Obesity: A Growing Global Health Concern
Over 1 billion people worldwide live with obesity, a global health challenge that is rapidly increasing in scale. Obesity is the second leading cause of preventable death, increasing the risk of diseases such as type 2 diabetes, cardiovascular disease, and certain types of cancer. Understanding the full range of social, psychological, and biological determinants of energy intake and expenditure is crucial to tackling this epidemic.
Childhood obesity is particularly alarming, with the global prevalence rising steadily over the past four decades. In 2016, more than 7% of children and adolescents were living with obesity, compared to less than 1% in 1975. This dramatic increase highlights the urgent need to address the root causes of this public health crisis, especially in young populations.
Recent advances in genetics have shed light on the complex interplay between genetic and environmental factors that contribute to the development of obesity. While changes in the environment have undoubtedly driven the rapid increase in prevalence, obesity also has a strong heritable component, with twin, family, and adoption studies estimating the heritability to be between 40-70%.
Genetic Insights into Obesity: From Monogenic to Polygenic
Traditionally, obesity has been considered in two broad categories: monogenic obesity, which is inherited in a Mendelian pattern and typically involves rare, early-onset, and severe cases; and polygenic obesity, the result of hundreds of genetic variants with small individual effects.
Early gene discovery studies for monogenic obesity focused on patients with severe obesity and their affected family members, using Sanger sequencing to identify potential gene-disrupting causal mutations. This approach led to the identification of key players in the leptin-melanocortin pathway, such as leptin (LEP), leptin receptor (LEPR), proopiomelanocortin (POMC), and the melanocortin 4 receptor (MC4R), as important regulators of appetite and body weight.
In contrast, genetic variation associated with common forms of obesity has been identified through large-scale population studies, either using a case-control design or by examining continuous traits like body mass index (BMI). The advent of genome-wide association studies (GWAS) has been a game-changer, enabling the interrogation of genetic variants across the whole genome for their role in body weight regulation. To date, nearly 60 GWAS have identified more than 1,100 independent loci associated with a range of obesity traits, including BMI, body fat percentage, and circulating leptin levels.
Converging Insights: The Central Nervous System as a Key Player
Despite the initial polarization of monogenic and polygenic obesity, gene discovery studies for both forms have converged on broadly similar underlying biology. The central nervous system (CNS), particularly the hypothalamus and its neuronal pathways that control the hedonic aspects of food intake, have emerged as the major drivers of body weight regulation.
Monogenic obesity studies have highlighted the critical role of the leptin-melanocortin pathway, in which defects in key components such as leptin, its receptor, or downstream melanocortin receptors can lead to severe, early-onset obesity. Similarly, GWAS have identified numerous obesity-associated loci near genes expressed in the brain, underscoring the importance of neuronal circuits in the regulation of energy balance.
Interestingly, recent evidence suggests that the expression of mutations causing monogenic obesity may be influenced by an individual’s polygenic susceptibility to obesity. This convergence of insights from both monogenic and polygenic forms of obesity highlights the complex interplay between genetic and environmental factors in the development of this multifactorial condition.
Whole Genome Sequencing Uncovers New Genetic Determinants of Obesity
The rapid advancement of high-throughput genomic technologies, such as whole-exome sequencing (WES) and whole-genome sequencing (WGS), has significantly accelerated the discovery of new genetic determinants of obesity. These unbiased, hypothesis-generating approaches have identified rare, protein-truncating variants in genes previously not associated with body weight regulation, such as BSN and APBA1.
A recent exome-wide association study (ExWAS) using WES data from over 400,000 UK Biobank participants found that rare, loss-of-function variants in BSN and APBA1 were associated with increased risk of severe adult-onset obesity. Interestingly, these rare variants were not associated with normal variation in childhood adiposity, suggesting a specific role in the development of obesity in adulthood.
Further analyses revealed that BSN protein-truncating variants amplified the influence of common genetic variants associated with BMI, with a polygenic risk score exhibiting an effect twice as large in BSN variant carriers compared to non-carriers. This finding highlights the complex interplay between rare and common genetic factors in the etiology of obesity.
Unraveling the Biological Mechanisms: From Genetics to Cellular Function
To better understand the biological mechanisms through which BSN and APBA1 may influence body weight, the researchers explored their potential roles using a combination of genetic, proteomic, and cellular approaches.
Analysis of plasma proteomic data from UK Biobank participants identified changes in the levels of several circulating proteins associated with BSN protein-truncating variants. These findings suggest that BSN may influence obesity-related pathways, such as synaptic function and neuronal development.
Furthermore, cellular studies using human induced pluripotent stem cell-derived hypothalamic neurons revealed functional consequences of BSN deletion, providing insights into the potential mechanisms by which BSN variants may contribute to the development of adult-onset obesity.
Collectively, these multifaceted approaches highlight the value of integrating genetic discoveries with functional studies to unravel the underlying biology of complex traits like obesity. By bridging the gap between genetic loci and their biological relevance, researchers can pave the way for the development of targeted interventions and personalized treatment strategies.
Implications for Obesity Prevention and Management
The growing understanding of the genetic underpinnings of obesity, coupled with advances in genomic technologies, holds promise for more effective prevention and management strategies. Genetic information can help identify individuals at high risk of developing obesity, enabling earlier intervention and tailored approaches to weight management.
Stanley Park High School is committed to supporting its students and families in addressing the challenges of obesity. By staying informed about the latest genetic research and its implications, we can work together to implement evidence-based strategies that promote healthy lifestyles and address the root causes of this complex condition.
Collaborations between researchers, healthcare providers, and educational institutions like ours are crucial in translating genetic insights into practical solutions. By fostering cross-disciplinary partnerships and empowering our community with knowledge, we can take meaningful steps towards a healthier future for our students and their families.
