Loading...
Exercises to determine if it is a syntax or semantic error in programming
Quiz by Carlos Alberto Iriarte Martinez
Customize this quiz to suit your class
Instantly translate to 100+ languages
Tag the questions with any skills you have. Your dashboard will track each student's mastery of each skill.
Give this quiz to my class
The advantage of direct method is that the teacher can control the class and fit in a lot of activity into a short class period. This leaves plenty of opportunities for the students to hone their skills, especially new ones. On the other hand, because the class is centered around the teacher, some students may not receive proper feedback, and creativity is limited. Also, the lesser talented athletes often tend to get lost in the shuffle while the great athletes shine. However, there are now a multitude of various teaching strategies that can be employed in addition to that method. Ex: Announcements, Module/Unit introductions, Descriptions/modeling of assignments and learning activities, Written or video lectures, Demonstration videos, Presentations, Discussions moderated by instructors, Interactive tutorials. Indirect Method The Indirect Teaching Style allows students to be involved in their own learning through experience and other peer’s knowledge. Students can use critical thinking to expand their learning capabilities by seeing what others may be doing correct and adjusting this to their own knowledge. The Indirect approach is the opposite of what the direct style suggests, but they are both strictly related, meaning you can’t have one without the other. Direct teaching: The instructor stands in front of the class or group and lectures or advises. Indirect teaching: The instructor assumes a more passive role and guides the student interactions. Movement exploration: Incorporates the use of equipment that involves movement. Movement Exploration The movement exploration class is founded on developing a strong, positive association to physical activity. Classes are aimed at developing movement skills and foundational strength through fun and engaging activities. The activities are age appropriate and include games, challenges, and exploration that positively challenge children’s competency while improving their physical capabilities. Skills such as the ability to climb, hold animal shapes, gymnastic style activities, and the introduction to athletic motor skill competencies are the foundations to youth training. This class provides the introduction to strength training to give children the opportunity to learn the skills required to safely and confidently engage in resistance training. Cooperative Skills Cooperative activities teach students to work together for their group's common good. By participating in these activities, students can learn the skills of listening, discussing, thinking as a group, group decision making, and sacrificing individual wants for the common good. There are two primary objectives guiding the teaching of cooperative activities. First, cooperative activities allow students to apply a variety of fundamental motor skills in a unique setting. Students are typically asked to perform motor skills in a specific way, such as “skip in general space” or “balance on one foot and one elbow.” Cooperative activities ask students to perform different activities such as skip with their hands on the shoulders of someone in front of them, walk with big steps while placing their feet on small spots, or walk across an area blindfolded while someone directs their moves. Due to the uniqueness of such experiences, students often find cooperative activities exciting and motivating. Second, cooperative activities are a wonderful medium for teaching social and emotional learning (SEL). SEL offers students an opportunity to understand and manage their emotions. In addition, such activities offer an opportunity to show empathy for others and develop positive relationships. Cooperative activities demand that all students play a role in completing the task or solving the movement problem. Every student, regardless of ability level, is important and contributes to group goals. 9 traits a PE teacher often needs Here are nine essential traits of an effective PE teacher: 1. Athletic ability Athletic ability is an essential trait for a PE teacher because they're often showing kids how to perform exercises. To demonstrate proper form and encourage the kids to continue their fitness education, it's important they can perform the exercises themselves. Having experience with fitness training can enhance a PE teacher's lesson planning because they're familiar with how each exercise affects a person's body. Athletic ability can also refer to an aptitude for sports and games. PE teachers can instruct students on how to play these games or lead after-school activities involving them, like soccer or basketball. An aptitude for sports and games can help a PE teacher encourage students to participate in the activities during class. If the PE teacher enjoys physical activity, they may make the lessons more enjoyable for the student. 