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English Project By Rehab Manna
Quiz by Rehab Alshammari
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“to destroy something completely”
C) prohibit
A) ruin
B) shot
“The law will ____ smoking in public places.”
A) ruin
C) prohibit
B) shot
Give this quiz to my class
“to destroy something completely”
“The law will ____ smoking in public places.”
“The police tried to ____ the thief.”
“He is always ____ his new car.”
“I will give it a ____ and try.”
They will build a new hospital next year. A. A new hospital will be built next year by them. B. A new hospital will build next year by them. C. A new hospital is built next year by them. D. A new hospital was built next year by them. The teacher explained the lesson carefully. A. The lesson was explained carefully by the teacher. B. The lesson is explained carefully by the teacher. C. The lesson was explaining carefully by the teacher. D. The lesson explained carefully by the teacher. People speak English all over the world. A. English is spoken all over the world. B. English speaks all over the world. C. English was spoken all over the world. D. English has been spoken all over the world. She is writing a letter now. A. A letter is being written now by her. B. A letter was being written now by her. C. A letter is written now by her. D. A letter has been written now by her. They have just finished the project. A. The project has just been finished by them. B. The project was just finished by them. C. The project has just finished by them. D. The project will just be finished by them. Somebody cleans the room every day. A. The room is cleaned every day. B. The room cleans every day. C. The room was cleaned every day. D. The room is cleaning every day. The students are going to hold a meeting tomorrow. A. A meeting is going to be held tomorrow by the students. B. A meeting is going to be holding tomorrow by the students. C. A meeting was going to be held tomorrow by the students. D. A meeting is held tomorrow by the students. They had repaired the car before I came. A. The car had been repaired before I came. B. The car was repaired before I came. C. The car is repaired before I came. D. The car had repaired before I came. The government has launched a new campaign. A. A new campaign has been launched by the government. B. A new campaign was launched by the government. C. A new campaign is launched by the government. D. A new campaign has launched by the government. The chef will prepare the meal. A. The meal will be prepared by the chef. B. The meal is prepared by the chef. C. The meal was prepared by the chef. D. The meal has been prepared by the chef.ILLINOIS PROFESSIONAL TEACHING STANDARDS (2013) Standard 1 - Teaching Diverse Students – The competent teacher understands the diverse characteristics and abilities of each student and how individuals develop and learn within the context of their social, economic, cultural, linguistic, and academic experiences. The teacher uses these experiences to create instructional opportunities that maximize student learning. Knowledge Indicators – The competent teacher: 1A) understands the spectrum of student diversity (e.g., race and ethnicity, socioeconomic status, special education, gifted, English language learners (ELL), sexual orientation, gender, gender identity) and the assets that each student brings to learning across the curriculum; 1B) understands how each student constructs knowledge, acquires skills, and develops effective and efficient critical thinking and problem-solving capabilities; 1C) understands how teaching and student learning are influenced by development (physical, social and emotional, cognitive, linguistic), past experiences, talents, prior knowledge, economic circumstances and diversity within the community; 1D) understands the impact of cognitive, emotional, physical, and sensory disabilities on learning and communication pursuant to the Individuals with Disabilities Education Improvement Act (also referred to as “IDEA”) (20 USC 1400 et seq.), its implementing regulations (34 CFR 300; 2006), Article 14 of the School Code [105 ILCS 5/Art.14] and 23 Ill. Adm. Code 226 (Special Education); 1E) understands the impact of linguistic and cultural diversity on learning and communication; 1F) understands his or her personal perspectives and biases and their effects on one’s teaching; and 1G) understands how to identify individual needs and how to locate and access technology, services, and resources to address those needs. Performance Indicators – The competent teacher: 1H) analyzes and uses student information to design instruction that meets the diverse needs of students and leads to ongoing growth and achievement; 1I) stimulates prior knowledge and links new ideas to already familiar ideas and experiences; 1J) differentiates strategies, materials, pace, levels of complexity, and language to introduce concepts and principles so that they are meaningful to students at varying levels of development and to students with diverse learning needs; 1K) facilitates a learning community in which individual differences are respected; and 1L) uses information about students’ individual experiences, families, cultures, and communities to create meaningful learning opportunities and enrich instruction for all students. Standard 2 - Content Area and Pedagogical Knowledge – The competent teacher has in-depth understanding of content area knowledge that includes central concepts, methods of inquiry, structures of the disciplines, and content area literacy. The teacher creates meaningful learning experiences for each student based upon interactions among content area and pedagogical knowledge, and evidence-based practice. Knowledge Indicators – The competent teacher: 2A) understands theories and philosophies of learning and human development as they relate to the range of students in the classroom; 2B) understands major concepts, assumptions, debates, and principles; processes of inquiry; and theories that are central to the disciplines; 2C) understands the cognitive processes associated with various kinds of learning (e.g., critical and creative thinking, problem-structuring and problem-solving, invention, memorization, and recall) 2 and ensures attention to these learning processes so that students can master content standards; 2D) understands the relationship of knowledge within the disciplines to other content areas and to life applications; 2E) understands how diverse student characteristics and abilities affect processes of inquiry and influence patterns of learning; 2F) knows how to access the tools and knowledge related to latest findings (e.g., research, practice, methodologies) and technologies in the disciplines; 2G) understands the theory behind and the process for providing support to promote learning when concepts and skills are first being introduced; and 2H) understands the relationship among language acquisition (first and second), literacy development, and acquisition of academic content and skills. Performance Indicators – The competent teacher: 2I) evaluates teaching resources and materials for appropriateness as related to curricular content and each student’s needs; 2J) uses differing viewpoints, theories, and methods of inquiry in teaching subject matter concepts; 2K) engages students in the processes of critical thinking and inquiry and addresses standards of evidence of the disciplines; 2L) demonstrates fluency in technology systems, uses technology to support instruction and enhance student learning, and designs learning experiences to develop student skills in the application of technology appropriate to the disciplines; 2M) uses a variety of explanations and multiple representations of concepts that capture key ideas to help each student develop conceptual understanding and address common misunderstandings; 2N) facilitates learning experiences that make connections to other content areas and to life experiences; 2O) designs learning experiences and utilizes assistive technology and digital tools to provide access to general curricular content to individuals with disabilities; 2P) adjusts practice to meet the needs of each student in the content areas; and 2Q) applies and adapts an array of content area literacy strategies to make all subject matter accessible to each student. Standard 3 - Planning for Differentiated Instruction – The competent teacher plans and designs instruction based on content area knowledge, diverse student characteristics, student performance data, curriculum goals, and the community context. The teacher plans for ongoing student growth and achievement. Knowledge Indicators – The competent teacher: 3A) understands the Illinois Learning Standards (23 Ill. Adm. Code 1.Appendix D), curriculum development process, content, learning theory, assessment, and student development and knows how to incorporate this knowledge in planning differentiated instruction; 3B) understands how to develop short- and long-range plans, including transition plans, consistent with curriculum goals, student diversity, and learning theory; 3C) understands cultural, linguistic, cognitive, physical, and social and emotional differences, and considers the needs of each student when planning instruction; 3D) understands when and how to adjust plans based on outcome data, as well as student needs, goals, and responses; 3E) understands the appropriate role of technology, including assistive technology, to address student needs, as well as how to incorporate contemporary tools and resources to maximize student learning; 3 3F) understands how to co-plan with other classroom teachers, parents or guardians, paraprofessionals, school specialists, and community representatives to design learning experiences; and 3G) understands how research and data guide instructional planning, delivery, and adaptation. Performance Indicators – The competent teacher: 3H) establishes high expectations for each student’s learning and behavior; 3I) creates short-term and long-term plans to achieve the expectations for student learning; 3J) uses data to plan for differentiated instruction to allow for variations in individual learning needs; 3K) incorporates experiences into instructional practices that relate to a student’s current life experiences and to future life experiences; 3L) creates approaches to learning that are interdisciplinary and that integrate multiple content areas; 3M) develops plans based on student responses and provides for different pathways based on student needs; 3N) accesses and uses a wide range of information and instructional technologies to enhance a student’s ongoing growth and achievement; 3O) when planning instruction, addresses goals and