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Genre et nombre de noms d'adjectifs
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Cette route est très (dangereux).
Cette nouvelle est (faux).
Cette route est très (dangereux).
Cette nouvelle est (faux).
Ma voisine est (curieux) et (indiscret).
Je vous présente mon (vieux) ami Pascal.
Ces élèves ne sont pas (original);ils sont (banal).
La chanteuse (américain) et l' actrice (italien) parlent bien français.
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Le genre et le nombre des adjectifs
I Suivre les ventes et les livraisons La plupart du temps, les commandes des clients vont déclencher les règlements. Réceptionner les commandes et les traiter rigoureusement est donc une activité essentielle pour la PME. 1. La réception de la commande Avant de traiter la commande, il est important qu’elle soit vérifiée pour optimiser la relation client et éviter les erreurs. Les points de contrôle sont : 2. Le traitement de la commande Les documents à générer sur le PGI sont : 3. Le suivi de la commande Le suivi permet à l’entreprise de surveiller la progression de l’ensemble des commandes. L’entreprise peut ainsi créer un tableau de suivi visuel lui permettant d’anticiper les problèmes de livraison. Voici un exemple : 4. L’organisation et le suivi des livraisons Livrer, c’est mettre à la disposition du client les produits commandés à la date prévue et au lieu convenu. L’entreprise peut décider de livrer elle-même out de faire appel à un transporteur : • La prise en charge de la livraison par le fournisseur La PME organise le planning et la tournée des livreurs en tenant compte des attentes du client, du temps de trajet et du volume à livrer. Elle utilise pour chaque étape le bon de livraison. Un exemplaire est conservé par l’entreprise et un exemplaire sera laissé au client lors de la livraison. • La prise en charge de la livraison via un transporteur Le suivi de la livraison : Le contrat général de vente permet d’anticiper les problèmes 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 : ▪ franco de port : ▪ port dû : Certains transporteurs offrent la possibilité de suivre les expéditions sur leur site Web. II Facturer, suivre les règlements et les relances clients 1. La facture A chaque étape du processus de vente, divers documents sont créés. Le dernier document du processus est la facture. Elle indique le paiement à faire au client et prouve la vente : facture de doit. Chaque facture portant une date et un numéro unique, une fois émise, il n’est donc plus possible de l’annuler ou la modifier .S’il se passe un évènement après l’édition, on devra alors émettre un avoir. Le processus peut se schématiser ainsi : 2. La présentation d’une facture La facture est établit en double exemplaire et doit être conservée pendant 10 ans. Elle résulte d’une obligation légale et se matérialise par un enregistrement comptable. Quelques règles sont à respecter : 3. Les éléments à contrôler sur la facture Il est nécessaire de vérifier les mentions obligatoires afin d’éviter les réclamations clients. Si elle est conforme, elle est envoyée au client et transmise au service comptabilité pour l’enregistrement. Les éléments à vérifier sont : 4. Les aspects fiscaux liés aux ventes : le mécanisme de TVA L’enregistrement des ventes doit se faire dans le respect des règles fiscales relatives à la TVA (taxe sur la valeur ajoutée) Il existe 4 taux principaux de TVA en France : Certaines activités et certains territoires sont exonérés de TVA. • Le taux de TVA intermédiaire de 10 % s’applique pour les activités suivantes : Restauration (pour consommation immédiate) Aide à la personne Hébergement et transport Produits agricoles non transformés et bois de chauffage Médicaments non remboursés Travaux et réparation pour les logements anciens (plus de deux ans) Musées et zoos • Le taux de TVA réduit à 5.5 % s’applique pour les activités et produits suivants : Produits alimentaires de première nécessité Fourniture de chaleur produite à partir d’énergies renouvelables Livres (y compris numériques) Billetterie de spectacle vivant Restauration pour les cantines scolaire Équipements pour personnes handicapées Travaux d’amélioration énergétique des logements de plus de 2 ans • Le taux de TVA spécifique à 2,1% s’applique pour les activités suivantes : Médicaments remboursés par la Sécurité sociale Publications de presse Billetterie de certains spectacles et cinémas Animaux vivants de boucherie et de charcuterie vendus à des non-assujettis • Les activités suivantes sont exonérées de TVA (0%) : Pêche en mer Certaines œuvres non lucratives à caractère social ou philanthropique Activités médicales et paramédicales Enseignement et formation Livraison ou récupération de déchets Le principe de la TVA pour les entreprises : Afin de bien réaliser les écritures comptables, il est important de différencier la TVA déductible de la TVA collectée : Une créance client est enregistrée en débit alors que la vente de marchandises de l’entreprise est enregistrée en crédit. 