2. Teaching ability A PE teacher is a member of a school faculty, so it's essential they have the teaching ability that allows them to communicate lessons to students. There are various skills involved in teaching, including the technical capabilities associated with each professional's particular field. Learning these skills can help PE teacher plan their lessons effectively and connect with their students, meaning they can encourage students to practice fitness skills in optimal ways for their health. Here are some important teaching skills for PE teachers: Having an engaging classroom presence Real-world learning Project building Lesson planning Technology 3. Interpersonal skills PE coaches are part of faculty teams, so working alongside other teachers is an essential part of their job. They often collaborate with a student's general education teacher to address any behavioral issues that arise. They can also team up with other classes to plan activities for students, like field days and special field trips. Communicating with peers can ensure these interactions remain productive and create opportunities for more fulfilling lessons. Teachers can also model emotional skills for their students by displaying positive social interactions. Interpersonal skills can also help PE teachers interact with students and their families. If a student can make a student feel comfortable expressing their needs and preferences, they can often perform physical exercises or play games to the best of their individual capacities. Understanding how to soothe nerves and support students' emotional needs are important examples of interpersonal skills. When interacting with family members, you may use some of these same techniques to communicate effectively and best uplift students. 4. Written and verbal communication Both verbal and written communication is important for PE teachers because they often communicate with students, families and various personnel on a day-to-day basis. For example, a PE teacher uses their communication skills in a lesson plan to describe any student assignments or expectations accurately. They may also write instructions in a document, then explain them in a classroom lecture. They also use communication skills to share their lesson plans with other PE teachers during conferences or classroom development exercises. Many teachers continue to learn their trade even after working as a teacher for many years. They may share tips with each other or special lessons they've developed if they feel another teacher may benefit from it. Creating a community can help PE teachers continue to expand their teaching methodology and receive feedback on their lessons. 5. Patience and adaptability Working with children can require patience and adaptability because they're encountering many new concepts at the same time and learning how to regulate their emotions. As a result, it's important to treat them with patience and care while they're in your class so they can feel comfortable and feel motivated to complete assignments. As children become teenagers, they may require patience and adaptability to account for their changing bodies and attention spans. Like any job where you perform tasks in real-time, certain circumstances may occur that require you to adapt lesson plans. For example, if the weather turns from sunshine to rain on a day you planned for students to run a mile outside, you may need to adapt the lesson plan so they can practice endurance sports inside a gymnasium instead. 6. Organization PE teachers can use organization skills to improve their lesson planning sessions. For example, they can keep their plans in one place, and determine which parts of a semester or quarter to introduce new concepts. Throughout the year, these objectives may change because of unforeseen setbacks, but organizational skills can help PE teachers control the trajectory of their class curriculum. PE teachers can also use organizational skills to maintain their classroom space. Physical education frequently requires balls, equipment and tools to play games that may be on a lesson plan. They also organize equipment and decide where to store it within their classroom or storage space. 7. Creativity Creativity can help a PE teacher develop fun ways to introduce new material to their students or reinforce previous lessons. They can teach new games or devise interesting ideas to change the rules of a game to help keep students engaged. To find inspiration for their lesson plans, they can turn to personal hobbies or media aspects they enjoy, like movie scenes, songs or dances. A varied lesson plan can foster more engagement among students who prefer action- based learning activities, rather than lectures. 