives Ă caractĂšre social ou philanthropique ActivitĂ©s mĂ©dicales et paramĂ©dicales Enseignement et formation Livraison ou rĂ©cupĂ©ration de dĂ©chets Le principe de la TVA pour les entreprises : Afin de bien rĂ©aliser les Ă©critures comptables, il est important de diffĂ©rencier la TVA dĂ©ductible de la TVA collectĂ©e : Une crĂ©ance client est enregistrĂ©e en dĂ©bit alors que la vente de marchandises de lâentreprise est enregistrĂ©e en crĂ©dit. 5. Les Ă©critures comptables relatives aux ventes Les diffĂ©rents Ă©lĂ©ments dâune facture doivent ĂȘtre enregistrĂ©s dans le journal et dans les comptes de lâentreprise. Si lâentreprise dispose dâun PGI, le devis gĂ©nĂšre automatiquement la commande. La commande gĂ©nĂšre automatiquement le bon de livraison qui gĂ©nĂšre la facture. La facture gĂ©nĂšre automatiquement les Ă©critures comptables au journal. Exemple de visualisation dâĂ©criture comptable sur le PGI : 6. La mise en place dâun suivi efficace des rĂšglements Le suivi des comptes clients permet de connaitre lâĂ©tat des crĂ©ances Ă tout moment. La relance remplit plusieurs objectifs : Les outils les plus utilisĂ©s dans cette dĂ©marche sont lâĂ©chĂ©ancier (il liste les crĂ©ances en attente de rĂšglement avec peu de dĂ©tails) et la balance ĂągĂ©e (elle prĂ©sente les soldes de crĂ©ances de maniĂšre plus visuelle avec une ligne par client). Exemples : EchĂ©ancier Balance ĂągĂ©e Lâentreprise peut Ă©galement pointer les crĂ©ances afin de faire ressortir les crĂ©ances impayĂ©es (lettrage des comptes). Enfin, compte tenu des enjeux pour les entreprises dâobtenir les rĂšglements dans des dĂ©lais raisonnables, elles mettent en place un vĂ©ritable processus de relance qui doit respecter les Ă©tapes suivantes : AprĂšs avoir pris connaissance du processus de relance, il devient nĂ©cessaire de crĂ©er un tableau de relance des impayĂ©s pour relancer les clients efficacement. Exemple : Tableau de relances des impayĂ©s : Enfin, il faudra relancer les clients par tĂ©lĂ©phone, mail ou courrier pour obtenir les sommes dues via des relances automatisĂ©es. Exemple de mise en demeure automatisĂ©e envoyĂ©e en recommandĂ© :
Escape from Unsuitable Conditions Some species can survive unfavorable environmental conditions by escaping from them temporarily. For example, desert animals usually hide underground or in the shade during the hottest part of the day. Many desert species are active at night, when temper- atures are much lower. A longer-term strategy is to enter a state of reduced activity, called dormancy, during periods of unfavorable conditions, such as winter or drought. Another strategy is to move to a more favorable habitat, called migration. An example of migration is the seasonal movements of birds, which spend spring and summer in cooler climates and migrate to warmer climates in the fall. THE NICHE Species do not use or occupy all parts of their habitat at once. The specific role, or way of life, of a species within its environment is its niche (NICH). The niche includes the range of conditions that the species can tolerate, the resources it uses, the methods by which it obtains resources, the number of offspring it has, its time of reproduction, and all other interactions with its environment. Parts of a lionâs niche are shown in Figure 18-6. Generalists are species with broad niches; they can tolerate a range of conditions and use a variety of resources. An example of a generalist is the Virginia opossum, found across much of the United States. The opossum feeds on almost anything, from eggs and dead animals to fruits and plants. In contrast, species that have narrow niches are called specialists. An example is the koala of Australia, which feeds only on the leaves of a few species of eucalyptus trees. Some species have more than one niche within a lifetime. For example, caterpillars eat the leaves of plants, but as adult butter- flies, they feed on nectar. Plants and animals are able to share the same habitats because they each have different niches. FIGURE 18-6 niche from the Old French nichier, meaning âto nestâ Word Roots and Origins www.scilinks.org Topic: Niche/Habitats Keyword: HM61029 mb06se_iecs02.qxd 5/24/07 10:25 AM Page 365 366 CHAPTER 18 ENERGY TRANSFER All organisms need energy to carry out essential functions, such as growth, movement, maintenance and repair, and reproduction. In an ecosystem, energy flows from the sun to autotrophs, then to organisms that eat the autotrophs, and then to organisms that feed on other organisms. The amount of energy an ecosystem receives and the amount that is transferred from organism to organism affect the ecosystemâs structure. PRODUCERS Autotrophs, which include plants and some kinds of protists and bacteria, manufacture their own food. Because autotrophs cap- ture energy and use it to make organic molecules, they are called producers. Recall that organic molecules are molecules that con- tain carbon. Most producers are photosynthetic, so they use solar energy to power the production of food. However, some autotrophic bacteria do not use sunlight as an energy source. These bacteria carry out chemosynthesis (KEE-moh-SIN-thuh-sis), in which they use energy stored in inorganic molecules to produce carbohydrates. In terres- trial ecosystems, plants are usually the major producers. In aquatic ecosystems, photosynthetic protists and bacteria are usu-