5. Les écritures comptables relatives aux ventes Les différents éléments d’une facture doivent être enregistrés dans le journal et dans les comptes de l’entreprise. Si l’entreprise dispose d’un PGI, le devis génère automatiquement la commande. La commande génère automatiquement le bon de livraison qui génère la facture. La facture génère automatiquement les écritures comptables au journal. Exemple de visualisation d’écriture comptable sur le PGI : 6. La mise en place d’un suivi efficace des règlements Le suivi des comptes clients permet de connaitre l’état des créances à tout moment. La relance remplit plusieurs objectifs : Les outils les plus utilisés dans cette démarche sont l’échéancier (il liste les créances en attente de règlement avec peu de détails) et la balance âgée (elle présente les soldes de créances de manière plus visuelle avec une ligne par client). Exemples : Echéancier Balance âgée L’entreprise peut également pointer les créances afin de faire ressortir les créances impayées (lettrage des comptes). Enfin, compte tenu des enjeux pour les entreprises d’obtenir les règlements dans des délais raisonnables, elles mettent en place un véritable processus de relance qui doit respecter les étapes suivantes : Après avoir pris connaissance du processus de relance, il devient nécessaire de créer un tableau de relance des impayés pour relancer les clients efficacement. Exemple : Tableau de relances des impayés : Enfin, il faudra relancer les clients par téléphone, mail ou courrier pour obtenir les sommes dues via des relances automatisées. Exemple de mise en demeure automatisée envoyée en recommandé :
La lettre de Jean être dans l’embarras : ne pas savoir quelle décision prendre, être gêné. le dévouement : c’est ce que fait une personne qui consacre son temps à aider les autres. Paris, le 18 février 2005 Ma chère Tatie, Je suis bien triste aujourd’hui. Maman est malade et le médecin que nous avons appelé dit que ce n’est pas grave, mais qu’il 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 s’occuper de nous, qui va soigner maman ? Papa n’est pas là de la journée et moi je vais à l’école ; le soir, j’ai mes devoirs, mes leçons. Et puis on ne peut laisser maman seule pendant de longues heures. Aussi, ma chère Tatie, je viens te demander si tu peux venir nous aider pendant la maladie de ta sœur. Tu sais à quel point tu nous rendrais service. Nous n’avons pas hésité à te demander de venir car nous connaissons ton dévouement et ta gentillesse. Pour moi, ce sera une grande joie de t’avoir près de nous et je sais que tes bons soins permettront à maman de se rétablir rapidement. Excuse-nous de tout le dérangement que nous allons te causer. Préviens-nous de l’heure de ton arrivée afin que j’aille te chercher à la gare. Merci d’avance, ma chère tante, pour tout ce que tu vas faire pour nous. Papa et maman se joignent à moi pour t’embrasser bien affectueusement. Ton neveu, Jean
Figlio di un decurione, Patricio, ancora pagano, e della cristiana Monnica, fu iscritto tra i catecumeni; compì gli studi in patria, a Madaura, poi a Cartagine: periodo da lui descritto come di abbandono alle passioni amorose. Da una concubina ebbe nel 372 un figlio, Adeodato. La lettura dell'Hortensius ciceroniano lo attrasse, diciannovenne, alla filosofia, e aderì presto al manicheismo, presentatogli come spiegazione scientifica dell'universo. Se ne fece anzi propagandista a Tagaste, dopo la morte del padre, e a Cartagine ove ottenne qualche successo come retore, e scrisse il suo primo libro, De pulchro et apto (perduto), in cui pare si sforzasse a dare veste filosofica al manicheismo, nel quale era però rimasto semplice uditore. Passò poi, abbandonando la madre, a Roma; quindi, su raccomandazione di Simmaco, come professore ufficiale di retorica (autunno 384), a Milano, ove maturò la crisi spirituale, in seguito alla quale, dimessa la concubina e rinunciando al matrimonio vantaggioso per cui insisteva Monnica, si decise ad abbracciare il cristianesimo, che gli si palesava, allora, come in pieno e perfetto accordo con la filosofia neoplatonica e la predicazione di s. Ambrogio. A Cassiciacum (probabilmente Cassago, in Brianza), dimessosi dalla cattedra, scrisse le prime opere pervenuteci (i dialoghi Contra academicos, De vita beata, De ordine e Soliloquia) e cominciò a comporre una serie di manuali delle arti liberali; fu battezzato da s. Ambrogio la notte del sabato santo (24-25 aprile) del 387. Trascorse a Roma l'inverno (Monnica morì ad Ostia nel novembre) e tornò a Tagaste, continuando, nella vita monastica, la sua attività di scrittore. Nel 391 fu ordinato sacerdote a Ippona, ove, tra la fine del 395 e il 396, fu consacrato come successore dal vescovo Valerio già prossimo a morte; lo stesso fece poi (426) A. col prete Eraclio. Le reliquie, portate in Sardegna da s. Fulgenzio e altri vescovi esuli nel 486, furono dopo l'invasione saracena trasportate, per opera del re Liutprando, a Pavia ove gli fu eretto il monumento: ma che fossero di lui quelle ritrovate nel 1695 fu contrastato dal Muratori e da altri. Nei 34 anni di episcopato lo tennero occupato, oltre le cure costanti dedicate alla sua chiesa, la copiosa corrispondenza (ci sono giunte 218 lettere di A., oltre i trattatelli in forma epistolare, e 53 dirette a lui), la predicazione (i sermoni conservati e noti finora sono più di 500), i concilî e le eresie e scismi, la lotta contro i quali assorbì grandissima parte dell'attività letteraria, che ha reso A. proverbiale come uno non solo dei più dotti e profondi, ma dei più fecondi scrittori mai esistiti. Appunto le polemiche, insieme con la conversione, l'ordinazione e la consacrazione, contrassegnano, all'ingrosso, anche periodi dello svolgimento del pensiero di lui. Con la conversione comincia la polemica contro i manichei, già accennata nei "Dialoghi di Cassiciaco" e continuata in una serie di scritti per lo più filosofico-religiosi (per es. De quantitate animae, De