8. Focus Focus is an essential trait of a PE teacher because students often require their full attention during class, especially if they're learning a complicated physical task. You can focus your lesson plans around specific elements of physical education you believe are essential for students of a certain age group or skill level. If students require mentorship, you can also focus on each student's needs to supply them with a steady support system. Focusing on your students can help guide your career purpose. It can give you a core value system that informs your lesson plans and mentorship activities. This passion for your student's well-being can also help you become an advocate for each student in your class. You can also help organize funding for different field trips or establish after-school activities to support their interests. 9. Enthusiasm for teaching sports and fitness Enthusiasm is essential for a PE teacher. Many physical education activities require high energy and may suit someone who enjoys teaching them to others. Being an effective PE teacher also requires an enthusiasm for working with kids and making a positive impact on their lives.Long Call Option Trading Strategy: Learn the Basics LONG CALL SUMMARY Purchasing a call option is a bullish strategy that gives the buyer the right, but not the obligation, to buy 100 shares of the underlying asset at a specified strike price on or before the expiration date. This strategy is typically employed when an investor believes that the price of the underlying asset will increase in the future. The value of a call option is influenced by several factors, including the underlying asset's price, the strike price, the time to expiration, and implied volatility. As the price of the underlying asset increases and approaches or breaches the long call's strike price, the option's value will appreciate. This is because the option holder has the right to buy the underlying asset at a lower price than the current market price, resulting in a potential profit. Out-of-the-money (OTM) calls have a strike price that is higher than the current market price of the underlying asset. These options are typically cheaper than in-the-money (ITM) calls, which have a strike price lower than the current market price. ITM calls have intrinsic value, which is the difference between the strike price and the current market price, and extrinsic value, which is the additional premium paid for the option's time value. Extrinsic value decays over time as the option approaches expiration, and this can cause the option to lose value, especially if the underlying asset does not move towards the strike price. LONG CALL OPTION Purchasing a call option grants you the privilege, but not the responsibility, to buy 100 shares of the underlying asset at the specified strike price on or before the expiration date. This option grants you the flexibility to capitalize on potential price increases of the underlying asset. The value of a call option is positively correlated with the price of the underlying asset. As the price of the stock or ETF rises and approaches your strike price, the value of your call option increases. This is because the difference between the market price and the strike price widens, giving you a greater potential profit. This characteristic makes call options suitable for bullish strategies where investors anticipate price increases. Conversely, the value of a call option diminishes when the price of the underlying asset drops or remains constant. Time decay, which refers to the gradual loss of an option's value as its expiration date approaches, also contributes to the depreciation of call options. Over time, the intrinsic value of the option, which represents the difference between the strike price and the underlying asset's market price, decreases as the option nears expiration. Additionally, if the price of the underlying asset remains below the strike price, the option may expire worthless, resulting in a total loss of the premium paid. Understanding these dynamics is crucial when trading call options. It allows you to make informed decisions about when to enter and exit positions, taking into account factors such as the underlying asset's price movements, time decay, and market sentiment. Buying call options can provide an alternative strategy to gain long exposure to a stock's price movement without the need for purchasing shares directly. This approach, known as a long call position, offers the potential advantage of lower capital outlay compared to buying shares outright. However, it's crucial to understand the concept of time decay, which significantly impacts the value of long call options. Time decay refers to the gradual decrease in the value of an option as time passes. This phenomenon occurs due to two primary factors: theta and vega. Theta measures the rate at which an option's value decays over time, while vega measures the sensitivity of an option's price to changes in implied volatility. As the expiration date of the call option approaches, both theta and vega work together to erode the option's value. Consequently, to offset the impact of time decay, the underlying stock price must rise at a greater velocity towards the call option's strike price. This is because the intrinsic value of a call