Write personal questions for a1-a2 kids after they read: Incredible Places to Stay Introduction. Do you want to see some of the world's most amazing hotels? Let's go! Sliding with Sharks. The first stop on your tour is Las Vegas, Nevada. At the Golden Nugget, you can ride a waterslide. It takes you through a shark tank. A Cool Place to Stay. The next stop is the HĂŽtel de Glace (O-tel DEH GLAHS) in Canada. Many parts of the hotel are made of ice. The ice melts away in the spring. Each winter, it takes a lot of work to build the hotel again. Breakfast with Giraffes. From Canada, you'll travel to Kenya. Giraffes live in the forests around a hotel called Giraffe Manor. Every morning, the giraffes come to the hotel to eat. If you stay there, you can feed them! In the Trees. The next stop on your tour is Sweden. The Treehotel is made up of many tree houses. The Mirrorcube has glass all around it. This tree house blends in with the woods. One tree house looks like a big bird's nest. The UFO tree house looks as if it is from outer space. A Room Without a View. When you are in Sweden, stop at the Sala Silvermine Hotel. When you get there, you can stay in the deepest hotel room in the world! It is a long way down to your room. Dress in warm clothes because it is very cold in the mine. Sleeping with Fish. Your last stop is Jules' Undersea Lodge in Florida. You have to swim down to reach your room! When you are ready to eat, you can even have pizza. Someone from the hotel will swim it down to you. Conclusion. It is time to go back home now. Each incredible hotel is more than just a place to stay for the night. At each one, you will have a lot of fun!
Received: 26 November 2019 Revised: 10 January 2020 Accepted: 19 January 2020 DOI: 10.1111/obr.13005 PEDIATRICS/PHYSIOLOGY Adipokines: A gear shift in puberty DesirĂ©e Nieuwenhuis | NatĂ lia Pujol-Gualdo Amanda J. Kiliaan Department of Anatomy, Radboud university medical center, Donders Institute for Brain, Cognition and Behaviour, Preclinical Imaging Center PRIME, Nijmegen, The Netherlands Correspondence Amanda J. Kiliaan, PhD, Associate Professor, Department of Anatomy, Donders Institute for Brain, Cognition, and Behaviour, Preclinical Imaging Center PRIME, Radboud university medical center, 6500 HB Nijmegen, Geert Grooteplein 21N 6525 EZ Nijmegen, The Netherlands. Email: amanda.kiliaan@radboudumc.nl Funding information Europees Fonds voor Regionale Ontwikkeling (EFRO), Grant/Award Number: BriteN 2016 1 | INTRODUCTION The prevalence of obesity in adolescents and children is increasing in | Ilse A.C. Arnoldussen | Summary In this review, we discuss the role of adipokines in the onset of puberty in children with obesity during adrenarche and gonadarche and provide a clear and detailed overview of the biological processes of two major players, leptin and adiponectin. Adipokines, especially leptin and adiponectin, seem to induce an early onset of puberty in girls and boys with obesity by affecting the hypothalamic-pituitary- gonadal (HPG) axis. Moreover, adipokines and their receptors are expressed in the gonads, suggesting a role in sexual maturation and reproduction. All in all, adipokines may be a clue in understanding mechanisms underlying the onset of puberty in child- hood obesity and puberty onset variability. KEYWORDS adipokines, obesity, puberty 1,2 the age of 5 years were overweight or were with obesity in 2016, and 3 Obesity is defined by an excessive accumulation of white adipose tissue (WAT), and it is often indicated by a body mass index (BMI) 4 above 30. Two main types of adipose tissue were described: WAT and brown adipose tissue (BAT), which differ in morphology and func- 5-7 Ilse A.C. Arnoldussen and Amanda J. Kiliaan contributed equally to this work. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2020 The Authors. Obesity Reviews published by John Wiley & Sons Ltd on behalf of World Obesity Federation Obesity Reviews. 2020;21:e13005. wileyonlinelibrary.com/journal/obr 1 of 10 https://doi.org/10.1111/obr.13005 alarming rates. Specifically, worldwide, 41 million children below this number is expected to increase to 70 million in 2025. obesity is associated with various severe health complications, includ- ing increased risk of diabetes mellitus type 2, hypertension, heart dis- eases, and disturbances in sex hormone levels. 