objectives contained in plans developed under Section 504 of the Rehabilitation Act of 1973 (29 USC 794), individualized education programs (IEP) (see 23 Ill. Adm. Code 226 (Special Education)) or individual family service plans (IFSP) (see 23 Ill. Adm. Code 226 and 34 CFR 300.24; 2006); 3P) works with others to adapt and modify instruction to meet individual student needs; and 3Q) develops or selects relevant instructional content, materials, resources, and strategies (e.g., project-based learning) for differentiating instruction. Standard 4 - Learning Environment – The competent teacher structures a safe and healthy learning environment that facilitates cultural and linguistic responsiveness, emotional well-being, self-efficacy, positive social interaction, mutual respect, active engagement, academic risk-taking, self-motivation, and personal goal-setting. Knowledge Indicators – The competent teacher: 4A) understands principles of and strategies for effective classroom and behavior management; 4B) understands how individuals influence groups and how groups function in society; 4C) understands how to help students work cooperatively and productively in groups; 4D) understands factors (e.g., self-efficacy, positive social interaction) that influence motivation and engagement; 4E) knows how to assess the instructional environment to determine how best to meet a student’s individual needs; 4F) understands laws, rules, and ethical considerations regarding behavior intervention planning and behavior management (e.g., bullying, crisis intervention, physical restraint); 4G) knows strategies to implement behavior management and behavior intervention planning to ensure a safe and productive learning environment; and 4H) understands the use of student data (formative and summative) to design and implement behavior management strategies. Performance Indicators – The competent teacher: 4I) creates a safe and healthy environment that maximizes student learning; 4J) creates clear expectations and procedures for communication and behavior and a physical setting conducive to achieving classroom goals; 4K) uses strategies to create a smoothly functioning learning community in which students assume responsibility for themselves and one another, participate in decision-making, work collaboratively and independently, use appropriate technology, and engage in purposeful learning activities; 4 4L) analyzes the classroom environment and makes decisions to enhance cultural and linguistic responsiveness, mutual respect, positive social relationships, student motivation, and classroom engagement; 4M) organizes, allocates, and manages time, materials, technology, and physical space to provide active and equitable engagement of students in productive learning activities; 4N) engages students in and monitors individual and group-learning activities that help them develop the motivation to learn; 4O) uses a variety of effective behavioral management techniques appropriate to the needs of all students that include positive behavior interventions and supports; 4P) modifies the learning environment (including the schedule and physical arrangement) to facilitate appropriate behaviors and learning for students with diverse learning characteristics; and 4Q) analyzes student behavior data to develop and support positive behavior. Standard 5 - Instructional Delivery – The competent teacher differentiates instruction by using a variety of strategies that support critical and creative thinking, problem-solving, and continuous growth and learning. This teacher understands that the classroom is a dynamic environment requiring ongoing modification of instruction to enhance learning for each student. Knowledge Indicators – The competent teacher: 5A) understands the cognitive processes associated with various kinds of learning; 5B) understands principles and techniques, along with advantages and limitations, associated with a wide range of evidence-based instructional practices; 5C) knows how to implement effective differentiated instruction through the use of a wide variety of materials, technologies, and resources; 5D) understands disciplinary and interdisciplinary instructional approaches and how they relate to life and career experiences; 5E) knows techniques for modifying instructional methods, materials, and the environment to facilitate learning for students with diverse learning characteristics; 5F) knows strategies to maximize student attentiveness and engagement; 5G) knows how to evaluate and use student performance data to adjust instruction while teaching; and 5H) understands when and how to adapt or modify instruction based on outcome data, as well as student needs, goals, and responses. Performance Indicators – The competent teacher: 5I) uses multiple teaching strategies, including adjusted pacing and flexible grouping, to engage students in active learning opportunities that promote the development of critical and creative thinking, problem-solving, and performance capabilities; 5J) monitors and adjusts strategies in response to feedback from the student; 5K) varies his or her role in the instructional process as instructor, facilitator, coach, or audience in relation to the content and purposes of instruction and the needs of students; 5L) develops a variety of clear, accurate presentations and representations of concepts, using alternative explanations to assist students’ understanding and presenting diverse perspectives to encourage critical and creative thinking; 5M) uses strategies and techniques for facilitating meaningful inclusion of individuals with a range of abilities and experiences; 5N) uses technology to accomplish differentiated instructional objectives that enhance learning for each student; 5O) models and facilitates effective use of current and emerging digital tools to locate, analyze, evaluate, and use information resources to support research and learning; 5P) uses student data to adapt the curriculum and implement instructional strategies and materials according to the characteristics of each student; 5 5Q) uses effective co-planning and co-teaching techniques to deliver instruction to all students; 5R) maximizes instructional time (e.g., minimizes transitional time); and 5S) implements appropriate evidence-based instructional strategies. Standard 6 - Reading, Writing, and Oral Communication – The competent teacher has foundational knowledge of reading, writing, and oral communication within the content area and recognizes and addresses student reading, writing, and oral communication needs to facilitate the acquisition of content knowledge. Knowledge Indicators – The competent teacher: 6A) understands appropriate and varied instructional approaches used before, during, and after reading, including those that develop word knowledge, vocabulary, comprehension, fluency, and strategy use in the content areas; 6B) understands that the reading process involves the construction of meaning through the interactions of the reader's background knowledge and experiences, the information in the text, and the purpose of the reading situation; 6C) understands communication theory, language development, and the role of language in learning; 6D) understands writing processes and their importance to content learning; 6E) knows and models standard conventions of written and oral communications; 6F) recognizes the relationships among reading, writing, and oral communication and understands how to integrate these components to increase content learning; 6G) understands how to design, select, modify, and evaluate a wide range of materials for the content areas and the reading needs of the student; 6H) understands how to use a variety of formal and informal assessments to recognize and address the reading, writing, and oral communication needs of each student; and 6I) knows appropriate and varied instructional approaches, including those that develop word knowledge, vocabulary, comprehension, fluency, and strategy use in the content areas. Performance Indicators – The competent teacher: 6J) selects, modifies, and uses a wide range of printed, visual, or auditory materials, and online resources appropriate to the content areas and the reading needs and levels of each student (including ELLs, and struggling and advanced readers); 6K) uses assessment data, student work samples, and observations from continuous monitoring of student progress to plan and evaluate effective content area reading, writing, and oral communication instruction; 6L) facilitates the use of appropriate word identification and vocabulary strategies to develop each student’s understanding of content; 6M) teaches fluency strategies to facilitate comprehension of content; 6N) uses modeling, explanation, practice, and feedback to teach students to monitor and apply comprehension strategies independently, appropriate to the content learning; 6O) teaches students to analyze, evaluate, synthesize, and summarize information in single texts and across multiple texts, including electronic resources; 6P) teaches students to develop written text appropriate to the content areas that utilizes organization (e.g., compare/contrast, problem/solution), focus, elaboration, word choice, and standard conventions (e.g., punctuation, grammar); 6Q) integrates reading, writing, and oral communication to engage students in content learning; 6R) works with other teachers and support personnel to design, adjust, and modify instruction to meet students’ reading, writing, and oral communication needs; and 6S) stimulates discussion in the content areas for varied instructional and conversational purposes. Standard 7 - Assessment – The competent teacher understands and uses appropriate formative and summative assessments for determining student needs, monitoring student progress, measuring student 6 growth, and evaluating student outcomes. The teacher makes decisions driven by data about curricular and instructional effectiveness and adjusts practices to meet the needs of each student. Knowledge Indicators – The competent teacher: 7A) understands the purposes, characteristics, and limitations of different types of assessments, including standardized assessments, universal screening, curriculum-based assessment, and progress monitoring tools; 7B) understands that assessment is a means of evaluating how students learn and what they know and are able to do in order to meet the Illinois Learning Standards; 7C) understands measurement theory and assessment-related issues, such as validity, reliability, bias, and appropriate and accurate scoring; 7D) understands current terminology and procedures necessary for the appropriate analysis and interpretation of assessment data; 7E) understands how to