libero arbitrio, il libro VI De musica, De magistro, De vera religione, De utilitate credendi), in cui vediamo A. passare gradatamente dall'affermazione della superiorità essenziale della ragione sulla fede, a quella dell'utilità e ragionevolezza dell'affidarsi all'auctoritas fondata sulla rivelazione e universalmente riconosciuta, della Chiesa; ed elaborare insieme la sua caratteristica dottrina della conoscenza. La felicità, cui gli uomini aspirano, non si consegue senza il possesso della verità. Contro gli scettici, egli usa l'argomento principe: se dubito, so di dubitare, dunque di essere; se sbaglio, sono (motivo che da taluni storici della filosofia viene indicato tra gli antecedenti del dubbio cartesiano: non sfugge comunque il diverso contesto). Ma la verità va cercata in me stesso: è la dottrina neoplatonica del ritorno su sé stessa dell'anima, che, riconosciuta la mutevolezza del mondo esteriore, percepito dai sensi, e la sua propria, si avvia a ricercare la verità immutabile, per cui è vero ogni ragionamento vero, e che è Dio medesimo. I sensi, dunque, e anche le parole del maestro, non fanno se non ridestare idee, che sono già nell'anima: non però nel senso della dottrina platonica della reminiscenza, ma in quanto in interiore homine habitat veritas, parla cioè, in fondo all'anima, il Maestro interiore, il Verbo divino; nell'uomo (in interiore homine) brilla la luce del vero che dona a ciascuno le rationes aeternae, principio e fondamento di ogni giudizio. È questa la teoria detta dell'illuminazione, che, non del tutto chiarita da A., si presta a varie interpretazioni (secondo che le rationes aeternae si intendano come "idee innate", o come "categorie" del giudizio); essa si collega alla dottrina del "maestro interiore", il Verbo, il solo vero maestro: sicché l'insegnare degli uomini è solo un preparare ad ascoltare la voce del Verbo divino. Queste dottrine furono da A. mantenute anche in opere posteriori ma il primitivo entusiasmo per Platone, Plotino e i "platonici" (che, se fossero vissuti ora, - dice - si sarebbero fatti cristiani) e per i neoplatonici si affievolì col tempo. La polemica antimanichea venne continuata in altri scritti (per es. Contra Adimantum, Contra epistolam Manichaei quam vocant fundamenti) fino al voluminoso Contra Faustum e ad altri opuscoli fino al 405 circa, poi sporadicamente in un paio di opuscoli e, in parte, nel trattatello contro tutte le eresie (De haeresibus, 428-29). L'ordinazione sacerdotale obbliga A. a spiegare al popolo i libri sacri; egli partecipa più intimamente della vita della Chiesa e viene a conoscere lo scisma che tormenta la Chiesa africana. Comincia così la polemica contro il donatismo, con l'interessante Psalmus abecedarius contra partem Donati, primo esempio degli scritti popolareggianti di A. (versi di 16 sillabe, abbandono della prosodia e metrica classica, assonanza in e), poi con una serie di opere (Contra epistolam Parmeniani, De baptismo, Contra litteras Petiliani, Contra Cresconium) fino alla grande "conferenza" di Cartagine (411; Breviculus collationis cum donatistis) quindi, con minor frequenza di scritti, sino al Contra Gaudentium (420 circa). In questa polemica, che lo portò a occuparsi dell'ecclesiologia, A. segue s. Cipriano e s. Ottato mantenendo fermissimo il principio della validità ed efficacia obiettiva (ex opere operato) dei Sacramenti, la cattolicità e l'unità della Chiesa, fuori della quale non v'è salvezza e che è corpus permixtum: ne fanno parte cioè grano e zizzania, buoni e malvagi, che soltanto Gesù Cristo ha diritto di separare nel giorno del Giudizio. Ma mentre all'inizio, e ancora nel 411, A. non voleva ricorrere ad altro mezzo che la persuasione attraverso la discussione, tuttavia, con le leggi di Onorio contro gli scismatici e di fronte alla loro ostinazione, cambiò parere: e come dalla netta distinzione tra scisma ed eresia passò a definire questa quale "scisma inveterato", così ammise la legittimità e necessità della coercizione e del ricorso all'autorità civile, fissando altresì il dovere per il sovrano cristiano di attenersi al magistero della chiesa.Ma con l'ordinazione A. si dedica anche con maggiore intensità allo studio della Bibbia: specialmente del Genesi, passando dall'interpretazione strettamente allegorica (De Genesi adversus Manichaeos, 388-90) a quella letterale, e insieme di valore filosofico (De Genesi ad litteram liber imperfectus), e di s. Paolo (Expositio quarundam propositionum ex Epistola ad Romanos, Epistolae ad Romanos expositio inchoata, Expositio Epistolae ad Galatas, parecchie delle questioni trattate nel De diversis quaestionibus octogintatribus). Cogliamo qui un momento importantissimo nello svolgimento del pensiero teologico di A., e oggetto di molte discussioni. Egli si è sforzato di mantenere in primo luogo la giustizia di Dio, che premia i buoni, cioè coloro che credendo si acquistano un merito, e che punisce i malvagi. Ma, dopo un lungo sforzo, A. viene a riconoscere che il momento iniziale dell'atto di fede, l'initium fidei, che è initium salutis, non è opera dell'uomo ma viene da Dio: al quale non si può tuttavia rimproverare alcuna ingiustizia, se, gratuitamente, fa grazia ad alcuni; mentre gli uomini tutti, in cui sopravvive il peccato originale, non meritano se non la condanna. Questi concetti appaiono per la prima volta con tutta chiarezza, nel primo scritto posteriore all'episcopato di A., il De diversis quaestionibus ad Simplicianum. Frutto di questa conquista del suo