5,6 and mitochondria and plays a role in thermogenesis. Adipocytes in tion. BAT consists of adipocytes containing multiple lipid droplets WAT contain only a few mitochondria and a single lipid droplet. Adipose tissue has several functions including the storage of energy, thermogenesis, and the production and secretion of adipokines Generally, two physiological processes, adrenarche and gonadarche, 11,24 Childhood 5,7,8 a key role in puberty onset. Puberty is known as a period through which the body changes physically, being a physiological process resulting in the maturation of children, i.e. they develop sexual characteristics and obtain reproduc- 9,11 Adipokines are involved in a number of physiological processes including blood pressure, metabo- lism, glucose, and vascular homeostasis and may play amongst others 8-10 (hormones, cytokines, and peptides). tive functions. between obesity and puberty,2,12-23 the biological mechanisms under- lying obesity and puberty onset remain unclear. Hereafter, we review in detail the role of adipokines in the onset of puberty in childhood obesity. Although many studies have shown associations 2 | INITIATION OF PUBERTY PHYSIOLOGICAL PROCESSES IN THE interact to regulate the onset of puberty. During adrenarche, the adrenal cortex secretes steroid hormones (including 2 of 10 NIEUWENHUIS ET AL. androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate (DHEAS), androstenedione, and cortisol), insulin-like growth factor, and growth hormone, which contribute to the pubertal insights on new genetic loci (e.g. melanocortin-4 receptor, mitochon- drial carrier 2, and mitogen-activated protein kinase 13) and on sev- eral pathways that regulate the timing of puberty; however, it partly 34 9,24,25 Both adrenarche and gonadarche are involved in the development growth spurt, body odor, skin oiliness, and skeletal maturation. explains puberty timing variation. Thereby, defining the role of 25 adipokines is of importance in elucidating the variability in puberty as the expression of adipokines is sex-specific and is altered with body composition, adiposity, and during growth spurts. Moreover, adipokines and their receptors are expressed in gonads and several brain regions suggesting involvement in the onset of puberty and sex- ual maturation. Lastly, adipokines interfere in processes regulating timing and duration of puberty, for instance in the HPA and HPG axes which are both key players during adrenarche and gonadarche. Involvement of adipokines in the onset of puberty and specifically in individuals with obesity will be further reviewed in the next 2,24 3 | Puberty onset in girls is assessed using different markers, such as thelarche (breast development), menarche (the start of of pubic hair. pituitary-gonadal (HPG) axis is activated,2,26 and several hormones have been identified to participate in the activation of the HPG axis During gonadarche (Figure 1), the hypothalamic- 2,27 Kisspeptin, neurokinin B, and dynorphin are released by specialized including kisspeptin, neurokinin B, dynorphin, leptin, and ghrelin. 28 key regulator of the pulsatile secretion of gonadotropin releasing neurons, the KNDy neurons in the hypothalamus. Kisspeptin is a 29,30 B stimulates, and dynorphin inhibits the release of kisspeptin, which hormone (GnRH) from the hypothalamus. In addition, neurokinin implies that both coordinate a pulsatile release of kisspeptin. 31 Sub- sections. sequently, the activated HPG axis induces the pituitary gland to secrete luteinising hormone (LH) and follicle stimulating hormone (FSH). As a result, gametogenesis occurs, and the gonads will release sex hormones. Consequently, secondary sex characteristics develop including breast development in girls and an increased testicular vol- 2,26,32 is possibly due to differences in levels of body fat, hypothalamic-pitui- THE ONSET OF PUBERTY IN GIRLS ume in boys. The age at puberty onset varies greatly among individuals, which 19 35 menstruation), and pubic hair development. 33 genome-wide association studies have provided important new tary-adrenal (HPA) axis activity, and genetic background. Recent The average age of However, this age differs between cultures and ethnicities, and since 1980, age at menarche is girls at start of menarche is 12.4 years. 36 significantly decreasing. 