select, construct, and use assessment strategies and instruments for diagnosis and evaluation of learning and instruction; 7F) knows research-based assessment strategies appropriate for each student; 7G) understands how to make data-driven decisions using assessment results to adjust practices to meet the needs of each student; 7H) knows legal provisions, rules, and guidelines regarding assessment and assessment accommodations for all student populations; and 7I) knows assessment and progress monitoring techniques to assess the effectiveness of instruction for each student. Performance Indicators – The competent teacher: 7J) uses assessment results to determine student performance levels, identify learning targets, select appropriate research-based instructional strategies, and implement instruction to enhance learning outcomes; 7K) appropriately uses a variety of formal and informal assessments to evaluate the understanding, progress, and performance of an individual student and the class as a whole; 7L) involves students in self-assessment activities to help them become aware of their strengths and needs and encourages them to establish goals for learning; 7M) maintains useful and accurate records of student work and performance; 7N) accurately interprets and clearly communicates aggregate student performance data to students, parents or guardians, colleagues, and the community in a manner that complies with the requirements of the Illinois School Student Records Act [105 ILCS 10], 23 Ill. Adm. Code 375 (Student Records), the Family Educational Rights and Privacy Act (FERPA) (20 USC 1232g) and its implementing regulations (34 CFR 99; December 9, 2008); 7O) effectively uses appropriate technologies to conduct assessments, monitor performance, and assess student progress; 7P) collaborates with families and other professionals involved in the assessment of each student; 7Q) uses various types of assessment procedures appropriately, including making accommodations for individual students in specific contexts; and 7R) uses assessment strategies and devices that are nondiscriminatory, and take into consideration the impact of disabilities, methods of communication, cultural background, and primary language on measuring knowledge and performance of students. Standard 8 - Collaborative Relationships – The competent teacher builds and maintains collaborative relationships to foster cognitive, linguistic, physical, and social and emotional development. This teacher works as a team member with professional colleagues, students, parents or guardians, and community members. Knowledge Indicators – The competent teacher: 8A) understands schools as organizations within the larger community context; 7 8B) understands the collaborative process and the skills necessary to initiate and carry out that process; 8C) collaborates with others in the use of data to design and implement effective school interventions that benefit all students; 8D) understands the benefits, barriers, and techniques involved in parent and family collaborations; 8E) understands school- and work-based learning environments and the need for collaboration with all organizations (e.g., businesses, community agencies, nonprofit organizations) to enhance student learning; 8F) understands the importance of participating on collaborative and problem-solving teams to create effective academic and behavioral interventions for all students; 8G) understands the various models of co-teaching and the procedures for implementing them across the curriculum; 8H) understands concerns of families of students with disabilities and knows appropriate strategies to collaborate with students and their families in addressing these concerns; and 8I) understands the roles and the importance of including students with disabilities, as appropriate, and all team members in planning individualized education programs (i.e, IEP, IFSP, Section 504 plan) for students with disabilities. Performance Indicators – The competent teacher: 8J) works with all school personnel (e.g., support staff, teachers, paraprofessionals) to develop learning climates for the school that encourage unity, support a sense of shared purpose, show trust in one another, and value individuals; 8K) participates in collaborative decision-making and problem-solving with colleagues and other professionals to achieve success for all students; 8L) initiates collaboration with others to create opportunities that enhance student learning; 8M) uses digital tools and resources to promote collaborative interactions; 8N) uses effective co-planning and co-teaching techniques to deliver instruction to each student; 8O) collaborates with school personnel in the implementation of appropriate assessment and instruction for designated students; 8P) develops professional relationships with parents and guardians that result in fair and equitable treatment of each student to support growth and learning; 8Q) establishes respectful and productive relationships with parents or guardians and seeks to develop cooperative partnerships to promote student learning and well-being; 8R) uses conflict resolution skills to enhance the effectiveness of collaboration and teamwork; 8S) participates in the design and implementation of individualized instruction for students with special needs (i.e., IEPs, IFSP, transition plans, Section 504 plans), ELLs, and students who are gifted; and 8T) identifies and utilizes community resources to enhance student learning and to provide opportunities for students to explore career opportunities. Standard 9 - Professionalism, Leadership, and Advocacy – The competent teacher is an ethical and reflective practitioner who exhibits professionalism; provides leadership in the learning community; and advocates for students, parents or guardians, and the profession. Knowledge Indicators – The competent teacher: 9A) evaluates best practices and research-based materials against benchmarks within the disciplines; 9B) knows laws and rules (e.g., mandatory reporting, sexual misconduct, corporal punishment) as a foundation for the fair and just treatment of all students and their families in the classroom and school; 9C) understands emergency response procedures as required under the School Safety Drill Act [105 ILCS 128/1], including school safety and crisis intervention protocol, initial response 8 actions (e.g., whether to stay in or evacuate a building), and first response to medical emergencies (e.g., first aid and life-saving techniques); 9D) identifies paths for continuous professional growth and improvement, including the design of a professional growth plan; 9E) is cognizant of his or her emerging and developed leadership skills and the applicability of those skills within a variety of learning communities; 9F) understands the roles of an advocate, the process of advocacy, and its place in combating or promoting certain school district practices affecting students; 9G) understands local and global societal issues and responsibilities in an evolving digital culture; and 9H) understands the importance of modeling appropriate dispositions in the classroom. Performance Indicators – The competent teacher: 9I) models professional behavior that reflects honesty, integrity, personal responsibility, confidentiality, altruism and respect; 9J) maintains accurate records, manages data effectively, and protects the confidentiality of information pertaining to each student and family; 9K) reflects on professional practice and resulting outcomes; engages in self-assessment; and adjusts practices to improve student performance, school goals, and professional growth; 9L) communicates with families, responds to concerns, and contributes to enhanced family participation in student education; 9M) communicates relevant information and ideas effectively to students, parents or guardians, and peers, using a variety of technology and digital-age media and formats; 9N) collaborates with other teachers, students, parents or guardians, specialists, administrators, and community partners to enhance students’ learning and school improvement; 9O) participates in professional development, professional organizations, and learning communities, and engages in peer coaching and mentoring activities to enhance personal growth and development; 9P) uses leadership skills that contribute to individual and collegial growth and development, school improvement, and the advancement of knowledge in the teaching profession; 9Q) proactively serves all students and their families with equity and honor and advocates on their behalf, ensuring the learning and well-being of each child in the classroom; 9R) is aware of and complies with the mandatory reporter provisions of Section 4 of the Abused and Neglected Child Reporting Act [325 ILCS 5/4]; 9S) models digital etiquette and responsible social actions in the use of digital technology; and 9T) models and teaches safe, legal, and ethical use of digital information and technology, including respect for copyright, intellectual property, and the appropriate documentation of sources. Received: 26 November 2019 Revised: 10 January 2020 Accepted: 19 January 2020 DOI: 10.1111/obr.13005 PEDIATRICS/PHYSIOLOGY Adipokines: A gear shift in puberty Desirée Nieuwenhuis | Natàlia Pujol-Gualdo Amanda J. Kiliaan Department of Anatomy, Radboud university medical center, Donders Institute for Brain, Cognition and Behaviour, Preclinical Imaging Center PRIME, Nijmegen, The Netherlands Correspondence Amanda J. Kiliaan, PhD, Associate Professor, Department of Anatomy, Donders Institute for Brain, Cognition, and Behaviour, Preclinical Imaging Center PRIME, Radboud university medical center, 6500 HB Nijmegen, Geert Grooteplein 21N 6525 EZ Nijmegen, The Netherlands. Email: amanda.kiliaan@radboudumc.nl Funding information Europees Fonds voor Regionale Ontwikkeling (EFRO), Grant/Award Number: BriteN 2016 1 | INTRODUCTION The prevalence of obesity in adolescents and children is increasing in | Ilse A.C. Arnoldussen | Summary In this review, we discuss the role of adipokines in the onset of puberty in children with obesity during adrenarche and gonadarche and provide a clear and detailed overview of the biological processes of two major players, leptin and adiponectin. Adipokines, especially leptin and adiponectin, seem to induce an early onset of puberty in girls and boys with obesity by affecting the hypothalamic-pituitary- gonadal (HPG) axis. Moreover, adipokines and their receptors are expressed in the gonads, suggesting a role in sexual maturation and reproduction. All in all, adipokines may be a clue in understanding mechanisms underlying the onset of puberty in child- hood obesity and puberty onset variability. KEYWORDS adipokines, obesity, puberty 1,2 the age of 5 years were overweight or were with obesity in 2016, and 3 Obesity is defined by an excessive accumulation of white adipose tissue (WAT), and it is often indicated by a body mass index (BMI) 4 above 30. Two main types of adipose tissue were described: WAT and brown adipose tissue (BAT), which differ in morphology and func- 5-7 Ilse A.C. Arnoldussen and Amanda J. Kiliaan contributed equally to this work. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2020 The Authors. Obesity Reviews published by John Wiley & Sons Ltd on behalf of World Obesity Federation Obesity Reviews. 2020;21:e13005. wileyonlinelibrary.com/journal/obr 1 of 10 https://doi.org/10.1111/obr.13005 alarming rates. Specifically, worldwide, 41 million children below this number is expected to increase to 70 million in 2025. obesity is associated with various severe health complications, includ- ing increased risk of diabetes mellitus type 2, hypertension, heart dis- eases, and disturbances in sex hormone levels. 5,6 and mitochondria and plays a role in thermogenesis. Adipocytes in tion. BAT consists of adipocytes containing multiple lipid droplets WAT contain only a few mitochondria and a single lipid droplet. Adipose tissue has several functions including the storage of energy, thermogenesis, and the production and secretion of adipokines Generally, two physiological processes, adrenarche and gonadarche, 11,24 Childhood 5,7,8 a key role in puberty onset. Puberty is known as a period through which the body changes physically, being a physiological process resulting in the maturation of children, i.e. they develop sexual characteristics and obtain reproduc- 9,11 Adipokines are involved in a number of physiological processes including blood pressure, metabo- lism, glucose, and vascular homeostasis and may play amongst others 8-10 (hormones, cytokines, and peptides). tive functions. between obesity and puberty,2,12-23 the biological mechanisms under- lying obesity and puberty onset remain unclear. Hereafter, we review in detail the role of adipokines in the onset of puberty in childhood obesity. Although many studies have shown associations 2 | INITIATION OF PUBERTY PHYSIOLOGICAL PROCESSES IN THE interact to regulate the onset of puberty. During adrenarche, the adrenal cortex secretes steroid hormones (including 2 of 10 NIEUWENHUIS ET AL. androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate (DHEAS), androstenedione, and cortisol), insulin-like growth factor, and growth hormone, which contribute to the pubertal insights on new genetic loci (e.g. melanocortin-4 receptor, mitochon- drial carrier 2, and mitogen-activated protein kinase 13) and on sev- eral pathways that regulate the timing of puberty; however, it partly 34 9,24,25 Both adrenarche and gonadarche are involved in the development growth spurt, body odor, skin oiliness, and skeletal maturation. explains puberty timing variation. Thereby, defining the role of 25 adipokines is of importance in elucidating the variability in puberty as the expression of adipokines is sex-specific and is altered with body composition, adiposity, and during growth spurts. Moreover, adipokines and their receptors are expressed in gonads and several brain regions suggesting involvement in the onset of puberty and sex- ual maturation. Lastly, adipokines interfere in processes regulating timing and duration of puberty, for instance in the HPA and HPG axes which are both key players during adrenarche and gonadarche. Involvement of adipokines in the onset of puberty and specifically in individuals with obesity will be further reviewed in the next 2,24 3 | Puberty onset in girls is assessed using different markers, such as thelarche (breast development), menarche (the start of of pubic hair. pituitary-gonadal (HPG) axis is activated,2,26 and several hormones have been identified to participate in the activation of the HPG axis During gonadarche (Figure 1), the hypothalamic- 2,27 Kisspeptin, neurokinin B, and dynorphin are released by specialized including kisspeptin, neurokinin B, dynorphin, leptin, and ghrelin. 28 key regulator of the pulsatile secretion of gonadotropin releasing neurons, the KNDy neurons in the hypothalamus. Kisspeptin is a 29,30 B stimulates, and dynorphin inhibits the release of kisspeptin, which hormone (GnRH) from the hypothalamus. In addition, neurokinin implies that both coordinate a pulsatile release of kisspeptin. 31 Sub- sections. sequently, the activated HPG axis induces the pituitary gland to secrete luteinising hormone (LH) and follicle stimulating hormone (FSH). As a result, gametogenesis occurs, and the gonads will release sex hormones. Consequently, secondary sex characteristics develop including breast development in girls and an increased testicular vol- 2,26,32 is possibly due to differences in levels of body fat, hypothalamic-pitui- THE ONSET OF PUBERTY IN GIRLS ume in boys. The age at puberty onset varies greatly among individuals, which 19 35 menstruation), and pubic hair development. 33 genome-wide association studies have provided important new tary-adrenal (HPA) axis activity, and genetic background. Recent The average age of However, this age differs between cultures and ethnicities, and since 1980, age at menarche is girls at start of menarche is 12.4 years. 36 significantly decreasing. 36-39 F I G U R E 1 Hormonal regulation in the initiation of puberty in boys and girls. The secretion of kisspeptin, neurokinin B, and dynorphin from KNDy neurons initiate the release of gonadotropin releasing hormone (GnRH) from the hypothalamus. This activates the pituitary gland to produce and secrete luteinising hormone (LH) and follicle stimulating hormone (FSH), which in turn stimulate the gonads to produce estrogen and testosterone in girls and boys, respectively 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License NIEUWENHUIS ET AL. 3 of 10 T A B L E 1 Summary of included studies Authors Year Country Study Design Primary Outcome Sex Sample Size (n) Age (y) Data Collection Lian et al21 2019 China Cross-sectional Puberty starts earlier in Chinese Han girls with obesity compared with Chinese Han girls with normal weight. Girls 2996 9-19 2012 and 2013 Biro et al12 Lazzeri et al20 2018 USA 2018 Italy Longitudinal Cross-sectional Body mass index had a greater effect on age at menarche than did race and ethnicity. Girls 946 6-16 2004-2014 Li et al23 2018 China Longitudinal For both, boys and girls, a higher BMI (ie, overweight and obese) is associated with earlier onset of puberty Girls Girls Boys Girls 542 Deng et al22 Flom et al15 2017 China Cross-sectional Increased BMI is associated with early timing spermarche and menarche. Boys Girls Girls 1278258 9-15 2005-2012 He et al24 Holmgren et al17 2017 China 2017 Sweden Cross-sectional Longitudinal Onset of puberty is not related to obesity in boys. Boys Boys Girls Girls 782 7-17 972 929 5839 Kelly et al19 2017 UK 2016 Brazil 2016 USA Longitudinal prospective cohort Higher BMI in girls is associated with the onset of menstruation at an earlier age. 11 10-18 11-17 Barcellos Gemelli et al25 Cross-sectional Longitudinal Excess weight is associated with early age of menarche. Girls 727 2014 2003-2009 Glass et al16 Lee et al26 In girls, but not in boys, greater adiposity is associated with the earlier onset of puberty. Boys Girls 135 Cabrera et al27 Leonibus et al14 2014 USA 2013 Italy Cross-sectional Longitudinal Thelarche occurred earlier than recently reported, while age of menarche remained unchanged. Girls 610 3-17.9 2007 2005-2012 Currie et al13 2012 Europe, USA, Canada Cross-sectional Overweight/obesity during childhood predicts the early onset of puberty in girls. Girls 20410 11, 13, 15 2005-2006 2017 USA Prospective birth cohort Overweight/obese status at the age of 7 ye was associated with increased risk of early menarche 788 From birth to menarche occurred Pregnancies 1959-1966 2016 USA Cross-sectional Boys with overweight enter puberty earlier compared with boys with normal weight or obesity, while puberty starts later in boys with obesity compared with boys with normal weight and overweight. Boys 3872 6-16 2005-2010 Overweight during childhood shows a relation with the early onset of puberty in girls. 6535 4259 695 11 15 5.8-12.2 2009/2010 2013/2014 2014-2017 Higher BMI during childhood is associated with early puberty. 2008 and 2009 2000-2002 Obesity during childhood is related to the earlier onset of puberty. Boys Girls 84 123 71 (Continues) 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 4 of 10 NIEUWENHUIS ET AL. 3.1 | Fat storage For the initiation of puberty, the timing of stimulation and/or inhibi- tion of different hormones is important, and additionally, a certain amount and distribution of body fat is needed in order to start menar- che, which emphasizes the importance of body fat. From an evolution- ary point of view, body fat increases in mammalian females during puberty onset, and it highlights the need to guarantee a healthy preg- 40 women with anorexia nervosa. particularly body fat localized predominantly on the gluteofemoral fat depots, is profoundly associated with start of menarche, more than nancy, offspring, and maternal survival. fat, sex-hormones, and neuroendocrine alterations can evolve in men- strual dysfunction, for instance, in women with severe obesity or in 41-43 44-46 to gluteofemoral fat depots suggesting that leptin may convey infor- amount of total body fat. mation on body fat distribution to the hypothalamus during puberty. An improper level of body Importantly, body fat distribution, Blood leptin levels are strongly related 45 3.2 | HPG axis The HPG axis is activated by the release of kisspeptin resulting in the release of GnRH from the hypothalamus, and LH and FSH from the pituitary gland. In girls, FSH is involved in the development of the folli- cles in the ovaries, and it promotes the secretion of estrogen. LH stim- ulates the production of androgen hormones and induces ovulation 48 9,47 the release of kisspeptin and neurokinin B, and kisspeptin thereby (Figure 1). The secretion of estrogen has an inhibitory effect on inhibits the GnRH release from the hypothalamus. pattern of GnRH is important for the regulation of the menstrual cycle. This roughly 28-day-cycle comprises several phases, including the follicular phase and luteal phase. During the follicular phase, increasing levels of FSH stimulate the maturation of follicles and the production of estrogen from the ovaries. This in turn inhibits the release of FSH from the pituitary gland. A high level of estrogen will induce the production of LH by the pituitary gland, resulting in ovula- tion. The matured follicle secretes progesterone thereby inhibiting the release of GnRH. When the corpus luteum is demolished, there is less 48 3.3 | Adipokines According to results from studies reported in Table 1, girls with obe- sity enter puberty earlier compared with girls with normal higher leptin concentrations inhibit the intake of food and increases inhibition of GnRH. As a consequence, the cycle will start again. whole process, starting from the activated HPG axis, results in the development of the secondary sex characteristics in girls including 9,47 thelarche and menarche. 