pensiero, che lo induce a rimeditare sulla sua vita, si possono considerare le Confessioni (398 circa), nelle quali, altresì, sono ripresi altri due temi che lo appassionano: quello della cultura cristiana e quello dei principî che presiedono all'interpretazione della Scrittura. La prima questione è da lui affrontata sotto l'aspetto teorico nel De doctrina christiana (interrotto, ma ripreso e terminato nel 426): come anche nelle Confessioni A. è sensibile ai pericoli della cultura tradizionale, pagana, ma vuole salvarne il buono, che va assunto e fatto proprio dal cristianesimo. Così, conchiudendo una lunga controversia, A. assicura col peso della sua autorità la trasmissione della cultura antica. Ma nelle Confessioni il problema della memoria (in essa è la misura del tempo) trascina seco quello della creazione. A. la ritiene avvenuta nel tempo, anzi col tempo, dal nulla, e per tutte le cose simultaneamente, ma non allo stesso modo: ché alcune furono create da Dio non in atto e nella loro forma perfetta, ma solo in potenza, o in germe (rationes seminales, energie latenti destinate a svilupparsi nel tempo e a produrre, al momento opportuno per ciascuno, i diversi esseri). A queste conclusioni A. è portato da un nuovo studio dei primi 3 capitoli del Genesi (De Genesi ad litteram libri XII, tra il 401 circa e il 415 circa). Accanto al quale, tra le opere esegetiche, vanno ricordati il De consensu evangelistarum (400 circa), le Enarrationes in Psalmos, e i Tractatus in evangelium Iohannis, raccolte di sermoni su questi libri. Ma nelle Confessioni A. ha inserito anche un'istruzione catechetica (proprio con il commento al Genesi), affine a quella da lui data in un'altra operetta, il De catechizandis rudibus (400 circa). E il motivo della memoria, che appare nelle Confessioni, diventa importantissimo in un altro trattato su cui A. si affaticò lungo (400 circa -416 circa): il De Trinitate. L'anima è un pensiero (mens) da cui nasce una conoscenza (notitia), e nel suo rapportarsi a questa conoscenza nasce l'amore che essa si porta (amor). Nell'anima o, meglio, nella memoria, nell'intelletto e nella volontà, nella parte cioè più alta e nobile di essa, che ricorda, comprende e ama sé stessa, ma soprattutto ricorda, conosce e ama Dio, A. scorge le "vestigia" della Trinità divina. Di essa, criticando talvolta le formule di s. Ilario di Poitiers, egli mette in rilievo l'unità di sostanza, insistendo sull'uguaglianza delle tre Persone: le operazioni ad extra sono l'opera indistinta di tutte, ciò che si dice di ciascuna quanto alla sostanza, e anche alla sapienza e altri attributi, è comune, uguale, identico e numericamente uno in tutte; mentre esse si distinguono e si oppongono secondo le loro relazioni reciproche. Teoria che, chiarendo la processione dello Spirito Santo principaliter, sì, dal Padre, ma anche dal Figlio, divenne importantissima per lo svolgimento della teologia occidentale, cui A. ha legato il carattere "cristocentrico", conforme alla tendenza fondamentale del suo pensiero, aggirantesi intorno alla persona e all'opera del Cristo ed alla redenzione dell'uomo dal peccato, mercé la grazia. Intorno a questi temi scoppiò la polemica con Pelagio, già scandalizzatosi in Roma per l'invocazione delle Confessioni a Dio: da quod iubes et iube quod vis e ora rifugiatosi in Africa con il suo compagno Celestio (che, denunciato da Paolino di Milano, venne condannato nel 411 da un concilio locale, a Cartagine). Si possono distinguere in essa varie fasi: quella iniziale, in cui A. combatte ancora soltanto le dottrine, non gli uomini, che sa molto stimati (De peccatorum meritis et remissione, a Marcellino, il l. III composto dopo che A. ebbe conosciuto il commento di Pelagio a s. Paolo; De spiritu et littera ad Marcellinum e, a complemento, per asserire la necessità delle opere buone accanto alla fede, De fide et operibus; nonché il De bono viduitatis, dedicato a Giuliana, madre di Demetriade, in occasione della monacazione di questa); quella della polemica diretta, provocata dalle vicende di Pelagio in Oriente fino alla condanna da parte del papa Innocenzo I (con la celebre affermazione che, dopo tanti concilî, anche Roma locuta est; causa finita est; utinam aliquando finiatur error) e, dopo il grande concilio di Cartagine (418) da papa Zosimo (De natura et gratia contra Pelagium, De perfectione iustitiae hominis, contro Celestio, De gestis Pelagii, De gratia Christi et peccato originali); quella della lotta contro i pertinaci difensori di Pelagio (De nuptiis et concupiscentia ad Valerium comitem, Contra duas epistolas Pelagianorum, Contra Iulianum, e Contra secundam Iuliani responsionem, il cosiddetto Opus imperfectum, contro lo stesso Giuliano di Eclano, interrotto per la morte di A.), intesa al tempo stesso a chiarire la sua dottrina ai monaci di Adrumeto (De gratia et libero arbitrio, e De correptione et gratia, dedicati all'abate Valentino) e a combattere i "semipelagiani" della Gallia meridionale, insorti contro questi scritti (De praedestinatione sanctorum e De dono perseverantiae). Questa dottrina agostiniana del peccato originale, della grazia e della predestinazione, precisatasi ma anche irrigiditasi e spinta alle estreme conseguenze nell'ardore della polemica, si è prestata a varie e contrastanti interpretazioni. A. prende le mosse dalla condizione di Adamo, creato esente dalla morte (posse non mori, diverso da non posse mori proprio degli esseri spirituali) e dalla concupiscenza, capace quindi di non peccare (il posse non peccare, diverso dal non posse peccare degli eletti), e nella piena libertà di optare per il bene conformandosi a una ragione che aveva il perfetto predominio sui sensi, capace altresì di perseverare nel bene, grazie all'aiuto (adiutorium sine quo non) concessogli da Dio. Avendo Adamo peccato, la sua colpa si trasmise all'intero genere umano, divenuto così massa damnata; peccato di origine, che A. dimostra, fra l'altro, in base all'uso della Chiesa di amministrare agli infanti il battesimo che annulla la concupiscenza in quanto reato, ma la lascia sopravvivere actu, così che l'uomo, pur conservando il libero arbitrio, è privato di quella libertas ... quae in Paradiso fuit (Enchir. 