36-39 F I G U R E 1 Hormonal regulation in the initiation of puberty in boys and girls. The secretion of kisspeptin, neurokinin B, and dynorphin from KNDy neurons initiate the release of gonadotropin releasing hormone (GnRH) from the hypothalamus. This activates the pituitary gland to produce and secrete luteinising hormone (LH) and follicle stimulating hormone (FSH), which in turn stimulate the gonads to produce estrogen and testosterone in girls and boys, respectively 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License NIEUWENHUIS ET AL. 3 of 10 T A B L E 1 Summary of included studies Authors Year Country Study Design Primary Outcome Sex Sample Size (n) Age (y) Data Collection Lian et al21 2019 China Cross-sectional Puberty starts earlier in Chinese Han girls with obesity compared with Chinese Han girls with normal weight. Girls 2996 9-19 2012 and 2013 Biro et al12 Lazzeri et al20 2018 USA 2018 Italy Longitudinal Cross-sectional Body mass index had a greater effect on age at menarche than did race and ethnicity. Girls 946 6-16 2004-2014 Li et al23 2018 China Longitudinal For both, boys and girls, a higher BMI (ie, overweight and obese) is associated with earlier onset of puberty Girls Girls Boys Girls 542 Deng et al22 Flom et al15 2017 China Cross-sectional Increased BMI is associated with early timing spermarche and menarche. Boys Girls Girls 1278258 9-15 2005-2012 He et al24 Holmgren et al17 2017 China 2017 Sweden Cross-sectional Longitudinal Onset of puberty is not related to obesity in boys. Boys Boys Girls Girls 782 7-17 972 929 5839 Kelly et al19 2017 UK 2016 Brazil 2016 USA Longitudinal prospective cohort Higher BMI in girls is associated with the onset of menstruation at an earlier age. 11 10-18 11-17 Barcellos Gemelli et al25 Cross-sectional Longitudinal Excess weight is associated with early age of menarche. Girls 727 2014 2003-2009 Glass et al16 Lee et al26 In girls, but not in boys, greater adiposity is associated with the earlier onset of puberty. Boys Girls 135 Cabrera et al27 Leonibus et al14 2014 USA 2013 Italy Cross-sectional Longitudinal Thelarche occurred earlier than recently reported, while age of menarche remained unchanged. Girls 610 3-17.9 2007 2005-2012 Currie et al13 2012 Europe, USA, Canada Cross-sectional Overweight/obesity during childhood predicts the early onset of puberty in girls. Girls 20410 11, 13, 15 2005-2006 2017 USA Prospective birth cohort Overweight/obese status at the age of 7 ye was associated with increased risk of early menarche 788 From birth to menarche occurred Pregnancies 1959-1966 2016 USA Cross-sectional Boys with overweight enter puberty earlier compared with boys with normal weight or obesity, while puberty starts later in boys with obesity compared with boys with normal weight and overweight. Boys 3872 6-16 2005-2010 Overweight during childhood shows a relation with the early onset of puberty in girls. 6535 4259 695 11 15 5.8-12.2 2009/2010 2013/2014 2014-2017 Higher BMI during childhood is associated with early puberty. 2008 and 2009 2000-2002 Obesity during childhood is related to the earlier onset of puberty. Boys Girls 84 123 71 (Continues) 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 4 of 10 NIEUWENHUIS ET AL. 3.1 | Fat storage For the initiation of puberty, the timing of stimulation and/or inhibi- tion of different hormones is important, and additionally, a certain amount and distribution of body fat is needed in order to start menar- che, which emphasizes the importance of body fat. From an evolution- ary point of view, body fat increases in mammalian females during puberty onset, and it highlights the need to guarantee a healthy preg- 40 women with anorexia nervosa. particularly body fat localized predominantly on the gluteofemoral fat depots, is profoundly associated with start of menarche, more than nancy, offspring, and maternal survival. fat, sex-hormones, and neuroendocrine alterations can evolve in men- strual dysfunction, for instance, in women with severe obesity or in 41-43 44-46 to gluteofemoral fat depots suggesting that leptin may convey infor- amount of total body fat. mation on body fat distribution to the hypothalamus during puberty. An improper level of body Importantly, body fat distribution, Blood leptin levels are strongly related 45 3.2 | HPG axis The HPG axis is activated by the release of kisspeptin resulting in the release of GnRH from the hypothalamus, and LH and FSH from the pituitary gland. In girls, FSH is involved in the development of the folli- cles in the ovaries, and it promotes the secretion of estrogen. LH stim- ulates the production of androgen hormones and induces ovulation 48 9,47 the release of kisspeptin and neurokinin B, and kisspeptin thereby (Figure 1). The secretion of estrogen has an inhibitory effect on inhibits the GnRH release from the hypothalamus. pattern of GnRH is important for the regulation of the menstrual cycle. This roughly 28-day-cycle comprises several phases, including the follicular phase and luteal phase. During the follicular phase, increasing levels of FSH stimulate the maturation of follicles and the production of estrogen from the ovaries. This in turn inhibits the release of FSH from the pituitary gland. A high level of estrogen will induce the production of LH by the pituitary gland, resulting in ovula- tion. The matured follicle secretes progesterone thereby inhibiting the release of GnRH. When the corpus luteum is demolished, there is less 48 3.3 | Adipokines According to results from studies reported in Table 1, girls with obe- sity enter puberty earlier compared with girls with normal higher leptin concentrations inhibit the intake of food and increases inhibition of GnRH. As a consequence, the cycle will start again. whole process, starting from the activated HPG axis, results in the development of the secondary sex characteristics in girls including 9,47 thelarche and menarche. 