option, which represents the difference between the strike price and the underlying stock's current market price, increases as the stock price moves higher. Another important consideration when evaluating call options is the distinction between out-of-the-money (OTM) and in-the-money (ITM) calls. OTM calls have a strike price higher than the current market price of the underlying stock, while ITM calls have a strike price lower than the current market price. OTM calls are typically less expensive than ITM calls because their value is composed entirely of extrinsic value. Extrinsic value refers to the portion of an option's price that is not attributable to its intrinsic value. ITM calls, on the other hand, have both intrinsic and extrinsic value, resulting in a higher cost per contract. As time relentlessly marches forward, the value of call options undergoes a transformation. The extrinsic value, which represents the premium paid for the potential of future price movements, steadily diminishes as expiration approaches. This decay is universal, affecting all call options regardless of their initial strike price or distance from the underlying asset's current price. However, amidst this gradual erosion of extrinsic value, ITM (in-the-money) call options stand as an exception. These options retain their intrinsic value at expiration, which is the difference between the strike price and the underlying asset's price. This characteristic sets ITM call options apart from their OTM (out-of-the-money) counterparts, whose extrinsic value decays entirely to zero near or at expiration. The distinction between ITM and OTM call options underscores the significance of carefully considering both the time frame and strike price when making investment decisions. Traders seeking to maximize their potential gains through call options must be mindful of the impending decay of extrinsic value as expiration draws near. For long ITM call options, the ideal scenario is for the underlying asset to exhibit a significant upward movement. Such a price increase would enhance the intrinsic value of the option, making it worth more at expiration than the initial purchase price. This scenario holds true for OTM call options as well, as they require the underlying asset to move ITM at expiration to possess any value. Prior to expiration, both OTM and ITM call options have the potential to gain a combination of extrinsic and intrinsic value if the stock exhibits a rapid upward trajectory. This dynamic underscores the importance of monitoring market conditions and adjusting investment strategies accordingly. Understanding the Interplay of Time, Strike Price, and Option Value in Call Option Trading: In the realm of call option trading, comprehending the intricate interplay between time, strike price, and option value is paramount to success. These three factors collectively shape the dynamics of call option contracts, allowing traders to make informed decisions and capitalize on market opportunities. Time (Days to Expiration): Time, measured in days until expiration, is a crucial element in call option trading. As expiration approaches, the value of a call option is directly influenced by the time premium. The closer an option gets to expiration, the less time value it holds. This time decay accelerates in the final days leading up to expiration. Therefore, traders must carefully consider the time factor when selecting their expiration dates. Strike Price: The strike price represents the predetermined price at which the underlying asset can be bought (in the case of a call option) or sold (in the case of a put option). When choosing a strike price, traders must assess the current market price of the underlying asset and make an educated guess about its future direction. ITM (In-the-Money) call options are those with a strike price below the current market price, while OTM (Out-of-the-Money) call options have a strike price above the current market price. Option Value: Option value refers to the premium paid by the buyer of an option contract to the seller. This premium comprises two components: intrinsic value and time value. Intrinsic value is the difference between the strike price and the underlying asset's current market price. Time value, as mentioned earlier, is the premium paid for the remaining time until expiration. Auto-Exercise and Expiration Scenarios: Auto-Exercise: Long call options that expire ITM by $0.01 or more will be automatically exercised. This means that the buyer of the call option has the right to purchase the underlying asset at the strike price. If the investor holds only a long call, this will result in 100 long shares per contract purchased at the call option's strike price. On the other hand, investors holding the corresponding short shares will cover or buy shares at the call option's strike price. Expiration Worthless: Any long call options that expire OTM will expire worthless. In this scenario, the investor loses the entire premium paid for the contract, resulting in a maximum loss. Understanding