Beyond diet and exercise: unravelling the complex causes of childhood obesity

Diet and lifestyle 12. may 2024 11 min Professor Antje Körner Written by Morten Busch

"Obesity among children and adolescents is a serious and often overlooked global health problem, which is alarmingly increasing and currently affects millions of children. The issue contains unique complexities that also require complex strategies to resolve. Since research and therapeutic interventions have previously focused primarily on adults, this often leaves children without sufficient support. The obesity epidemic imposes a significant psychosocial burden on the affected youth and predisposes them to severe health conditions like diabetes and heart diseases."

Childhood obesity is a silent and unseen giant facing the world. Currently, the world is witnessing an alarming rise in obesity among children and adolescents, with more than 340 million young individuals affected worldwide. This epidemic not only predisposes them to severe health conditions such as diabetes, heart disease and certain types of cancer and has an enormous individual burden (psychosocial and stigma) but also challenges healthcare systems and societal structures worldwide. Nevertheless, research, diagnosis and therapeutic interventions primarily focus on adults, leaving the younger population underserved.

“The numbers are staggering, but it is a fight that begins with understanding because there is no easy fix. My worldview is that one must approach a complex disease in a complex way. By integrating interdisciplinary research methods, we are working to and aim to illuminate these complexities of childhood obesity. The aim is to not only enhance our understanding of the disease’s multifaceted nature but also to spur the development of tailored interventions that can mitigate its impact from an early age, ensuring a healthier future for the next generation,” explains Professor Antje Körner from HI-MAG/Helmholtz Munich and the University of Leipzig, Germany, who has been named as the recipient of the 2024 EASO–Novo Nordisk Foundation Obesity Prize for Excellence.

One size does not fit all

Antje Körner’s journey into the world of childhood obesity and metabolism research began with fascination for the roles of leptin and adiponectin, two hormones critical in regulating energy balance and metabolic processes. Early in her career, during her medical studies when preparing for the examination at medical school, she was intrigued by leptin, the first “hormone” discovered from adipose tissue known for its ability to signal satiety to the brain and thus regulate food intake.

“My interest in the field of obesity, which began well before my specialisation in paediatrics, was initially sparked during my medical studies. It was here that I first engaged in research on leptin, a hormone integral to appetite regulation. This curiosity was further solidified through my doctoral work, which investigated how leptin’s regulation by the sympathetic nervous system in a mouse model could influence metabolic processes.”

Subsequently, her focus expanded to include adiponectin, recognised for enhancing insulin sensitivity and its anti-inflammatory effects, exploring its potential impact on obesity and associated metabolic disorders. These laid the groundwork for her future obesity research trajectory, but her focus eventually steered towards paediatric endocrinology, influenced by her mentors and the scientific environment at the time.

To comprehend the origins of obesity, it is crucial to understand why the body always works to accumulate fat. Evolutionarily, the human body stores energy as fat to create reserves for times of scarcity, a survival mechanism from our evolutionary past.

Nevertheless, in today’s world of plentiful food and sedentary lifestyles, this once-essential adaptation now contributes to the obesity epidemic, resulting in health problems such as diabetes and heart disease.

“The clinical management and understanding of how the risk factors confer the risk among children and adolescents presents an unexpectedly complex challenge. The threshold of obesity at which health risks escalate is not a one size fits all but intricately linked to factors such as genetic background, gender, developmental stage and age. This complexity intrigued me and underscored the urgent and formidable tasks that lay ahead for healthcare providers and societies alike: treating and preventing obesity during these crucial developmental years.”

Landmark study in 2007

Antje Körner’s transition to focusing specifically on childhood obesity and metabolism was driven by a combination of her clinical insights and the realisation that obesity’s roots often begin early in life, with profound implications for children’s long-term health. It soon became clear that more knowledge and data are needed. Launched in the early 2000s, the Leipzig Obesity Cohorts were born from this critical realisation.