26-27). Per poter resistere cioè alla concupiscenza, occorre ora un aiuto divino maggiore di quello dato ad Adamo: la grazia è dunque necessaria per avere la fede, e questa perché vi sia quell'amore di Dio, in quanto sommo bene, senza di che non esiste né beatitudine né vera moralità (e non vi sono pertanto vere virtù fra i pagani). Ma questo soccorso (adiutorium quo) non è concesso a tutti: Dio, senza alcuna ingiustizia, ma per un suo gratuito atto di misericordia, prepara per alcuni i mezzi, pienamente efficaci, per condurli alla salvezza cui li ha predestinati ab aeterno. Accusato dai pelagiani di manicheismo, A. tuttavia, come si vede, non considera come malvagia la stessa natura umana, e non condanna la procreazione: nel matrimonio, il male è la concupiscentia carnis; e anche questo può essere rivolto a un fine buono, la generazione dei figli congiunta alla volontà della loro rigenerazione attraverso il battesimo. Ma i bambini morti senza di questo, secondo A., non si sottraggono alla pena eterna. Poiché la trasmissione del peccato originale si spiegava più facilmente mediante la teoria secondo cui l'anima è generata, spiritualmente, da quella dei genitori (traducianismo), mentre, più conforme alla sua dottrina dell'illuminazione, era l'altra teoria, della creazione di ogni anima da Dio (creazionismo), A. rimase incerto fino all'ultimo (De anima et eius origine, 419-20). E poiché è ignoto chi siano gli eletti, la concezione agostiniana della predestinazione coincide con quella della Chiesa come corpus permixtum (v. sopra). La scossa profonda data a tutto il mondo romano dall'incursione di Alarico, le querimonie dei pagani additanti nel cristianesimo la causa di tutti i mali del mondo, indussero A. a meditare sulla storia, e a scrivere l'altra delle sue opere maggiori e più celebri dopo le Confessioni: il De civitate Dei. Nel corso della storia procedono unite le due città (Civitas Dei e Civitas terrena), nate l'una dall'amor Dei usque ad contemptum sui, l'altra dall'amor sui usque ad contemptum Dei e predestinate, la prima a regnare in eterno con Dio, l'altra a subire l'eterno supplizio. Neppure quest'opera è, in fondo, davvero sistematica; cosciente dello sviluppo del proprio pensiero, A. sembra invitare i lettori a imitarlo nello sforzo di progredire: del resto volle egli stesso correggere i suoi errori (ma anche dimostrare, specie contro i manichei, la sua fondamentale coerenza) in quella originalissima rassegna dei suoi scritti che sono le Retractationes (426-27). Va menzionato ancora, breve e bellissimo compendio della dottrina cristiana, l'Enchiridium ad Laurentium (De fide, spe, charitate, 421); e va almeno accennato il valore letterario dei suoi scritti, specie delle Confessioni. Festa, 28 agosto. L'interesse educativo di A. non è limitato ai problemi pedagogici più dibattuti dalla Patristica, e cioè all'utilizzazione della cultura pagana nella formazione dei ragazzi, ed ai modi e metodi dell'educazione religiosa. Esso si connette piuttosto ad un tema filosofico fondamentale nella sua speculazione, quello della "verità interiore" e quindi con la dottrina dell'illuminazione. Il processo educativo consiste nel trarre alla luce la verità, nel ritrovare Dio-maestro nel profondo dell'anima (Christus intus docet). Il maestro vero è quindi solo Cristo, i maestri terreni non possono far altro che stimolare la riscoperta della verità stessa che è in noi come segno della presenza di Dio. Dal punto di vista didattico A. accoglie la necessaria propedeutica delle "arti liberali", ma la cultura per sé non è indispensabile, poiché le virtù cristiane si realizzano anche al di fuori di esse. Necessaria è invece la cultura religiosa da impartire anche alle menti più rozze: nel De catechizandis rudibus Agostino parla di tale opera educativa, ponendo in rilievo la funzione fondamentale che ha in essa l'amore con cui il maestro discende al livello dell'educando (così come Cristo ha fatto per l'uomo facendosi uomo) e vivifica anche gli aspetti più elementari e consueti del fatto educativo.