13,14,16-23,49-51 weight. these girls might be found in the secretion of adipokines. For instance, leptin is positively associated with the amount of body fat. Generally, energy expenditure. 9,52-54 An explanation for the early onset of puberty in The expression This TABLE 1 (Continued) Authors Year Country Study Design Primary Outcome Sample Sex Size (n) Age (y) Data Collection Herman-Giddens et al28 2012 USA Cross-sectional Observed mean ages of beginning genital and pubic hair growth and early testicular volumes were earlier than in past studies, depending on the characteristic and race/ethnicity. Boys 4131 6-16 2005-2010 Sorensen et al29 Aksglaede et al30 2010 2009 Denmark Denmark Cross-sectional/longitudinal Longitudinal Puberty onset at earlier ages was associated with an increased BMI in boys. Boys 1528 5.8-19.9 1991-1993/2006-2008 1930-1969 Juul et al31 Ribeiro et al32 2007 2006 Denmark Portugal Retrospective cohort Cross-sectional Higher BMI is associated with early voice break. 11-15 10-15 1990-1999 Kaplowitz et al18 Abbreviation: BMI, body mass USA Cross-sectional The early onset of puberty in Caucasian girls is likely related to an increased BMI. 5-12 1992-1993 2001 index. The higher BMI in boys and girls at 7 y of age, the earlier they enter puberty. Boys 21 612 Girls 135 223 Boys 463 Boys 382 Girls 437 Girls 10 750 Early sexual maturation in boys and girls is associated with overweight. 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License NIEUWENHUIS ET AL. 5 of 10 Leptin may possibly play a role in adrenarche as its plasma level increases with higher levels of body fat and as it can modulate both girls. 33 ing adrenarche. In coherence, in children with obesity, the androgen These findings suggested that lower reproductive status was associated with higher total adiponectin concentrations and that a higher reproductive status was related to higher HMW adiponectin the HPA and HPG axes. These axes are functionally integrated dur- DHEAS was positively associated with leptin levels. Nevertheless, concentrations in girls. In addition, individuals with obesity often another study showed that enhanced adrenal androgen secretion in girls with premature adrenarche was not explained by leptin or BMI 55 ated with androgen levels in girls ; however, it was not related to levels. and IL-6. TNF-α alters, and IL-6 inhibits the expression of 56 8 In addition, the adipokine adiponectin was negatively associ- 57 differences of adiponectin seem to develop during the progression of 56 adiponectin (Figure 2). Thereby, a low level of total adiponectin and/or high levels of inflammatory cytokines in individuals with obe- sity can promote the onset of puberty. Many more adipokines are secreted by WAT including omentin, 52,65-67 9,36,62,68 adrenarche in girls with Prader-Willi syndrome. Interestingly, sex puberty. adrenarche; however, both are not required factors. Thus, leptin and adiponectin might be able to influence In gonadarche, leptin can stimulate the secretion of kisspeptin, and subsequently activation of the HPG axis, which eventually increases the expression of estrogen and androstenedione in the ova- 58 2,60 65-67 The expression of these ries (Figure 2). Ob gene in WAT, resulting in the synthesis and secretion of leptin. Thus, high levels of leptin promote onset of puberty in girls via secre- tion of kisspeptin, and estrogen stimulates leptin secretion addition- ally. Moreover, adiponectin can affect the HPG axis due to the expression of adiponectin receptors in the hypothalamus, pituitary In return, estrogen stimulates the expression of the 59 gland, and gonads. onset as it inhibits the secretion of kisspeptin and GnRH in the hypo- thalamus and the release of GH and LH in the pituitary gland, and 2,60-62 52,60 63 girls with central precocious puberty (CPP). Moreover, total adiponectin had negative correlations with progression of puberty in girls (defined by Tanner stages), whereas HMW adiponectin had FIGURE 2 Adipokinesaffectingthe initiation of puberty in girls. Leptin stimulates the release of kisspeptin in KNDy neurons, which activates the hypothalamus to produce gonadotropin releasing hormone (GnRH). In response to the release of GnRH, the pituitary gland secretes follicle stimulating hormone (FSH) and luteinising hormone (LH), which stimulates the ovaries to release estrogen resulting in the formation of secondary sex characteristics in girls. Estrogen stimulates the production of leptin. Adiponectin inhibits GnRH release resulting in reduced levels of GnRH and thereby a delayed onset of puberty. TNF- α and IL-6 inhibit the production of adiponectin and therefore stimulate the onset of puberty In detail, adiponectin is a regulator of puberty thereby inhibiting the onset of puberty (Figure 2). with obesity often have low levels of adiponectin. et al. showed that total adiponectin was significantly lower, whereas high molecular weight (HMW) adiponectin was significantly higher in ment. 55 63 develop a chronic low-grade inflammatory state, which can be indi- cated by a high level of circulating inflammatory cytokines like TNF-α 64 Individuals Sitticharoon positive associations with LH levels and the progression of puberty in 63 visfatin, resistin, and chemerin. and visfatin are expressed in the ovaries. adipokines in the ovaries suggests a role within the reproductive sys- tem; however, the exact biological processes have to be examined. Thus, specifically leptin, adiponectin, and inflammatory cytokines pro- duced by WAT could be permissive key players during an early onset of puberty in girls with obesity. As an exception, HMW adiponectin seems to have a stimulatory effect on peripheral repro- ductive function as HMW is not able to cross the blood brain 63 barrier. 4 | Markers that are used to assess puberty onset in boys are THE ONSET OF PUBERTY IN BOYS spermarche, voice break, testicular volume, and pubic hair develop- 35 spermarche develop in the early stages of puberty onset, voice In women, omentin, chemerin, While pubic hair development, larger testicular volume, and 69 testicular volume increases, which occurs at an average age of break usually appears in later stages of puberty. Generally, first 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 6 of 10 NIEUWENHUIS ET AL. 11.9 years, followed by the development of pubic hair at 12.2 years of average, and lastly, boys experience spermarche around an aver- 55 related with leptin levels. Thereby, leptin plausibly has a minor impact in adrenarche in boys. Since leptin receptors are found in the hypothalamus, pituitary gland, and testes, they might be involved in the onset of puberty by affecting the HPG axis during gonadarche. Leptin stimulates the release of kisspeptin and GnRH, and as a consequence, it accelerates the onset of puberty (Table 1, Figure 3). In contrast, adiponectin inhibits the secretion of GnRH, GH, LH, and FSH therewith delaying the onset of puberty. However, adiponectin levels are generally lower in men compared with women and even lower in men with obe- age age of 13.4 years. 70 4.1 | Fat storage Many aspects of the reproductive physiology are energetically demanding,71 and therefore, an adequate energy level is necessary. In boys, a dynamic change in body composition occurs around the age of 10 to 13 years, in which they gain approximately 40% of sity. culating inflammatory cytokines. levels can stimulate the HPG axis and therewith an early onset of puberty in boys. Nevertheless, leptin can inhibit the production of tes- 72 mostly consisting of lean mass, which causes exhaustion of most of fat. Subsequently, a growth spurt follows in which they gain tissue 72 in boys, an adequate amount of body fat is important in the onset of their body fat. These alterations in amount of body fat indicate that 4.2 | Puberty in boys is initiated by the release of kisspeptin. As mentioned before, this activates the HPG axis, resulting in the release of GnRH from the hypothalamus, and consequently the release of LH and FSH 9,74 puberty. tosterone from the testes, to estrogen (Figure 3). of the development of secondary sex characteristics in boys. Additionally, leptin can affect fertility in men as it can modulate the nutritional support of spermatogenesis, and moreover, dysfunction of spermatogenesis is associated with an increased leptin level and 73 58 2,60-62 HPG axis from the pituitary gland (Figure 1). and LH stimulates the secretion of testosterone from the testes, which inhibits the release of kisspeptin from the KNDy neurons and 9,48 in men, the release of kisspeptin is more consistent, causing a con- 29,48 subsequently GnRH from the hypothalamus. receptors expressed on KNDy neurons. In humans, KNDy neurons Contrarily to women, LH-induced testosterone levels lead to the stant release of LH. development of secondary sex characteristics in boys. differences between sexes in kisspeptin release are related to a sex- specific and sex steroid-dependent kisspeptin system as