Obesity is rising globally in both adult and pediatric populations.¹ While traditionally attributed to an imbalance between energy intake and expenditure, current evidence supports a more complex etiology involving genetic susceptibility, epigenetic regulation, and early-life developmental programming.² At the 2^nd Malaysian Obesity Society (MYOS) National Obesity Scientific Conference (NOSC) 2026, Professor Dr. Muhammad Yazid Jalaludin from Universiti Malaya Medical Centre, Malaysia, discussed the complex multifactorial nature of obesity and highlighted how early-life biological and environmental influences contribute to obesity, reinforcing the importance of early biological imprinting and upstream preventive strategies across the life course.²

At the genetic level, obesity is largely considered polygenic, arising from the interplay between multiple genetic variants and environmental exposures that together determine the phenotype expression.¹ Genome-wide association studies have identified ≥1,100 loci associated with obesity-related traits, including the fat mass and obesity-associated (FTO) gene.¹ Within this context, the “thrifty gene” hypothesis provides an evolutionary perspective, suggesting that genes favoring energy storage were once advantageous during periods of food scarcity but now predispose individuals to obesity in modern obesogenic environments.³

Extending beyond genetic predisposition, the Developmental Origins of Health and Disease (DOHaD) hypothesis provides a unifying framework linking early-life exposures to long-term cardiometabolic risk.⁴ Within this paradigm, both ends of the nutritional spectrum are implicated.⁴ Low birth weight, as well as maternal obesity or excessive gestational weight gain, are consistently associated with increased risk of obesity, cardiovascular disease, and type 2 diabetes in offspring.⁴ Mechanistically, the placenta functions as a critical intermediary, integrating maternal environmental signals and regulating fetal gene expression, thereby shaping developmental programming and long-term health outcomes.⁵ Ultimately, this epigenetic programming contributes to the “double burden” model, in which undernutrition promotes a thrifty phenotype, whereas later overnutrition promotes excess adiposity.² Consequently, the mismatch between early-life programming and modern obesogenic environments may help explain the rising incidence of type 2 diabetes in low- and middle-income countries.²

Central to this developmental framework is epigenetic regulation, which governs gene expression without altering the underlying DNA sequence.⁴ Key mechanisms such as DNA methylation, histone modifications, and microRNA regulation act as an interface between the genome and the environmental exposures.⁴ As highlighted by Prof. Yazid, maternal diet, environmental factors, and gut microbiome interactions can induce lasting changes in fetal gene expression, creating a form of biological memory that embeds early exposures into long-term metabolic risk.^2,4,6 Importantly, these processes are most active during the first 1000 days of life, spanning from preconception through the first two years, a critical window of high developmental plasticity.² During this time, metabolic and epigenetic programming are most responsive to environmental inputs, representing a key opportunity for early intervention.² Such early-life exposures influence metabolic programming through structural and functional changes in organs, endocrine axes, leptin signaling, and hypothalamic appetite regulation.^1,7-9 Disruptions to these systems during development can lead to persistent metabolic dysregulation and long-term alterations in metabolic function.²

Given that obesity risk is transmitted across generations through both genetic and non-genetic pathways, this intergenerational cycle will perpetually drive metabolic disease if left unaddressed.² Parental obesity remains another strong predictor of childhood obesity risk, with a 4-5-fold increase when one parent is overweight and up to a 13-fold increase when both parents are obese.¹⁰ This risk is further compounded by maternal obesity, gestational diabetes, rapid infant weight gain, and early adiposity rebound.² Against this backdrop, Prof. Yazid emphasized that adult-focused lifestyle interventions alone are often insufficient, as they do not reverse early-life biological programming.² Effective prevention, therefore, requires a comprehensive life-course approach, encompassing preconception weight optimization, appropriate gestational weight gain, glycemic control during pregnancy, promotion of exclusive breastfeeding, and sustained promotion of physical activity throughout childhood, coupled with early risk stratification.^2,11

In Malaysia, efforts to address this growing burden already reflect a shift toward community-based strategies.² National initiatives such as Komuniti Sihat Pembina Negara (KOSPEN), My Body is Fit and Fabulous (MyBFF), and JomMAMA, target risk factors across different stages of life, supporting a life-course approach to prevention.² Emerging approaches increasingly incorporate precision medicine, early biomarker detection, digital health, and AI-driven risk prediction integrating genomic data into these strategies, alongside family-based interventions.^1,2,12-16

In conclusion, obesity and related metabolic diseases originate early in life through the interaction of genetic susceptibility, epigenetic regulation, and environmental exposure.² Recognizing and addressing these upstream determinants is essential to interrupt intergenerational transmission and achieve meaningful long-term reductions in metabolic disease burden.²