“To untangle the complex web of obesity’s origins and the intricate link between children’s metabolic health and obesity, we had to analyse real patient data to detect patterns. Therefore, we started laying the groundwork for these pivotal cohorts. By 2007, their utility was evident as they started to provide crucial insights into the genetic and environmental factors contributing to childhood obesity.”

A 2007 landmark study published in Nature Genetics was based on data from more than 8,000 individuals and underlined the substantial genetic component of obesity – including identifying genetic contributors such as the FTO gene – offering potential targets for future research and therapy. Because of the efforts of Antje Körner and colleagues, these findings included data from their cohort of 1,000 Leipzig children, underscoring the genetic dimensions of obesity – also for children.

“The article sheds light on the genetic aspects of obesity, pinpointing specific single-nucleotide polymorphisms in the FTO gene associated with obesity risk. This discovery emphasises the critical need for early intervention in children and has opened new avenues for understanding the genetic basis of this complex condition of obesity.”

But Antje Körner´s team moved forward aiming to identify factors, also molecular, that drive obesity and also looking at what is behind those associations. Ever since, the cohorts have grown and guided the development of even more targeted interventions, heralding a new era of precision medicine for childhood obesity and diabetes.

Early childhood stages as pivotal windows

In 2011, Antje Körner complemented the paediatric obesity cohorts and was pivotal in establishing the LIFE Child study, a populational cohort of normal (and lean) children, and a project of the Leipzig Research Center for Civilization Diseases. This longitudinal research delves into the genetic, environmental and lifestyle factors influencing healthy development of children and the origin of common diseases from childhood through adolescence.

“By tracking health data over time, we aim to uncover how early life influences contribute to obesity, providing insights for personalised prevention and treatment strategies. Its holistic, multidisciplinary approach is pivotal in understanding and combatting the obesity epidemic among young people.”

As of November 2019, the Leipzig Obesity Cohorts and the LIFE Child study, encompassed more than 8,000 children and 1,000 pregnant women.

“These cohorts stand as a significant resource in deciphering the complexities of childhood obesity. A groundbreaking study published in The New England Journal of Medicine in 2018 provided profound insights into trajectories of childhood obesity, asking and answering questions such as: When does obesity develop? Is there a vulnerable age? How does it track into adulthood?”

Born larger than average

The study was based on data from more than 50,000 children and adolescents – tracking their body-mass index (BMI) from childhood to adolescence.

“The study illuminated a consistent pattern. Teenagers who maintain a healthy weight generally carry this status from childhood. Conversely, more than half the teens facing obesity already had overweight by the age of 5 years, experiencing an escalating BMI as they aged. Strikingly, nearly 90% of children who have obesity by age 3 years remained so into their teenage years, with the most substantial annual increases in BMI occurring between ages 2 and 6 years.”

This rapid growth in BMI during early years significantly heightens the risk of persistent obesity, particularly among those born large for their gestational age. Infants born larger than average face a 55% higher risk of developing overweight or obesity in adolescence compared with their peers born at or below the average size. This underscores the importance of the prenatal and early childhood stages as pivotal windows for interventions aimed at mitigating obesity risks.

“We have since been able to substantiate that excessive weight gain among children younger than 6 years of age can drive later diseases. Early life stages are therefore crucial for modifying long-term health trajectories, highlighting the necessity of integrating children’s perspectives into obesity research. This revealed to us the enduring influence of birthweight on future health, marking not only pregnancy and but also early childhood as critical periods for introducing obesity prevention measures.”

Instructs cells to store fat

Interdisciplinarity has proven pivotal in Antje Körner’s work on childhood obesity for several reasons. By intertwining experimental, clinical, genetic and epidemiological methods, her approach offers a holistic view of obesity, transcending the limitations of single-discipline studies. Studies published in Cell Reports in 2019 and in the Journal of Clinical Investigation in 2020 exemplify this synergy.

“In the 2019 study, we contributed to the effects of breastfeeding on adipose tissue and uncovered how specific lipids in breast-milk can foster healthy fat tissue development. This offered insights into obesity prevention from infancy. This research not only underscores the critical impact of early nutrition but also opened up new therapeutic avenues grounded in understanding these early environmental influences on obesity.”