13,14,16-23,49-51 weight. these girls might be found in the secretion of adipokines. For instance, leptin is positively associated with the amount of body fat. Generally, energy expenditure. 9,52-54 An explanation for the early onset of puberty in The expression This TABLE 1 (Continued) Authors Year Country Study Design Primary Outcome Sample Sex Size (n) Age (y) Data Collection Herman-Giddens et al28 2012 USA Cross-sectional Observed mean ages of beginning genital and pubic hair growth and early testicular volumes were earlier than in past studies, depending on the characteristic and race/ethnicity. Boys 4131 6-16 2005-2010 Sorensen et al29 Aksglaede et al30 2010 2009 Denmark Denmark Cross-sectional/longitudinal Longitudinal Puberty onset at earlier ages was associated with an increased BMI in boys. Boys 1528 5.8-19.9 1991-1993/2006-2008 1930-1969 Juul et al31 Ribeiro et al32 2007 2006 Denmark Portugal Retrospective cohort Cross-sectional Higher BMI is associated with early voice break. 11-15 10-15 1990-1999 Kaplowitz et al18 Abbreviation: BMI, body mass USA Cross-sectional The early onset of puberty in Caucasian girls is likely related to an increased BMI. 5-12 1992-1993 2001 index. The higher BMI in boys and girls at 7 y of age, the earlier they enter puberty. Boys 21 612 Girls 135 223 Boys 463 Boys 382 Girls 437 Girls 10 750 Early sexual maturation in boys and girls is associated with overweight. 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License NIEUWENHUIS ET AL. 5 of 10 Leptin may possibly play a role in adrenarche as its plasma level increases with higher levels of body fat and as it can modulate both girls. 33 ing adrenarche. In coherence, in children with obesity, the androgen These findings suggested that lower reproductive status was associated with higher total adiponectin concentrations and that a higher reproductive status was related to higher HMW adiponectin the HPA and HPG axes. These axes are functionally integrated dur- DHEAS was positively associated with leptin levels. Nevertheless, concentrations in girls. In addition, individuals with obesity often another study showed that enhanced adrenal androgen secretion in girls with premature adrenarche was not explained by leptin or BMI 55 ated with androgen levels in girls ; however, it was not related to levels. and IL-6. TNF-α alters, and IL-6 inhibits the expression of 56 8 In addition, the adipokine adiponectin was negatively associ- 57 differences of adiponectin seem to develop during the progression of 56 adiponectin (Figure 2). Thereby, a low level of total adiponectin and/or high levels of inflammatory cytokines in individuals with obe- sity can promote the onset of puberty. Many more adipokines are secreted by WAT including omentin, 52,65-67 9,36,62,68 adrenarche in girls with Prader-Willi syndrome. Interestingly, sex puberty. adrenarche; however, both are not required factors. Thus, leptin and adiponectin might be able to influence In gonadarche, leptin can stimulate the secretion of kisspeptin, and subsequently activation of the HPG axis, which eventually increases the expression of estrogen and androstenedione in the ova- 58 2,60 65-67 The expression of these ries (Figure 2). Ob gene in WAT, resulting in the synthesis and secretion of leptin. Thus, high levels of leptin promote onset of puberty in girls via secre- tion of kisspeptin, and estrogen stimulates leptin secretion addition- ally. Moreover, adiponectin can affect the HPG axis due to the expression of adiponectin receptors in the hypothalamus, pituitary In return, estrogen stimulates the expression of the 59 gland, and gonads. onset as it inhibits the secretion of kisspeptin and GnRH in the hypo- thalamus and the release of GH and LH in the pituitary gland, and 2,60-62 52,60 63 girls with central precocious puberty (CPP). Moreover, total adiponectin had negative correlations with progression of puberty in girls (defined by Tanner stages), whereas HMW adiponectin had FIGURE 2 Adipokinesaffectingthe initiation of puberty in girls. Leptin stimulates the release of kisspeptin in KNDy neurons, which activates the hypothalamus to produce gonadotropin releasing hormone (GnRH). In response to the release of GnRH, the pituitary gland secretes follicle stimulating hormone (FSH) and luteinising hormone (LH), which stimulates the ovaries to release estrogen resulting in the formation of secondary sex characteristics in girls. Estrogen stimulates the production of leptin. Adiponectin inhibits GnRH release resulting in reduced levels of GnRH and thereby a delayed onset of puberty. TNF- α and IL-6 inhibit the production of adiponectin and therefore stimulate the onset of puberty In detail, adiponectin is a regulator of puberty thereby inhibiting the onset of puberty (Figure 2). with obesity often have low levels of adiponectin. et al. showed that total adiponectin was significantly lower, whereas high molecular weight (HMW) adiponectin was significantly higher in ment. 55 63 develop a chronic low-grade inflammatory state, which can be indi- cated by a high level of circulating inflammatory cytokines like TNF-α 64 Individuals Sitticharoon positive associations with LH levels and the progression of puberty in 63 visfatin, resistin, and chemerin. and visfatin are expressed in the ovaries. adipokines in the ovaries suggests a role within the reproductive sys- tem; however, the exact biological processes have to be examined. Thus, specifically leptin, adiponectin, and inflammatory cytokines pro- duced by WAT could be permissive key players during an early onset of puberty in girls with obesity. As an exception, HMW adiponectin seems to have a stimulatory effect on peripheral repro- ductive function as HMW is not able to cross the blood brain 63 barrier. 4 | Markers that are used to assess puberty onset in boys are THE ONSET OF PUBERTY IN BOYS spermarche, voice break, testicular volume, and pubic hair develop- 35 spermarche develop in the early stages of puberty onset, voice In women, omentin, chemerin, While pubic hair development, larger testicular volume, and 69 testicular volume increases, which occurs at an average age of break usually appears in later stages of puberty. Generally, first 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 6 of 10 NIEUWENHUIS ET AL. 11.9 years, followed by the development of pubic hair at 12.2 years of average, and lastly, boys experience spermarche around an aver- 55 related with leptin levels. Thereby, leptin plausibly has a minor impact in adrenarche in boys. Since leptin receptors are found in the hypothalamus, pituitary gland, and testes, they might be involved in the onset of puberty by affecting the HPG axis during gonadarche. Leptin stimulates the release of kisspeptin and GnRH, and as a consequence, it accelerates the onset of puberty (Table 1, Figure 3). In contrast, adiponectin inhibits the secretion of GnRH, GH, LH, and FSH therewith delaying the onset of puberty. However, adiponectin levels are generally lower in men compared with women and even lower in men with obe- age age of 13.4 years. 70 4.1 | Fat storage Many aspects of the reproductive physiology are energetically demanding,71 and therefore, an adequate energy level is necessary. In boys, a dynamic change in body composition occurs around the age of 10 to 13 years, in which they gain approximately 40% of sity. culating inflammatory cytokines. levels can stimulate the HPG axis and therewith an early onset of puberty in boys. Nevertheless, leptin can inhibit the production of tes- 72 mostly consisting of lean mass, which causes exhaustion of most of fat. Subsequently, a growth spurt follows in which they gain tissue 72 in boys, an adequate amount of body fat is important in the onset of their body fat. These alterations in amount of body fat indicate that 4.2 | Puberty in boys is initiated by the release of kisspeptin. As mentioned before, this activates the HPG axis, resulting in the release of GnRH from the hypothalamus, and consequently the release of LH and FSH 9,74 puberty. tosterone from the testes, to estrogen (Figure 3). of the development of secondary sex characteristics in boys. Additionally, leptin can affect fertility in men as it can modulate the nutritional support of spermatogenesis, and moreover, dysfunction of spermatogenesis is associated with an increased leptin level and 73 58 2,60-62 HPG axis from the pituitary gland (Figure 1). and LH stimulates the secretion of testosterone from the testes, which inhibits the release of kisspeptin from the KNDy neurons and 9,48 in men, the release of kisspeptin is more consistent, causing a con- 29,48 subsequently GnRH from the hypothalamus. receptors expressed on KNDy neurons. In humans, KNDy neurons Contrarily to women, LH-induced testosterone levels lead to the stant release of LH. development of secondary sex characteristics in boys. differences between sexes in kisspeptin release are related to a sex- specific and sex steroid-dependent kisspeptin system as estrogen and progesterone modulate kisspeptin activity through the sex-steroid 48 in the infundibular nucleus are involved in negative and positive sex- 48 tal exposure to sex steroids and result in sex-specific differences in steroid feedbacks. kisspeptin release. These sexual dimorphisms are induced by perina- 75,76 4.3 | Adipokines The association between obesity and puberty onset in boys is rather controversial compared with findings in girls. Most studies reported an early onset of puberty in boys associated with increased ate adipose tissue from actual breast tissue. stages are more difficult to assess than female stages as boys lack a more determined marker such as menarche. Thirdly, puberty onset can be indicated by the activation of the HPG axis, and the presence of these secondary sex characteristics is the result of hormonal 2 14,17,22,23,50,51,77,78 BMI, 20,49 all while others reported no associations at Current markers used 79 16,80 or a delayed onset of puberty (Table 1). The presence of excessive adipose tissue can be involved in puberty onset in boys as the secretion of adipokines can modulate both adrenarche and gonadarche. Leptin can affect adrenarche by modulating both the HPG and HPA axes,33 and moreover, androgen levels were positively 55 nal androgen secretion in boys with premature adrenarche was not associated with plasma leptin levels. Nevertheless, enhanced adre- 9 In more detail, 61,62 adiponectin, and individuals with obesity often have high levels of cir- Moreover, inflammatory cytokines, TNF-α, and IL-6, inhibit expression of the leptin receptor in the testis. FSH induces spermatogenesis, too. function and role still have to be examined. 