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. Dif- ferential role of adipose tissues in obesity and related metabolic and vas- cular complications. 2016;2016:1-15, 1216783. 6. Zwick RK, Guerrero-Juarez CF, Horsley V, Plikus MV. Anatomical, physiological, and functional diversity of adipose tissue. Cell Metab. 2018;27(1):68-83. 7. Gulyaeva O, Dempersmier J, Sul HS. Genetic and epigenetic control of adipose development. Biochimica et Biophysica Acta (BBA)— Molecular and Cell Biology of Lipids. 2019;1864:3-12. 8. Khan M, Joseph F. Adipose tissue and adipokines: the association with and application of adipokines in obesity. Forensic Sci. 2014;2014: 711-724, 328592. 9. Alotaibi MF. Physiology of puberty in boys and girls and pathological disorders affecting its onset. J Adolesc. 2019;71:63-71. 10. Cousminer DL, Stergiakouli E, Berry DJ, et al. Genome-wide associa- tion study of sexual maturation in males and females highlights a role for body mass and menarche loci in male puberty. Hum Mol Genet. 2014;23(16):4452-4464. 11. Ahmed ML, Ong KK, Dunger DB. Childhood obesity and the timing of puberty. Trends in endocrinology and metabolism: TEM. 2009;20(5): 237-242. 12. Biro FM, Pajak A, Wolff MS, et al. Age of menarche in a longitudinal US cohort. J Pediatr Adolesc Gynecol. 2018;31(4):339-345. 13. Currie C, Ahluwalia N, Godeau E, Nic Gabhainn S, Due P, Currie DB. Is obesity at individual and national level associated with lower age at menarche? Evidence from 34 countries in the Health Behaviour in School-aged Children Study. The Journal of adolescent health: official publication of the Society for Adolescent Medicine. 2012;50(6): 621-626. 14. De Leonibus C, Marcovecchio ML, Chiavaroli V, de Giorgis T, Chiarelli F, Mohn A. Timing of puberty and physical growth in obese children: a longitudinal study in boys and girls. Pediatr Obes. 2014; 9(4):292-299. 15. Flom JD, Cohn BA, Tehranifar P, et al. Earlier age at menarche in girls with rapid early life growth: cohort and within sibling analyses. Ann Epidemiol. 2017;27(3):187-93.e2. 16. Glass NA, Torner JC, Letuchy EM, et al. The relationship between greater prepubertal adiposity, subsequent age of maturation, and bone strength during adolescence. Journal of bone and mineral research: the official journal of the American Society for Bone and Min- eral Research. 2016;31(7):1455-1465. 17. Holmgren A, Niklasson A, Nierop AF, et al. Pubertal height gain is inversely related to peak BMI in childhood. Pediatr Res. 2017;81(3): 448-454. 18. Kaplowitz PB, Slora EJ, Wasserman RC, Pedlow SE, Herman- Giddens ME. Earlier onset of puberty in girls: relation to increased body mass index and race. Pediatrics. 2001;108(2):347-353. 19. Kelly Y, Zilanawala A, Sacker A, Hiatt R, Viner R. Early puberty in 11-year-old girls: Millennium Cohort Study findings. Arch Dis Child. 2017;102(3):232-237. 20. Lazzeri G, Tosti C, Pammolli A, et al. Overweight and lower age at menarche: evidence from the Italian HBSC cross-sectional survey. BMC Womens Health. 2018;18(1):168-174. thereby an early onset of obesity. leptin can inhibit the production of testosterone in boys and subse- quently inhibit the development of secondary sex characteristics affecting spermatogenesis. for other adipokines, like resistin and omentin, are present in the testes and ovaries suggesting a role in puberty or reproduction; 58, 71 however, their plausible function is still unknown. that adipokines may be key regulators in an early onset of puberty in both girls and boys with obesity, specifically by affecting the HPG axis during gonadarche. Future research should focus on assessing puberty onset by measuring consistent puberty markers and determine the percentage of body fat and its distribution and adipokines and hormone serum levels particularly involved in the HPG axis. CONFLICTS OF INTEREST The authors declare no conflict of interest. FUNDING INFORMATION This research was funded by Europees Fonds voor Regionale Ontwikkeling (EFRO), project BriteN 2016. ORCID Ilse A.C. Arnoldussen Amanda J. Kiliaan https://orcid.org/0000-0002-7395-5284 https://orcid.org/0000-0002-2158-6210 13, 14, 16-26, 29-32 Furthermore, several receptors Nevertheless, We conclude Search strategy We searched PubMed for articles published before Novem- ber 15th, 2019 using relevant keywords, including ‘onset of puberty and adiposity/obesity’, ‘onset of puberty’, ‘children with obesity’, ‘adipose tissue’, ‘childhood obesity’, ‘adiposity’, ‘obesity’, ‘adipokine(s)’, ‘HPG axis’, ‘adipokines ovary/ova- ries’, or ‘adipokines testes’, either alone or in combination. Selection criteria used were English language, longitudinal or cross-sectional studies assessing the onset of puberty, including menarche, thelarche, spermarche, or voice break, combined with high BMI or obesity/adiposity, and articles assessing or reviewing adipokines and its effects on the reproductive system. 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License NIEUWENHUIS ET AL. 9 of 10 21. Lian Q, Mao Y, Luo S, et al. Puberty timing associated with obesity and central obesity in Chinese Han girls. BMC Pediatr. 2019; 19(1):1-7. 22. Deng Y, Liang J, Zong Y, et al. Timing of spermarche and menarche among urban students in Guangzhou, China: trends from 2005 to 2012 and association with Obesity. Sci Rep. 2018;8(1):263-270. 23. Li W, Liu Q. Association of prepubertal obesity with pubertal devel- opment in Chinese girls and boys: a longitudinal study. 2018;30: e23195. 24. Mendle J, Beltz AM, Carter R, Dorn LD. Understanding puberty and its measurement: ideas for research in a new generation. Journal of research on adolescence: the official journal of the Society for Research on Adolescence. 2019;29(1):82-95. 25. Pagani S, Meazza C, Gertosio C, Bozzola E, Bozzola M. Growth hor- mone receptor gene expression in puberty. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme. 2015;47:581-584. 26. Abreu AP, Kaiser UB. Pubertal development and regulation. Lancet Diabetes Endocrinol. 2016;4(3):254-264. 27. Aguirre RS, Eugster EA. Central precocious puberty: from genetics to treatment. Best Pract Res Clin Endocrinol Metab. 2018;32(4): 343-354. 28. Sultan C, Gaspari L, Maimoun L, Kalfa N, Paris F. Disorders of puberty. Best Pract Res Clin Obstet Gynaecol. 