these concepts is instrumental in developing effective call option trading strategies. By carefully considering the interplay between time, strike price, and option value, traders can position themselves to make profitable trades and minimize potential losses. PROFIT & LOSS DIAGRAM OF A LONG OTM CALL A long OTM call option can be profitable if the current market value of the option exceeds the price paid to purchase it. This can occur in two main scenarios: Stock Price Surpasses Strike Price: If the underlying asset's price rises above the strike price of the call option by more than the premium paid for the option, the call option becomes profitable. This is because the intrinsic value of the call option (the difference between the strike price and the underlying asset's price) becomes positive, and the call option can be exercised to purchase the underlying asset at a price below the market price. OTM Call Moves Closer to Underlying Asset Price: Even if the underlying asset's price does not reach the strike price, a long OTM call can still be profitable if the option's price increases. This can happen when there is a quick rally in the underlying asset's price, causing the call option's price to increase as well, even if the strike price is not reached. This is because the time value of the call option increases as the expiration date approaches, and the call option becomes more likely to be in the money. However, it's important to note that long OTM call options can also result in losses if the underlying asset's price does not surpass the breakeven point. The breakeven point is the price at which the call option's intrinsic value becomes equal to the purchase price of the option. If the underlying asset's price remains below the breakeven point until expiration, the call option will expire worthless, and the investor will lose the entire amount paid for the option. The maximum profit potential of a long OTM call option indeed has no theoretical limit, as a stock's price can theoretically rise indefinitely. This means that if the underlying stock price increases significantly, the call option holder can potentially reap substantial profits by exercising the option and buying the stock at the predetermined strike price. On the downside, the maximum loss on a long call option is limited to the premium paid for the option. This premium represents the total amount invested in the option contract and acts as a protective barrier against further losses. If the stock price declines or stays below the strike price at expiration, the option will expire worthless, and the investor will lose the entire premium paid. The flattened red loss zone in the diagram illustrates this limited loss potential. This zone represents the range of stock prices below the strike price at expiration where the option holder will lose money. The loss amount decreases as the stock price approaches the strike price and becomes zero when the stock price equals the strike price. Beyond the strike price, the option holder starts to make a profit. It's important to note that while the maximum profit potential is theoretically unlimited, it is highly unlikely for a stock price to rise dramatically within the short timeframe of an OTM option's expiration period. Therefore, while the potential rewards can be significant, the probability of achieving them is relatively low. PROFIT & LOSS DIAGRAM OF A LONG ITM CALL ITM (In-the-Money) options have a unique characteristic where the price of their intrinsic value directly correlates with the underlying asset's price. This means that for every one point movement in the underlying asset's price, the ITM option's intrinsic value moves by the same amount. While purchasing an ITM option provides immediate intrinsic value, it does not guarantee profitability upon execution. Similar to buying an OTM (Out-of-the-Money) call option, the purchase price of an ITM call must increase for it to be profitable. This requires the stock price to move further above the call strike price. This relationship is visually represented in the diagram, where the red and green zones converge on the x-axis. The maximum potential loss on a long call option is limited to the debit paid for the option, which is represented by the flattened red area in the diagram. This means that the most an investor can lose on a long call is the premium paid for the option, regardless of how far the underlying asset's price moves below the strike price. Understanding the price dynamics and potential risks associated with ITM options is crucial for traders and investors. While ITM options offer immediate intrinsic value, careful analysis and consideration of market conditions are necessary to determine their potential profitability. EXAMPLE OF A LONG OTM CALL OPTION XYZ currently trading @ $45 Buy to Open +1 XYZ 50-strike call @ $4 debit Cost: $4 debit ($400 total, ($4 x 100 shares)) Time Decay Affect Works against the option’s value Max Profit Theoretically unlimited Max Loss Debit paid per contract ($400) Breakeven Price (at