estrogen and progesterone modulate kisspeptin activity through the sex-steroid 48 in the infundibular nucleus are involved in negative and positive sex- 48 tal exposure to sex steroids and result in sex-specific differences in steroid feedbacks. kisspeptin release. These sexual dimorphisms are induced by perina- 75,76 4.3 | Adipokines The association between obesity and puberty onset in boys is rather controversial compared with findings in girls. Most studies reported an early onset of puberty in boys associated with increased ate adipose tissue from actual breast tissue. stages are more difficult to assess than female stages as boys lack a more determined marker such as menarche. Thirdly, puberty onset can be indicated by the activation of the HPG axis, and the presence of these secondary sex characteristics is the result of hormonal 2 14,17,22,23,50,51,77,78 BMI, 20,49 all while others reported no associations at Current markers used 79 16,80 or a delayed onset of puberty (Table 1). The presence of excessive adipose tissue can be involved in puberty onset in boys as the secretion of adipokines can modulate both adrenarche and gonadarche. Leptin can affect adrenarche by modulating both the HPG and HPA axes,33 and moreover, androgen levels were positively 55 nal androgen secretion in boys with premature adrenarche was not associated with plasma leptin levels. Nevertheless, enhanced adre- 9 In more detail, 61,62 adiponectin, and individuals with obesity often have high levels of cir- Moreover, inflammatory cytokines, TNF-α, and IL-6, inhibit expression of the leptin receptor in the testis. FSH induces spermatogenesis, too. function and role still have to be examined. 64 High leptin and low adiponectin and fat tissue can convert testosterone Both processes might result in the delay 29,61,79 81,82 In men, other adipokines like chemerin are found in the gonads 65 Thus, particularly high leptin and low adiponectin levels stimulate the HPG axis and thereby accelerate the onset of puberty in boys. Additionally, leptin can dysregulate the development of secondary sex characteristics and spermatogenesis by affecting testosterone levels and nutritional sup- port of spermatogenesis. 5 | LIMITATIONS AND FUTURE RESEARCH DIRECTIONS Even though multiple epidemiological studies have shown the link between puberty onset and obesity, there are some important limita- tions. Firstly, determining both the onset and stage of puberty is rather difficult. For instance, assessing the stage of breast develop- ment in girls with obesity is complicated as clinicians should differenti- 2 changes in response to the activated HPG axis. to determine the onset of puberty refer to secondary sex characteris- tics, such as testicular volume in boys and breast development in girls. A more accurate measurement of puberty onset would be to combine secondary sex characteristics with plasma or serum hormone level measurements such as LH, FSH, adipokines, e.g. leptin. Thereby, differences in puberty measurements could explain variations in the age of puberty onset between boys and girls within different Thereby, resistin is expressed in the testes of rats, but its exact 83 Secondly, male pubertal 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License NIEUWENHUIS ET AL. 7 of 10 FIGURE 3 Adipokines affecting the initiation of puberty in boys. Leptin activates kisspeptin secretion in KNDy neurons, this activates the production of gonadotropin releasing hormone (GnRH) from the hypothalamus. GnRH stimulates the pituitary gland to secrete follicle stimulating hormone (FSH) and luteinising hormone (LH), activating the production of testosterone from the testes allowing the development of secondary sex characteristics. Leptin also inhibits the production of testosterone, which may cause a delayed onset of puberty. Adiponectin inhibits GnRH release. Low levels of adiponectin, as a result of TNF-α and IL-6 expression, lead to a reduced inhibition of GnRH. In response to GnRH release, the pituitary gland will secrete FSH and LH, and the testes will produce testosterone resulting in the development of secondary sex characteristics in boys countries, and In addition, the inclusion of a of puberty. ferent time points is complicated, as subjects examined several decades ago presented pronounced differences concerning lifestyle patterns such as nutrition and exercise habits. Lastly, obesity or over- weight is often determined by BMI, a classification based on weight and height measurements. Additionally, it is important that all studies studies or across continents, ethnicities proper age range (8-16 years) is important when assessing the onset (Figure 4). 