64 High leptin and low adiponectin and fat tissue can convert testosterone Both processes might result in the delay 29,61,79 81,82 In men, other adipokines like chemerin are found in the gonads 65 Thus, particularly high leptin and low adiponectin levels stimulate the HPG axis and thereby accelerate the onset of puberty in boys. Additionally, leptin can dysregulate the development of secondary sex characteristics and spermatogenesis by affecting testosterone levels and nutritional sup- port of spermatogenesis. 5 | LIMITATIONS AND FUTURE RESEARCH DIRECTIONS Even though multiple epidemiological studies have shown the link between puberty onset and obesity, there are some important limita- tions. Firstly, determining both the onset and stage of puberty is rather difficult. For instance, assessing the stage of breast develop- ment in girls with obesity is complicated as clinicians should differenti- 2 changes in response to the activated HPG axis. to determine the onset of puberty refer to secondary sex characteris- tics, such as testicular volume in boys and breast development in girls. A more accurate measurement of puberty onset would be to combine secondary sex characteristics with plasma or serum hormone level measurements such as LH, FSH, adipokines, e.g. leptin. Thereby, differences in puberty measurements could explain variations in the age of puberty onset between boys and girls within different Thereby, resistin is expressed in the testes of rats, but its exact 83 Secondly, male pubertal 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License NIEUWENHUIS ET AL. 7 of 10 FIGURE 3 Adipokines affecting the initiation of puberty in boys. Leptin activates kisspeptin secretion in KNDy neurons, this activates the production of gonadotropin releasing hormone (GnRH) from the hypothalamus. GnRH stimulates the pituitary gland to secrete follicle stimulating hormone (FSH) and luteinising hormone (LH), activating the production of testosterone from the testes allowing the development of secondary sex characteristics. Leptin also inhibits the production of testosterone, which may cause a delayed onset of puberty. Adiponectin inhibits GnRH release. Low levels of adiponectin, as a result of TNF-α and IL-6 expression, lead to a reduced inhibition of GnRH. In response to GnRH release, the pituitary gland will secrete FSH and LH, and the testes will produce testosterone resulting in the development of secondary sex characteristics in boys countries, and In addition, the inclusion of a of puberty. ferent time points is complicated, as subjects examined several decades ago presented pronounced differences concerning lifestyle patterns such as nutrition and exercise habits. Lastly, obesity or over- weight is often determined by BMI, a classification based on weight and height measurements. Additionally, it is important that all studies studies or across continents, ethnicities proper age range (8-16 years) is important when assessing the onset (Figure 4). 12-15,17,20-23,49,77-79,84,85 30,47 Furthermore, comparison between studies from dif- 86 Specifically in children, BMI is often dependent on age and growth use the same anthropometric standards and sex-specific cut-offs. 13,14,16-23,49-51,77-80 fat and would represent a more accurate measurement in its regard. Based on this review, several suggestions can be made for further research. Firstly, the roles of adipokines like resistin, chemerin, visfatin, and omentin in puberty onset, fertility, and sexual maturation should be examined in detail. Secondly, future research examining the onset of puberty should combine indicators of puberty onset (e.g. breast development or testicular volume) with plasma or serum hor- mone measurements such as LH, FSH, sex-steroids, adipokines (e.g. spurts. ment in case of growth spurts. distribution of body fat should be taken into account in determining puberty and obesity in children. For instance, the body adiposity index (BAI), which was introduced in 2011 by Bergman et al.,87 uses hip cir- cumference and height in order to estimate the percentage of body 87 Thereby, BMI is a less accurate measure- F I G U R E 4 87,88 Therefore, both percentage and Average age of puberty onset in Europe, China, and the United States according to several studies from Table 1. Age of puberty onset ranges from 8.47 to 13.33 years in girls and from 8.63 leptin), and body fat distribution (e.g. BAI,87 waist-hip ratio's and/or dual-energy X-ray absorptiometry (DXA)2). Additionally, defining con- sistent and general measurements of puberty in both boys and girls, combined with a proper age range (8-16 years), would facilitate the comparisons between different studies and their results. 12-15, 17, 20-23, 25-29, 31 to 13.7 years in boys. included if average age of markers used to assess puberty was not reported. Pink: girls. Blue: boys Studies (Table 1) were not 39, 56 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 8 of 10 NIEUWENHUIS ET AL. 6 | CONCLUSION In conclusion, epidemiological data regarding obesity and puberty onset in girls show similar outcomes as adiposity results in the early onset of puberty in girls. The majority of the studies examining boys with obesity indicate an early onset of puberty, while not all reported an earlier onset of puberty. In detail, high leptin, TNF-α, and IL-6 levels combined with low adiponectin levels stimulate the activation of the HPG axis in girls and boys with obesity, and 5, 45, 50, 51 REFERENCES 1. Kumar S, Kelly AS. Review of childhood obesity: from epidemiology, etiology, and comorbidities to clinical assessment and treatment. May- o Clin Proc. 2017;92(2):251-265. 2. Reinehr T, Roth CL. Is there a causal relationship between obesity and puberty? The Lancet Child & adolescent health. 2019;3(1):44-54. 3. WorldHealthOrganization. Facts and figures on childhood obesity. 2017. 4. Guglielmi V, Sbraccia P. Obesity phenotypes: depot-differences in adipose tissue and their clinical implications. Eat Weight Disord. 2018; 23(1):3-14. 5. Gomez-Hernandez A, Beneit N, Diaz-Castroverde S. Escribano O. 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FUNDING INFORMATION This research was funded by Europees Fonds voor Regionale Ontwikkeling (EFRO), project BriteN 2016. ORCID Ilse A.C. Arnoldussen Amanda J. Kiliaan https://orcid.org/0000-0002-7395-5284 https://orcid.org/0000-0002-2158-6210 13, 14, 16-26, 29-32 Furthermore, several receptors Nevertheless, We conclude Search strategy We searched PubMed for articles published before Novem- ber 15th, 2019 using relevant keywords, including ‘onset of puberty and adiposity/obesity’, ‘onset of puberty’, ‘children with obesity’, ‘adipose tissue’, ‘childhood obesity’, ‘adiposity’, ‘obesity’, ‘adipokine(s)’, ‘HPG axis’, ‘adipokines ovary/ova- ries’, or ‘adipokines testes’, either alone or in combination. 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Obesity Reviews. 2020;21:e13005. https://doi.org/ 10.1111/obr.13005 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are goverThe Revolt of the Northern Earls (1569) Most people in the North remained loyal to the Catholic noble families who controlled the north and their Catholic faith. When Elizabeth came to power, she promoted ‘new men’ (Protestants) from the gentry and the powerful Catholic nobles lost their power and influence. This led them to organise the most serious rebellion of Elizabeth’s reign in 1569. Why did the Northern Earl’s revolt? The Earls had lost their power when Elizabeth became Queen (and wanted it back). They wanted Catholicism restored in England (and felt that ordinary Catholics would support it). Elizabeth was refusing to marry or to name an heir, causing uncertainty about England’s future. Mary Queen of Scots (if freed from prison) could replace Elizabeth and solve all these problems Who were the key players in the Revolt? Earl of Northumberland • A Catholic who had held an important position under Mary I. • He lost a lot of influence under Elizabeth (as she favoured Protestant gentry) • Elizabeth also took the rights to a valuable copper mine found on his lands Earl of Westmorland • From a rich Catholic family in the north Also the Duke of Norfolk’s brother in law Duke of Norfolk • England’s most senior Protestant noble, but he had very close links to old northern Catholic families, & was sympathetic to them & greedy for power. • He hated William Cecil & Robert Dudley, Earl of Leicester (Elizabeth’s favourite) who were Protestant and from the gentry • He planned to marry Mary QS, but later backed down and urged the earls to call off the rebellion. Mary also supported the plan to marry him What role did religion play? (7/10 – but only because it was linked to power) • Most northerners held onto their Catholic beliefs & although Elizabeth didn’t persecute them, they knew that she wanted their religion to gradually die out, so they supported the revolt. • In 1561 Elizabeth hired a strict Protestant as archbishop of Durham to promote Protestantism in the north, but he was unpopular & turned many northerners against the Protestant religion. What role did politics/power play? (9/10 – this was the most important cause of the revolt) • The Northern Earls lost a lot of their power/influence (even jobs/money under Elizabeth) • Northumberland was jealous of new Protestant families being given top jobs in the North • William Cecil & Robert Dudley were not from ancient noble families, but were very close to the Queen, so the northern Earls resented them getting top jobs in her Government • Elizabeth also confiscated large areas of land & the profits from their copper mines • It is possible, that had Elizabeth allowed the Catholic Northern Earls to keep their jobs, money and influence at court, they may have ‘tolerated’ her as a Protestant Queen (greedy/selfish). What role did Mary Queen of Scots and the Succession play? • Elizabeth was refusing to name an heir and it was becoming clear that she would not marry • If Mary Queen of Scots married the Duke of Norfolk, England would have an heir and England would be Catholic again. The country would be stable without people competing for power. • However, some of Elizabeth’s courtiers got worried that it might not work and that it might lead to charges of treason (punishable by death) • So by September 1569, Robert Dudley (Earl of Leicester) decided to tell Elizabeth