expiration) Strike price + debit paid ($54) Account Type Required Cash, Margin, and IRA EXAMPLE OF A LONG ITM CALL OPTION XYZ currently trading @ $45 Buy to Open +1 XYZ 40-strike call @ $7 debit ($5 intrinsic value + $2 extrinsic value) Cost: $7 debit ($700 total) Time Decay Affect Works against the option’s value Max Profit Theoretically unlimited Max Loss Debit paid per contract ($700) Breakeven Price (at expiration) Strike price + debit paid ($47) Account Type Required Cash, Margin, and IRAIons Ions are charged substances that have formed through the gain or loss of electrons. Cations form from the loss of electrons and have a positive charge while anions form through the gain of electrons and have a negative charge. Cation Formation Cations are the positive ions formed by the loss of one or more electrons. The most commonly formed cations of the representative elements are those that involve the loss of all of the valence electrons. Consider the alkali metal sodium (Na) . It has one valence electron in the n=3 energy level. Upon losing that electron, the sodiu ion now has an octet of electrons from the second energy level and a charge of 1+ . The electron arrangement of the sodium ion is now the same as that of the noble gas neon. Consider a similar process with magnesium and aluminum. In this case, the magnesium atom loses its two valence electrons in order to achieve the same arrangement as the noble gas neon and a charge of 2+ . The aluminum atom loses its three valence electrons to have the same electron arrangement as neon and a charge of 3+ . For representative elements under typical conditions, three electrons is usually the maximum number that will be los. Representative elements will not lose electrons beyond their valence because they would have to "break" the octet of the previous energy level which provides stability to the ion. Anions Anions are the negative ions formed from the gain of one or more electrons. When nonmetal atoms gain elections, they often do so until their outermost principal energy level achieves an octet. For fluorine, which has an electron arrangement of (2, 7), it only needs to gain one electron to have the same electron arrangement as neon. Forming an octet (eight electrons in the outer shell) provides stability to the atom. Fluorine will gain one electron and have a charge of 1− . The electron arrangement of the fluoride ion (2, 8) will also change to reflect the gain of an electron. Oxygen has an electron arrangement of (2, 6) and needs to gain two electrons to fill the n=2 energy level and achieve an octet of electrons in the outermost shell. The oxide ion will have a charge of 2− as a result of gaining two electrons. Under typical conditions, three electrons is the maximum that will be gained in the formation of anions. Subatomic Particles in an Ion Since ions form from the gain or loss of electrons, we can also look at the number of subatomic particles (protons, neutrons, and electrons) found in an ion. Remember that the number of protons determines the identity of the element and will not change in a chemical process. Example 2.5.1 How many protons, neutrons, and electrons in a single oxide (O2−) ion? Solution Oxygen has the atomic number 8 so both the atom and the ion will have 8 protons. The average atomic mass of oxygen is 16. Therefore, there will be 8 neutrons (atomic mass−atomic number=neutrons) . A neutral oxygen atom would have 8 electrons. However, the anion has gained two electrons so O2− has 10 electrons. We can also use information about the subatomic particles to determine the identity of an ion. Example 2.5.2 An ion with a 2+ charge has 18 electrons. Determine the identity of the ion. Solution If an ion has a 2+ charge then it must have lost electrons to form the cation. If the ion has 18 electrons and the atom lost 2 to form the ion, then the neutral atom contained 20 electrons. Since it was neutral, it must also have had 20 protons. Therefore the element is calcium. Polyatomic Ions A polyatomic ion is an ion composed of two or more atoms that have a charge as a group (poly = many). The ammonium ion (see figure below) consists of one nitrogen atom and four hydrogen atoms. Together, they comprise a single ion with a 1+ charge and a formula of NH+4 . The hydroxide ion (see figure below) contains one hydrogen atom and one oxygen atom with an overall charge of 1− . The carbonate ion (see figure below) consists of one carbon atom and three oxygen atoms and carries an overall charge of 2− . The formula of the carbonate ion is CO2−3 . The atoms of a polyatomic ion are tightly bonded together and so the entire ion behaves as a single unit. The figures below show several examples. Soult Screenshot 2-2-1.png Figure 2.5.1 : The ammonium ion (NH+4) is a nitrogen atom (blue) bonded to four hydrogen atoms (white). Soult Screenshot 2-2-2.png Figure 2.5.2 : The hydroxide ion (OH−) is an oxygen atom (red) bonded to a hydrogen atom. Soult Screenshot 2-2-3.png Figure 2.5.3 : The carbonate ion (CO2−3) is a carbon atom (black) bonded to three oxygen atoms. The table below lists a number of polyatomic ions by name and by structure. The heading for each column indicates the charge on the polyatomic ions in that group. Note that the vast majority of the ions listed are anions - there are very few polyatomic cations. 