2018;48:62-89. 29. Skorupskaite K, George JT, Anderson RA. The kisspeptin-GnRH path- way in human reproductive health and disease. Hum Reprod Update. 2014;20(4):485-500. 30. Dahl SK, Amstalden M, Coolen L, Fitzgerald M, Lehman M. Dynorphin immunoreactive fibers contact GnRH neurons in the human hypothal- amus. Reprod Sci. 2009;16(8):781-787. 31. Navarro VM, Gottsch ML, Chavkin C, Okamura H, Clifton DK, Steiner RA. Regulation of gonadotropin-releasing hormone secretion by kisspeptin/dynorphin/neurokinin B neurons in the arcuate nucleus of the mouse. J Neurosci. 2009;29(38):11859-11866. 32. Zhai L, Liu J, Zhao J, et al. Association of obesity with onset of puberty and sex hormones in chinese girls: a 4-year longitudinal study. PLoS ONE. 2015;10(8):1-12, e0134656. 33. Cizza G, Dorn LD, Lotsikas A, Sereika S, Rotenstein D, Chrousos GP. Circulating plasma leptin and IGF-1 levels in girls with premature adrenarche: potential implications of a preliminary study. Horm Metab Res. 2001;33(3):138-143. 34. Cousminer DL, Widén E, Palmert MR. The genetics of pubertal timing in the general population: recent advances and evidence for sex-spec- ificity. Curr Opin Endocrinol Diabetes Obes. 2016;23(1):57-65. 35. Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. Arch Dis Child. 1969;44(235):291-303. 36. Lacroix AE, Whitten R. Physiology. Treasure Island (FL): Menarche. StatPearls. StatPearls Publishing; 2018. 37. McDowell MA, Brody DJ, Hughes JP. Has Age at Menarche Chan- ged? Results from the National Health and Nutrition Examination Sur- vey (NHANES) 1999–2004. J Adolesc Health. 2007;40(3):227-231. 38. de Muinich Keizer SM, Mul D. Trends in pubertal development in Europe. Hum Reprod Update. 2001;7(3):287-291. 39. Talma H, Schönbeck Y, van Dommelen P, Bakker B, van Buuren S, Hirasing RA. Trends in menarcheal age between 1955 and 2009 in the Netherlands. PLoS ONE. 2013;8:e60056-e60056. 40. Kaplan HS, Lancaster JB. An evolutionary and ecological analysis of human fertility, mating patterns, and parental investment. Off- spring: Human fertility behavior in biodemographic perspective. 2003;1: 170-223. 41. Mitan LA. Menstrual dysfunction in anorexia nervosa. J Pediatr Adolesc Gynecol. 2004;17(2):81-85. 42. Xu H, Li P-H, Barrow TM, et al. Obesity as an effect modifier of the association between menstrual abnormalities and hypertension in young adult women: Results from Project ELEFANT. PLoS ONE. 2018; 13(11):e0207929-e0207929. 43. Tauqeer Z, Gomez G, Stanford FC. Obesity in women: insights for the clinician. J Womens Health (Larchmt). 2018;27(4):444-457. 44. de Ridder CM, Thijssen JH, Bruning PF, Van den Brande JL, Zonderland ML, Erich WB. Body fat mass, body fat distribution, and pubertal development: a longitudinal study of physical and hormonal sexual maturation of girls. J Clin Endocrinol Metab. 1992;75(2): 442-446. 45. Lassek W, Gaulin S. Brief communication: menarche is related to fat distribution. Am J Phys Anthropol. 2007;133(4):1147-1151. 46. Loomba-Albrecht LA, Styne DM. Effect of puberty on body composi- tion. Curr Opin Endocrinol Diabetes Obes. 2009;16:10-15. 47. Simonneaux V, Bahougne T. A multi-oscillatory circadian system times female reproduction. Front Endocrinol. 2015;6:1-15. 48. Marques P, Skorupskaite K, George JT, Anderson RA. Physiology of GNRH and gonadotropin secretion. In: Feingold KR, Anawalt B, Boyce A, et al., eds. Endotext. Endotext.org: South Dartmouth (MA); 2000. 49. Barcellos Gemelli IF, Farias EDS, Souza OF. Age at menarche and its association with excess weight and body fat percentage in girls in the Southwestern Region of the Brazilian Amazon. J Pediatr Adolesc Gynecol. 2016;29(5):482-488. 50. Aksglaede L, Juul A, Olsen LW, Sorensen TI. Age at puberty and the emerging obesity epidemic. PLoS ONE. 2009;4:1-6, e8450. 51. Ribeiro J, Santos P, Duarte J, Mota J. Association between over- weight and early sexual maturation in Portuguese boys and girls. Ann Hum Biol. 2006;33(1):55-63. 52. Budak E, Fernandez Sanchez M, Bellver J, Cervero A, Simon C, Pellicer A. Interactions of the hormones leptin, ghrelin, adiponectin, resistin, and PYY3-36 with the reproductive system. Fertil Steril. 2006;85(6):1563-1581. 53. Castellano JM, Tena-Sempere M. Metabolic control of female puberty: potential therapeutic targets. Expert Opin Ther Targets. 2016; 20(10):1181-1193. 54. Venancio JC, Margatho LO, Rorato R, et al. Short-term high-fat diet increases leptin activation of CART neurons and advances puberty in female mice. Endocrinology. 2017;158(11):3929-3942. 55. l'Allemand D, Schmidt S, Rousson V, Brabant G, Gasser T, Gruters A. Associations between body mass, leptin, IGF-I and circulating adrenal androgens in children with obesity and premature adrenarche. Eur J Endocrinol. 2002;146(4):537-543. 56. Böttner A, Jr K, Müller G, et al. Gender Differences of adiponectin levels develop during the progression of puberty and are related to serum androgen levels. J Clin Endocrinol Metabol. 2004;89(8):4053- 4061. 57. Unanue N, Bazaes R, Iñiguez G, Cortes F, Avila A, Mericq V. Adre- narche in Prader-Willi syndrome appears not related to insulin sensi- tivity and serum adiponectin. Horm Res. 2007;67(3):152-158. 58. Michalakis K, Mintziori G, Kaprara A, Tarlatzis BC, Goulis DG. The complex interaction between obesity, metabolic syndrome and repro- ductive axis: a narrative review. Metabolism: clinical and experimental. 2013;62(4):457-478. 