about the plot. By this time it was much more serious than simply marrying Norfolk to Mary. • Mary QS had secretly asked Spain to send troops to help the rebellion & overthrow Elizabeth Plan for the Revolt of the Northern Earls (1569) • The Earls of Northumberland & Westmorland will raise rebel troops from their lands in the north and take control of Durham. • The rebels will then march south towards London to join with the Duke of Norfolk • 1000s of Spanish troops will land in England to support the rebel forces • The Duke of Norfolk & rebel forces will seize control of Government & overthrow Elizabeth • Mary Queen of Scots is to be freed, ready to marry the Duke of Norfolk Key Events of the Revolt • Once Elizabeth knew of the plot, Norfolk was arrested and sent to the Tower of London • The Northern Earls were worried they would be executed for their involvement and in a desperate attempt to avoid punishment, pushed ahead with the revolt • They raised an army of ordinary Catholics and took control of Durham cathedral • Catholic mass was celebrated across the north for 2 weeks. • They then headed south, to try and free Mary • Mary QSs was moved south to Coventry on the orders of Elizabeth, so she couldn’t escape • The rebellion failed as Spanish troops never arrived • Elizabeth’s friend (Earl of Sussex) had raised an army of 7,000 men to defend her throne. Results: • The rebellion was a serious threat to Elizabeth • She executed 450 rebels in the north • Northumberland was executed in 1572 & his head was put on a spike on the city gate • The Privy Council called for the Duke of Norfolk’s execution too, but Elizabeth released him. • Mary Queen of Scots was kept in prison for the next 14 years. • The failed plot also led the Pope to take action against Elizabeth • In 1570 he excommunicated Elizabeth from the Catholic Church • He also issued a Papal Bull (order) calling on all loyal Catholics to overthrow her hoping it would encourage another rebellion. • In 1571 Elizabeth called parliament to pass an Act making it treason to claim that she was not the rightful Queen and to bring in/print papal bulls in England. The Significance of the Revolt of the Northern Earls • It was the first and most serious rebellion by English Catholics against Elizabeth • Treason laws were made much harsher • It ended the influence of the powerful Catholic Earls in the North • It led to harsher treatment of Catholics, e.g. 1572 Elizabeth sent the Earl of Huntingdon (strict Protestant) to the north to carry out laws against Catholics (and suppress Catholicism). • Although Elizabeth’s brutal revenge on the rebels show how serious a threat it was, most Catholics in the north stayed loyal, but the Pope’s Papal Bull now put their loyalty in doubt There was little support for the revolt among the rest of the Catholic nobility and ordinary people. When faced with a choice between Elizabeth and their religion, most Catholics chose to support the Queen. 1569, was the last time English Catholics tried to remove Elizabeth by force. The future plots against her were always uncovered by Cecil & Walsingham, before they had a chance to get any public support. Despite this, the Northern Revolt & Papal Bull changed Elizabeth’s attitude towards Catholics who were now seen as potential traitors. From 1570, Elizabeth became less tolerant of recusants (people refusing to attend her church) & took increasingly tough measures against Catholics. The Ridolfi, Throckmorton & Babington plots • In the 1870s-80s, there were 3 Catholic plots to assassinate Elizabeth & replace her with Mary. • The plots were supported by France, Spain, the Pope and some Catholic nobles. • They reinforced the form Mary & from Catholics at home and abroad. Also the threat from Spain. The Ridolfi Plot (1571) • Ridolfi was an Italian banker living in England and a spy for the Pope. • He organised a plot to murder Eliz, marry Mary QS to the Duke of Norfolk & make her Queen. • The Pope & King Philip supported the plot & Philip told the Duke of Alba in the Netherlands to prepare 10,000 troops (but to only invade AFTER the English had overthrown Elizabeth). • The plot failed because Sir William Cecil intercepted coded letters & Norfolk was executed. • Mary was kept under closer watch. • Ridolfi was abroad when the plot was discovered and never returned to England. 1574: Catholic Priests and Priest Holes • From 1574 Catholic priests were smuggled into England to keep the religion alive. • They stayed with rich Catholic families, so Catholic families were kept under surveillance. • Catholic homes were raided – to find ‘priest holes’ where Catholic priests were hiding. • Catholic priests who were found could be hung, drawn and quartered (although not all were) • In 1581, Parliament also passed 2 new tougher laws against Catholics: • Recusants would be fined £20 (which would bankrupt most families) • Trying to convert people to Catholicism was now treason (punishable by death) The Throckmorton Plot (1583) • It aimed to assassinate Elizabeth and replace her with Mary. The French Duke of Guise (Mary’s cousin) would invade England with an army, funded by King Philip (Pope also supported it). • An Englishman, Throckmorton carried messages between Mary & Catholic plotters abroad. • Sir Walsingham (Secretary of State) uncovered the plot after his agents found the plans for the plot in Throckmorton’s house. Throckmorton confessed under torture and was executed. Significance: • The plots showed that Mary’s presence in England posed a serious threat • It also showed that France & Spain were a serious threat (& could invade) • Throckmorton’s papers showed a list of Catholic supporters in England, so the threat from English Catholics was also real • 1,000s of Catholics were imprisoned or kept under surveillance/house arrest • In 1585 another Act was passed to make helping Catholic priests punishable by death. • The Bond of Association was signed by the English nobles & gentry & forced them to promise to execute anyone who tried to overthrow the Queen. Weaknesses of the Plots The plots lacked public support & were uncovered by informers & spies before they had the chance to work King Philip was reluctant to destroy his alliance with Elizabeth (France was still a bigger rival) so is support for the plots was half-hearted, he rarely followed through on his promises to help the plotters or send an army The Babington Plot (1586) In 1586, Walsingham used his spy network to PROVE that Mary supported the Babington plot. His evidence persuaded Elizabeth to put Mary on trial & execute her for treason. • This was a plot to murder Elizabeth and put Mary on the throne • France would invade England with 60,000 men and Spain would also send an army • Babington was passing coded letters between Mary & her supporters in England & Europe. • But all of her letters were being intercepted and read by Walsingham. • Walsingham used his spies to follow every stage of the plot & had the letters decoded • One of Mary’s letters approved plans to murder the Queen and free Mary from prison • They also contained the names of 6 Catholics who planned to kill Elizabeth • They were arrested, hung, drawn and quartered for treason. • Mary had been implicated in plots before, but Elizabeth was always reluctant to execute her • But the proof found by Walsingham finally persuaded her to put Mary on trial • In October 1586, Mary was found guilty & was sentenced to death • But Elizabeth still hesitated, and did not sign the death warrant until February 1587. Significance 1) This plot was very significant because by 1585 England was effectively at war with Spain since Elizabeth had sent her army to help the Dutch Protestants fight the Spanish 2) This meant that Elizabeth’ situation was more dangerous than during previous plots. 3) Elizabeth’s government also became more determined to crush Catholicism 4) 1000s of recusants were arrested & 31 priests were executed 5) Mary’s execution removed the Catholic threat at home 6) English Catholics had no one to rally around, & lost hope of overthrowing Elizabeth 7) But Mary’s death increased the threat of a foreign invasion as England was at war with Spain and King Philip had been preparing an attack on England since 1585 8) Mary’s death made Philip even more determined to invade, Mary had left her claim to the English throne to King Philip upon her death Why was Mary Queen of Scots finally executed? 1 • A new Act in 1585 stated that in the event of Elizabeth’s assassination, Mary could be executed as long as she had been proved guilty & Walsingham had provided hard proof. 2 • Another reason was that by 1587, it was clear that Philip was planning to invade England • There were rumours that Spanish ships had landed in Wales & that Mary had escaped. This convinced Elizabeth that Mary had to be executed if she wanted to keep her throne. Walsingham’s Spy Network: • Walsingham (Secretary of State from 1573) had a network of spies all over England & abroad. He had spies in every English town, some were normal people paid to spy on neighbours. • He also had agents and spies in Spain, France, Germany and Italy • He hired mathematicians to crack written codes and people to open/seal letters secretly • He also pressured captured Catholic priests to spy on others for him in return for a pardon. • He used double agents to infiltrate Catholic networks - to help him discover traitors • But he only used torture against Catholic priests caught in England in the most serious cases • But 130 priests and 60 of their supporters were still executed during Elizabeth’s reign. Why did Relations with Spain get worse (1569-1588) • England had tried to stay on good terms with Spain, because Eliz wanted to avoid an expensive war that could lead to her being overthrown (English Catholics could support it) • But by the 1570s, Elizabeth wanted to have an empire of her own. • She also needed to make more money to defend her country and throne (by improving trade) • This religious, political and economic rivalry led to growing tensions between England & Spain Political and Religious Rivalry 1) Land abroad, gave countries wealth/power. By the 1580s, Eliz wanted an empire to rival Spain’s (especially as Spain had supported the Catholic plots against Eliz – even if it was half-hearted) 2) Religion was another cause of conflict. Philip opposed Elizabeth’s religious settlement 1559 3) Luckily for Elizabeth, in the 1550s Spain & France were competing to be the greatest European power and both wanted England as an ally against the other. 