Merging genetics and environmental science is crucial for unravelling complex health puzzles, a truth that shone brightly in the 2020 study.

This research ventured into the world of genes, spotlighting TMEM18 in the process of creating fat cells, known as adipogenesis, and the molecular interactions: how this gene activates PPARG, a pivotal factor that essentially drives the formation of new, healthy adipocytes, hence unravelling what is behind the associations seen in epidemiological studies.

“This is not the major factor but is an example how we search for factors that regulate adipose tissue function and some day use this knowledge to find ways to revert the malfunction of adipose tissue, so that energy can be stored safely.”

Complex aetiology of obesity

Antje has shown with her group that with the early development of obesity seen clinically in the children, not only is the adipose tissue increased in overall size but the biological and functional alterations, collectively known as adipose tissue dysfunction, are evident already in early childhood.

“This adipose tissue dysfunction, such as enlarged fat cells, inflammation in the adipose tissue and imbalance in adipokines, is tightly related to the metabolic comorbidities seen clinically.”

She is now further working on which molecular factors drive the development of this adipose tissue dysfunction and how could this be reverted into healthy, metabolically active adipose tissue capable of safely storing excess energy without doing metabolic harm.

“These studies gave us much deeper insight into the roots of obesity and collectively highlight the power of interdisciplinarity by connecting genetic predispositions to the physiological process of fat cell development. By integrating clinical, genetic and environmental perspectives, we are working on unravelling the complex aetiology of obesity. This demonstrates the critical role of this type of research in developing evidence-based, context-specific strategies, crucial for dissecting the intricate web of obesity’s causes.”

Therapy for children significantly lags behind

The challenge in current treatment approaches for childhood obesity is multifaceted, stemming from a critical gap in effective options and societal support. This deficiency is aggravated by a lack of attention and resources dedicated to the unique needs of children with obesity. The prevalent strategies, largely adapted from adult treatment models, fail to address the complex interaction of genetic, environmental and behavioural factors that contribute to obesity among children.

“There is a critical gap in effective treatment options and societal support for children with obesity. The societal misconception that obesity can be resolved solely through better diet and more exercise overlooks the fact that obesity is a chronic disease and there is a critical need for comprehensive, tailored interventions that encompass medical, psychological and social support. Compounding this challenge is the absence of specialised medications for children, which further complicates the treatment landscape.”

Although recent advances have yielded promising drug treatments for adults, such as incretin agonists, the translation of these therapies to children significantly lags behind. This delay not only hinders the timely and effective management of childhood obesity but also reflects a broader issue of underrepresentation of children in obesity research and pharmaceutical development.

“Furthermore, the stigmatisation of obesity worsens the challenge, often deterring families from seeking help and contributing to a cycle of ineffectiveness in current treatment approaches. This scenario underscores the urgent need for a paradigm shift toward developing and implementing holistic, age-appropriate treatment modalities that are accessible, effective and sensitive to the complexities of managing obesity among children.”

Working towards personalised treatment

In 2021 and 2022, obesity genetics research significantly expanded the understanding of its impact on children’s growth. A 2021 study with Antje Körner’s involvement, published in EClinicalMedicine, discovered a clear link between obesity and accelerated growth among children. Data from thousands of children showed that those with obesity tended to be taller than peers of normal weight in early childhood.

This finding was crucial because it expanded the comprehension of obesity’s physiological implications far beyond the conventional perspective of excessive weight gain. This finding underscores the need for tailored growth monitoring of children with obesity. Antje Körner’s group provides open access for the new growth references that may help to differentiate underlying causes (such as monogenic or syndromic obesity) from typical obesity phenotypes that are associated with transient growth acceleration and target diagnostics.

Building on this understanding, the discovery, under Antje Körner’s guidance, of a monogenic form of obesity published in Nature Metabolism marked a watershed moment derived from a bottom-up approach: finding biological alterations in adipose tissue and identifying the molecular mechanism and finally the genetic cause leading to this.