59. Machinal-Quelin F, Dieudonne MN, Pecquery R, Leneveu MC, Giudicelli Y. Direct in vitro effects of androgens and estrogens on ob gene expression and leptin secretion in human adipose tissue. Endo- crine. 2002;18(2):179-184. 60. Dobrzyn K, Smolinska N, Kiezun M. Adiponectin: A new regulator of female reproductive system. Int J Endocrinol. 2018;2018:1-12, 7965071. 61. Martin LJ. Implications of adiponectin in linking metabolism to testic- ular function. Endocrine. 2014;46(1):16-28. 62. Mathew H, Castracane VD, Mantzoros C. Adipose tissue and repro- ductive health. Metabolism: clinical and experimental. 2018;86:18-32. 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 10 of 10 NIEUWENHUIS ET AL. 63. Sitticharoon C, Sukharomana M, Likitmaskul S, Churintaraphan M, Maikaew P. Corrigendum to: Increased high molecular weight adiponectin, but decreased total adiponectin and kisspeptin, in central precocious puberty compared with aged-matched prepubertal girls. Reprod Fertil Dev. 2017;29:2506-2517. 64. Das UN. Is obesity an inflammatory condition? Nutrition. 2001; 17(11-12):953-966. 65. Comninos AN, Jayasena CN, Dhillo WS. The relationship between gut and adipose hormones, and reproduction. Hum Reprod Update. 2014; 20(2):153-174. 66. Singh A, Choubey M, Bora P, Krishna A. Adiponectin and chemerin: contrary adipokines in regulating reproduction and metabolic disor- ders. Reproductive sciences (Thousand Oaks, Calif). 2018;25:1462- 1473. 67. Tsatsanis C, Dermitzaki E, Avgoustinaki P, Malliaraki N, Mytaras V, Margioris AN. The impact of adipose tissue-derived factors on the hypothalamic-pituitary-gonadal (HPG) axis. Hormones (Athens). 2015; 14:549-562. 68. Kang MJ, Oh YJ, Shim YS, Baek JW, Yang S. Hwang IT. The usefulness of circulating levels of leptin, kisspeptin, and neurokinin B in obese girls with precocious puberty. 2018;34:627-630. 69. Lee J, Song J, Hootman JM, et al. Obesity and other modifiable fac- tors for physical inactivity measured by accelerometer in adults with knee osteoarthritis: data from the osteoarthritis initiative (OAI). Arthritis Care Res (Hoboken). 2012;53-61. 70. Bramswig J, Dubbers A. Disorders of pubertal development. Deutsches Arzteblatt international. 2009;106:295-303. quiz 04 71. Elias CF, Purohit D. Leptin signaling and circuits in puberty and fertil- ity. Cell Mol Life Sci. 2013;70(5):841-862. 72. Riumallo J, Durnin JV. Changes in body composition in adolescent boys. Eur J Clin Nutr. 1988;42(2):107-112. 73. Siervogel RM, Demerath EW, Schubert C, et al. Puberty and body composition. Horm Res. 2003;60(Suppl 1):36-45. 74. Zhang J. Gong M. Andrologia: Review of the role of leptin in the regu- lation of male reproductive function; 2018. 75. Kauffman AS, Gottsch ML, Roa J, et al. Sexual differentiation of Kiss1 gene expression in the brain of the rat. Endocrinology. 2007;148(4): 1774-1783. 76. Zeydabadi Nejad S, Ramezani Tehrani F, Zadeh-Vakili A. The role of kisspeptin in female reproduction. Int J Endocrinol Metab. 2017;15:1- 11, e44337. 77. Sorensen K, Aksglaede L, Petersen JH, Juul A. Recent changes in pubertal timing in healthy Danish boys: associations with body mass index. J Clin Endocrinol Metab. 2010;95(1):263-270. 78. Juul A, Magnusdottir S, Scheike T, Prytz S, Skakkebaek NE. Age at voice break in Danish boys: effects of pre-pubertal body mass index and secular trend. Int J Androl. 2007;30(6):537-542. 79. Lee JM, Wasserman R, Kaciroti N, et al. Timing of puberty in overweight versus obese boys. Pediatrics. 2016;137(2):137-146, e20150164. 80. He F, Guan P, Liu Q, Crabtree D, Peng L, Wang H. The relationship between obesity and body compositions with respect to the timing of puberty in Chongqing adolescents: a cross-sectional study. BMC Pub- lic Health. 2017;17:664-673. 81. Ishikawa T, Fujioka H, Ishimura T, Takenaka A, Fujisawa M. Expres- sion of leptin and leptin receptor in the testis of fertile and infertile patients. Andrologia. 2007;39(1):22-27. 82. Martins AD, Moreira AC, Sa R, et al. Leptin modulates human Sertoli cells acetate production and glycolytic profile: a novel mechanism of obesity-induced male infertility? Biochim Biophys Acta. 1852;2015: 1824-1832. 83. Morash BA, Willkinson D, Ur E, Wilkinson M. Resistin expression and regulation in mouse pituitary. FEBS Lett. 2002;526(1-3):26-30. 84. Cabrera SM, Bright GM, Frane JW, Blethen SL, Lee PA. Age of thelarche and menarche in contemporary US females: a cross- sectional analysis. Journal of pediatric endocrinology & metabolism: JPEM. 2014;27(1-2):47-51. 85. Herman-Giddens ME, Steffes J, Harris D, et al. Secondary sexual characteristics in boys: data from the Pediatric Research in Office Settings Network. Pediatrics. 2012;130(5):e1058-e1068. 86. WHO. Physical status: the use and interpretation of anthropometry. Report of a WHO Expert Committee. World Health Organ Tech Rep Ser. 1995;854:1-452. 87. Akin I, Tolg R, Hochadel M, et al. No evidence of “obesity paradox” after treatment with drug-eluting stents in a routine clinical practice: results from the prospective multicenter German DES.DE (German Drug-Eluting Stent) Registry. JACC Cardiovasc Interv. 2012;5(2): 162-169. 88. Marcovecchio ML, Chiarelli F. Obesity and growth during childhood and puberty. World Rev Nutr Diet. 2013;106:135-141. How to cite this article: Nieuwenhuis D, Pujol-Gualdo N, Arnoldussen IAC, Kiliaan AJ. Adipokines: A gear shift in puberty. Obesity Reviews. 2020;21:e13005. https://doi.org/ 10.1111/obr.13005 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are gover
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