4) But from 1567, Spanish ships were sailing to the Netherlands with money for the Alba’s army 5) This alarmed English Protestants and Elizabeth’s Privy Council who put more and more pressure on her to send an army to help the Dutch Protestant rebels (in the Netherlands). Economic (commercial) Rivalry: The New World, privateers and Sir Francis Drake • Under Elizabeth, English merchants wanted to make big profits in the New World (Americas). • However, trading in the New World was difficult because of Spain’s power 1) Spain controlled most of the New World where there were huge profits to be made and anyone who wanted to trade there needed a licence from Spain (which it would not give): 2) But the Americas had valuable crops like tobacco, sugar, and also silver and gold 3) Elizabeth secretly encouraged privateers to trade illegally & raid Spanish ports & ships 4) At first Elizabeth denied responsibility for their actions, which delaye war with Spain Sir Francis Drake: Elizabeth sends Drake to rob Spanish colonies and ships (which infuriates Spain) 1) Spain’s support for the Ridolfi plot (1571) made her more willing to support Drake • In 1572 Eliz hired Drake to sail to the New World & steal £40,000 of Spanish silver • In 1577 she sent Drake back again with a secret mission to rob Spain’s colonies/ships • Drake brought back £400,000 of Spanish treasure & claimed an area of California in Elizabeth’s name (New Albion). He gave a lot of this money to Elizabeth • He boosted England’s finances at a time of growing concern over Spain’s threat • He became famous as the first Englishman to circumnavigate the globe. • Eliz knighted Drake as a reward, which infuriated Philip (as he saw Drake as a pirate) • Drake’s actions & his claim to California made it clear that England did not accept Spain’s domination of the New World. Elizabeth’s Support for the Dutch Rebels led to War with Spain (1585-88) • By the 1580s, tension between England & Spain had reached boiling point • At first, Eliz refused to send her army to help the Dutch rebels, because she wanted to avoid a war with Spain. So she tried to get the Spanish to leave the Netherlands in other INDIRECT ways: 1) By allowing Drake (& other English privateers) to attack and rob Spanish ships and colonies 2) By encouraging others (the French heir/mercenaries) to fight the Spanish in the Netherlands • In the 1570s, Elizabeth promised to marry the heir to the French throne (the Duke of Alencon) so that he would take an army to fight the Spanish in the Netherlands The Spanish Fury (1576) and the Pacification of Ghent (1576) • By 1576, the Spanish Govt in the Netherlands was bankrupt (the war was expensive) • After months without pay, Spain’s soldiers violently robbed Dutch towns in the “Spanish Fury” Spanish troops rebelling and robbing cities in the Netherlands in 1576. This united the Dutch Protestants & Catholics against Spain. They drew up the ‘Pacification of Ghent’ (demanding that): • Spanish troops leave the Netherlands • Spain allows the Dutch to rule themselves • The persecution of Dutch Protestants stops What did Elizabeth do? • Elizabeth sent £100,000 to help the Dutch rebels • In 1577 King Philip’s brother, Don Juan agreed to the rebels demands (but this was a trick) as just 6 months later Philip sent an even bigger army to attack the Dutch. • Elizabeth then hired a mercenary army of 6000 English & Scottish volunteers to help the Dutch. • But her plan backfired because the mercenaries destroyed Dutch Catholic churches, which caused the Catholics to make peace with Spain. • In 1578, her Privy Council urged Eliz to send her official army to help the Dutch, but she refused. The Dutch were disappointed & turned to France for help. The French Duke of Alencon arrived with an army to fight the Spanish, but by 1579 Spain had taken control again. • In 1580 Spain got even stronger after Philip won control of Portugal & its empire. • So Elizabeth gave the Duke of Alencon £70,000 to help him fight the Spanish • In 1582, Alencon took his army the Netherlands but failed to defeat Spain. • Elizabeth’s foreign policy in the Netherlands had failed & she had only managed to annoy Spain 1585: Why did Eliz finally decide to send her army to the Netherlands? (she lost her 2 main allies) • 1584 the Duke of Alencon died (so he could no longer fight the Spanish in the Netherlands) • 1 month later, William of Orange, the leader of the Dutch Protestant rebels was assassinated. • In 1585, Spain signed the Treaty of Joinville with France, agreeing to stamp out Protestantism in France/Europe meaning France & Spain were now allies against Protestantism • Elizabeth now felt she had no choice but to send her official army to the Netherlands • She signed the Treaty of Nonsuch with the Dutch rebels which promised them military help 1585: Robert Dudley’s campaign in the Netherlands was unsuccessful She sent 7,400 man army to the Netherlands led by Dudley. But he accepted the title of ‘Governor General’. Eliz was angry as it suggested that she had deposed King Philip so she told Dudley to resign this position. His army was defeated by the bigger Spanish Army as Eliz had not provided him with enough money to win. In 1587 Dudley resigned and returned to England. At the same time, Eliz had sent Drake to raid Spanish colonies in the New World to disrupt King Philip’s flow of money. Philip was furious and told the Pope he planned to invade England at the end of 1585. Drake singes the King of Spain’s beard 1587 • In 1587 Elizabeth ordered Drake to attack Spain’s most important port Cadiz • He destroyed 30 ships in 3 days – known as the ‘Singeing of the King of Spain’s Beard’ • He also stole lots of wood, meaning the Armada did not have quality barrels for food/water • Drake’s disruption delayed the Armada by a year (& meant that its food rotted in 1588). • This bought England more time to prepare for war. The Spanish Armada (1588) The Plan • By 1588, the Spanish Armada was ready to invade England • It had 130 ships with 8000 sailors & 18,000 soldiers • The Duke of Medina Sidonia would lead the Armada, but he had little experience at sea and didn’t want the job • The Armada would collect Parma’s army from France & sail to England under the protection of the Armada’s warships • Parma would march to London to depose Elizabeth & impose a Catholic government in England. 1) The Armada reached the English Channel The Armada set out in May 1588, but was delayed for a few weeks by bad weather In July the Armada was near England & signal fires were lit to warn Elizabeth English ships set sail to meet the Armada The Armada sailed up the channel in a crescent (half moon) formation, to use the large armed galleons to protect the weaker supply and army ships The English navy carried out a few minor raids, but did not inflict much damage Only 2 Spanish ships were lost (by accident) 2) The English attack the Spanish at Calais (with fire ships) and at Gravelines The Armada sailed up the English channel & anchored at Calais to wait for Parma’s army But Parma’s men didn't reach the coast in time (news had reached them too late) At midnight, the English sent 8 fireships into the Spanish ships causing panic They cut their anchors, broke formation & headed for the open sea (without Parma) The Spanish ships sailed to Gravelines, but bad weather stopped them returning to Calais The English attacked and the battle lasted many hours (5 Spanish ships were sunk) The rest were forced to sail away from France towards Scotland The English ships followed them to make sure they didn’t come back to collect Parma’s army 3) The Armada’s Journey back to Spain around Ireland was a disaster The Spanish called off the attack and returned to Spain around Scotland & Ireland Bad storms sank many ships and wrecked more on the Irish coast Many sailors died from starvation & disease – less than half the men made it back to Spain How did England defeat the Spanish Armada? !) Faster Ships • Years before the battle, England had started building smaller, faster ships (galleons) that could fire canon balls quicker & further than Spanish ships • Spanish ships were huge and slow to change direction. 2) Bad Planning & Communication (Spanish) • Philip’s plan to join with the Duke of Parma’s army in France was risky. • Parma had lots of small ships which took 48 hours to load, man and set sail. • It took too long (a week) for word to reach Parma that Medina was in the English Channel, by which time Medina had set sail to Calais. • Parma was not ready to set sail & the English were already ready to attack (leaving Medina with very little back up when anchored in France). 2) English Tactics were more effective • Spanish ships aimed to come alongside the English ones, jump on board & fight the enemy. But the English ships were faster & kept a safe distance. • They chased the Armada down the Channel, with heavy cannon fire, which forced the Spanish to arrive in France before Parma’s army was ready • As the Armada was waiting, the English sent fireships into the Spanish fleet. • This caused the Armada to panic, cut their anchors & sail away to the north • When the Spanish ships regrouped, the English attacked them in the Battle of Gravelines & the Armada was forced to sail north, chased by faster ships. 5) Bad Weather • Strong winds made it impossible for the Armada to return & pick up Parma’s army and storms wrecked or sunk Spanish ships as they tried to return home along the Scottish-Irish coasts. 2) Spanish Supplies • The Armada was not well supplied with food/weapons. Drake’s attack on Cadiz port in 1587 had destroyed food barrels. Delays in setting sail meant that by the time the English attacked the Armada it had been at sea for 10 weeks and had rotting food. 1000s died from starvation/disease. The consequences of the English victory? • Victory over the Spanish Armada gave Elizabeth a great propaganda victory • A new portrait was made, and a medal was made to commemorate her victory, it said “God blew and they were scattered”. • Elizabeth claimed that God was on the side of Protestantism • This led to a feeling of English pride and encouraged the Dutch rebels to renew their fight against the Spanish • The defeat of the Armada showed the strength of the English navy and gave England the confidence to trade and explore more widely at sea • Although Philip did not give up and continued the war for the rest of Elizabeth’s reign, the defeat had cost Spain dearly, both financially and in terms of its power • The Armada marked the start of a long decline in Spain’s power and fortunes. • English ships were sent on voyages of discovery and set up valuable new trade routes • By the end of Elizabeth’s reign, the navy was also trying to set up a new colony in Virginia • The English victory boosted Elizabeth’s popularity & strengthened the Protestant causeEnglish project English Project- Past TensesEnglish Project - BrazilEnglish Project "Rehab Manna Alabdala"