Ionel Sandovici, Tiago Morais, Miguel Constância, Mariana P Monteiro
Journal of the Endocrine Society, Volume 9, Issue 9, September 2025, bvaf129
https://doi.org/10.1210/jendso/bvaf129
Obesity arises from a complex interaction of genetic, hormonal, dietary, and behavioral factors that drive chronic energy imbalance, excessive fat accumulation, systemic inflammation, and insulin resistance, thus increasing the risk of metabolic diseases. Recent evidence suggests a significant role for epigenetic mechanisms, such as changes in patterns of DNA methylation, histone modifications, and chromatin accessibility, in the aetiology, progression, and intergenerational transmission of obesity risk. In this review, we first explore the link between cellular metabolism and epigenetics in the context of an obesogenic environment and highlight the mechanisms leading to cell-type and sex-specific epigenetic changes. We then highlight recent human studies that uncovered epigenetic alterations in key metabolic organs that distinguish metabolically healthy obesity from obesity complicated with insulin resistance, metabolic syndrome, type 2 diabetes, and metabolic dysfunction-associated steatotic liver disease. Mechanistic studies performed in the mouse support an important role for epigenetic mechanisms in driving the metabolic comorbidities of obesity. Given the difficulty of accessing tissues directly implicated in metabolic homeostasis, peripheral blood epigenetic biomarkers offer insights into the pathogenesis of these metabolic comorbidities of obesity and may predict their future development. The dynamic and reversible nature of obesity-associated epigenetic changes underscores their therapeutic potential. Future research should address challenges such as tissue specificity, interactions with genetic variants, and the functional impact of epigenetic alterations. Expanding studies on intergenerational inheritance, RNA modifications, and the development of epigenetic therapies hold promise for mitigating the impact of obesity-related metabolic comorbidities and informing precision interventions in clinical practice.
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