“By doing so, we found 10 more patients with the same conditions that were previously not discovered in genetic diagnostics. Our study identified a specific genetic mutation in a girl leading to ectopic expression of the gene ASIP, disrupting signalling of the hormone melanocortin and leading to increased appetite. The girl’s clinical presentation phenocopies that of the agouti mouse, the oldest obesity mouse model.”

Hence, the group found a long unknown missing puzzle piece, a finding that was made possible by following an unconventional approach beyond the beaten track and combining clinical and experimental research to enable new discoveries.

“Such alterations are pivotal in understanding the disease’s progression. Our study sheds light on the complex mechanisms driving early-onset obesity and related phenotypes. So, the study not only expanded the understanding of genetic factors in obesity but also suggests new directions for diagnosis and treatment, emphasising the need for revisiting our diagnostic algorithms for genetic screening in identifying at-risk individuals. It also offers hope for personalised treatment strategies for children with monogenic forms of obesity.”

Age affects insulin resistance

Childhood obesity has escalated, with 18% of 5- to 19-year-olds overweight, up from 4% in 1975. More than 38 million children younger than 5 years have obesity in 2020, with notable increases in lower-income and urban areas. This growing epidemic not only heightens the risk of chronic diseases in adulthood but also imposes an economic burden, costing the global economy approximately USD 2 trillion, or 2.8% of GDP, annually. Immediate interventions are essential.

“Already, one in six children in Germany has overweight. The global health crisis of childhood obesity demands immediate action to develop and implement more effective therapies and enhance societal support. But our research also underscores a need for new diagnostic cut-offs for children. Age affects insulin resistance, fasting glucose and metabolism significantly, showing a need for age-specific reference ranges. This is pertinent to enable the identification of patients at highest risk for early metabolic disease. Again, they provide open access for new age-specific references.”

The 2023 study by Antje Körner in The Lancet uncovered early hyperinsulinaemia as a critical phenomenon in obesity-related metabolic dysfunction among children, emphasising the necessity of early intervention. The study also showed that enhanced glycaemic decline predictions with fasting insulin indices, beyond just glucose, can more accurately identify metabolic risks in children with obesity.

“This highlights the critical need to tackle metabolic disturbances early on to avoid serious health issues later in life. However, despite this understanding, children’s unique needs remain underrepresented in research and treatment approaches, frequently resulting in recommendations that do not fully address their complexities.”

Precision medicine is needed

Antje Körner criticises the oversimplified view that lifestyle changes alone can address childhood obesity, ignoring its complex causes, including genetics, environment and the socioeconomic context. There is a widespread misconception that children will simply outgrow it just by eating better and moving more. She advocates a holistic, multidisciplinary strategy, emphasising the need for a multimodal approach (including lifestyle intervention as a backbone) with the option to complement it with innovative and effective treatments including pharmacological options tailored to individual children’s unique needs.

“Including comprehensive support for psychological, nutritional and physical health, as well as pharmacological approaches, this approach necessitates clinical innovation and societal shifts to combat stigma and efficiently utilise resources.”

There is a gap and a need to identify the drivers, the risk and the protective factors and importantly understand the mechanisms behind them. Only this will enable the development of effective prevention and treatment strategies.

Highlighting the urgency for child-centred clinical approaches, the text underscores the importance of integrating research into effective strategies to mitigate the health effects of childhood obesity. It champions a move towards precision medicine, leveraging genetic insights for personalised treatment plans that consider individual genetic and environmental interactions.

“We need precision medicine for obesity, especially for children, as a beacon of hope. It provides effective and compassionate interventions, recognising obesity’s diverse causes. With advances in genetics, personalised treatments become real, showing that understanding each person’s genetic predisposition, clinical, biological and pathophysiological mechanisms and environmental context is key to unlocking the full potential of treatment. This moves us towards a future of combatting obesity with unprecedented precision and personalisation.”

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