1− 2− 3− 1+ Table 2.5.1 : Common Polyatomic Ions acetate, CH3COO− carbonate, CO2−3 arsenate, AsO3−3 ammonium, NH+4 bromate, BrO−3 chromate, CrO2−4 phosphite, PO3−3 chlorate, ClO−3 dichromate, Cr2O2−7 phosphate, PO3−4 chlorite, ClO−2 hydrogen phosphate, HPO2−4 cyanide, CN− oxalate, C2O2−4 dihydrogen phosphate, H2PO−4 peroxide, O2−2 hydrogen carbonate, HCO−3 silicate, SiO2−3 hydrogen sulfate, HSO−4 sulfate, SO2−4 hydrogen sulfide, HS− sulfite, SO2−3 hydroxide, OH− hypochlorite, ClO− nitrate, NO−3 nitrite, NO−2 perchlorate, ClO−4 permanganate, MnO−4 The vast majority of polyatomic ions are anions, many of which end in -ate or -ite. Notice that in some cases such as nitrate (NO−3) and nitrite (NO−2) , there are multiple anions that consist of the same two elements. In these cases, the difference between the ions is the number of oxygen atoms present, while the overall charge is the same. As a class, these are called oxyanions. When there are two oxyanions for a particular element, the one with the greater number of oxygen atoms gets the -ate suffix, while the one with the fewer number of oxygen atoms gets the -ite suffix. The four oxyanions of chlorine are shown below, which also includes the use of the prefixes hypo- and per-. ClO− , hypochlorite ClO−2 , chlorite ClO−3 , chlorate ClO−4 , perchlorate Not your usual ion Soult Screenshot 2-2-4.png "Drink you milk. It's good for your bones." We're told this from early childhood, and with good reason. Milk contains a good supply of calcium, part of the structure of bone. However, there are two other ionic components of hydroxyapatite, the mineral component. Phosphate ion and hydroxide ion make up the remainder of the inorganic material in bone. News You Can Use Bone is a very complex structure. It is composed of protein (mainly collagen), hydroxyapatite (a calcium-phosphate-hydroxide mixture), some other minerals, and contains 10 - 20% water. The calcium/phosphate ratios are not stoichiometric, but vary somewhat from one portion of bone to the next. Bones are very strong but will break under enough stress. Regular exercise and proper nutrition help to increase bone strength. Watch a video about bone structure at http://www.youtube.com/watch?v=d9owEvYdouk Nitrate is an anion with a complex bonding structure. Major sources for this ion in drinking water are runoff from fertilizer, septic tank leakage, sewage, and natural deposits. High concentrations of nitrates represent a significant health hazard, especially to infants. The nitrate in the body is converted to nitrite, which then binds to hemoglobin. This binding decreases the ability of hemoglobin to transport oxygen, thus depriving the cells of the O2 needed for proper functioning. Cyanide production is widespread throughout nature. Forest fires will produce significant amounts of cyanide. Many plants contain cyanide, and it is produced by a number of bacteria, algae, and fungi. Cyanide is used industrially in metal finishing, iron and steel mills, and in organic synthesis processes. This material is also an important component for the refining of precious metals. Formation of a complex between cyanide and gold allows extraction of this metal from a mixture. 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 goverCreate a matching exercise between words and their definitions for example convince is matched to persuade, for students CEFR B2. create a matching exercise to the words: creative, well known, adopt, bring in, nevertheless, sibling, significant, determine, personality, genes, environment, share, The price of electricity has risen (1) ______ over the last year. A) specially | B) obviously | C) significantly | D) remarkably The heavy rain led to floods, (2) ______ a lot of trouble for local farmers. A) causing | B) making | C) resulting | D) affecting I have never seen (3) ______ a beautiful sunset in my entire life! A) as | B) like | C) so | D) such It is very (4) ______ that some people still don't believe in climate change. A) doubtful | B) suspicious | C) worrying | D) uncertain My brother is learning how to (5) ______ a small business. A) adjust | B) run | C) manage | D) direct Can you (6) ______ the person who took your bag? A) inform | B) identify | C) tell | D) know On a daily (7) ______, we should try to use less plastic. A) basis | B) motive | C) cause | D) method Regular exercise and a healthy diet are very (8) ______ for your heart. A) rewarding | B) valuable | C) beneficial | D) productive She was (9) ______ to win the race, so she practiced every single day. A) fixed | B) decided | C) committed | D) determined An (10) ______ student spends about three hours on homework every evening. A) everyday | B) average | C) normal | D) regularMake a set of 10 exercises to use passive voiceExercises verb to be, complete senteces