12-15,17,20-23,49,77-79,84,85 30,47 Furthermore, comparison between studies from dif- 86 Specifically in children, BMI is often dependent on age and growth use the same anthropometric standards and sex-specific cut-offs. 13,14,16-23,49-51,77-80 fat and would represent a more accurate measurement in its regard. Based on this review, several suggestions can be made for further research. Firstly, the roles of adipokines like resistin, chemerin, visfatin, and omentin in puberty onset, fertility, and sexual maturation should be examined in detail. Secondly, future research examining the onset of puberty should combine indicators of puberty onset (e.g. breast development or testicular volume) with plasma or serum hor- mone measurements such as LH, FSH, sex-steroids, adipokines (e.g. spurts. ment in case of growth spurts. distribution of body fat should be taken into account in determining puberty and obesity in children. For instance, the body adiposity index (BAI), which was introduced in 2011 by Bergman et al.,87 uses hip cir- cumference and height in order to estimate the percentage of body 87 Thereby, BMI is a less accurate measure- F I G U R E 4 87,88 Therefore, both percentage and Average age of puberty onset in Europe, China, and the United States according to several studies from Table 1. Age of puberty onset ranges from 8.47 to 13.33 years in girls and from 8.63 leptin), and body fat distribution (e.g. BAI,87 waist-hip ratio's and/or dual-energy X-ray absorptiometry (DXA)2). Additionally, defining con- sistent and general measurements of puberty in both boys and girls, combined with a proper age range (8-16 years), would facilitate the comparisons between different studies and their results. 12-15, 17, 20-23, 25-29, 31 to 13.7 years in boys. included if average age of markers used to assess puberty was not reported. Pink: girls. Blue: boys Studies (Table 1) were not 39, 56 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 8 of 10 NIEUWENHUIS ET AL. 6 | CONCLUSION In conclusion, epidemiological data regarding obesity and puberty onset in girls show similar outcomes as adiposity results in the early onset of puberty in girls. The majority of the studies examining boys with obesity indicate an early onset of puberty, while not all reported an earlier onset of puberty. In detail, high leptin, TNF-α, and IL-6 levels combined with low adiponectin levels stimulate the activation of the HPG axis in girls and boys with obesity, and 5, 45, 50, 51 REFERENCES 1. Kumar S, Kelly AS. Review of childhood obesity: from epidemiology, etiology, and comorbidities to clinical assessment and treatment. May- o Clin Proc. 2017;92(2):251-265. 2. Reinehr T, Roth CL. Is there a causal relationship between obesity and puberty? The Lancet Child & adolescent health. 2019;3(1):44-54. 3. WorldHealthOrganization. Facts and figures on childhood obesity. 2017. 4. Guglielmi V, Sbraccia P. Obesity phenotypes: depot-differences in adipose tissue and their clinical implications. Eat Weight Disord. 2018; 23(1):3-14. 5. Gomez-Hernandez A, Beneit N, Diaz-Castroverde S. Escribano O. 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BMC Womens Health. 2018;18(1):168-174. thereby an early onset of obesity. leptin can inhibit the production of testosterone in boys and subse- quently inhibit the development of secondary sex characteristics affecting spermatogenesis. for other adipokines, like resistin and omentin, are present in the testes and ovaries suggesting a role in puberty or reproduction; 58, 71 however, their plausible function is still unknown. that adipokines may be key regulators in an early onset of puberty in both girls and boys with obesity, specifically by affecting the HPG axis during gonadarche. Future research should focus on assessing puberty onset by measuring consistent puberty markers and determine the percentage of body fat and its distribution and adipokines and hormone serum levels particularly involved in the HPG axis. CONFLICTS OF INTEREST The authors declare no conflict of interest. FUNDING INFORMATION This research was funded by Europees Fonds voor Regionale Ontwikkeling (EFRO), project BriteN 2016. ORCID Ilse A.C. Arnoldussen Amanda J. Kiliaan https://orcid.org/0000-0002-7395-5284 https://orcid.org/0000-0002-2158-6210 13, 14, 16-26, 29-32 Furthermore, several receptors Nevertheless, We conclude Search strategy We searched PubMed for articles published before Novem- ber 15th, 2019 using relevant keywords, including âonset of puberty and adiposity/obesityâ, âonset of pubertyâ, âchildren with obesityâ, âadipose tissueâ, âchildhood obesityâ, âadiposityâ, âobesityâ, âadipokine(s)â, âHPG axisâ, âadipokines ovary/ova- riesâ, or âadipokines testesâ, either alone or in combination. 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Obesity Reviews. 2020;21:e13005. https://doi.org/ 10.1111/obr.13005 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are gover
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