Sandovici Ionel, Morais Tiago, Constância Miguel, Monteiro Mariana P
Department of Obstetrics and Gynaecology, National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge CB2 0SW, UK.
Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge CB2 0QQ, UK.
J Endocr Soc. 2025 Aug 4;9(9):bvaf129. doi: 10.1210/jendso/bvaf129. eCollection 2025 Sep.
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.
肥胖源于遗传、激素、饮食和行为因素的复杂相互作用，这些因素导致慢性能量失衡、脂肪过度堆积、全身炎症和胰岛素抵抗，从而增加代谢性疾病的风险。最近的证据表明，表观遗传机制，如DNA甲基化模式、组蛋白修饰和染色质可及性的变化，在肥胖风险的病因、进展和代际传递中发挥着重要作用。在这篇综述中，我们首先探讨在致肥胖环境背景下细胞代谢与表观遗传学之间的联系，并强调导致细胞类型和性别特异性表观遗传变化的机制。然后，我们重点介绍了最近的人体研究，这些研究揭示了关键代谢器官中的表观遗传改变，这些改变区分了代谢健康的肥胖与合并胰岛素抵抗、代谢综合征、2型糖尿病和代谢功能障碍相关脂肪性肝病的肥胖。在小鼠身上进行的机制研究支持表观遗传机制在驱动肥胖的代谢合并症方面发挥重要作用。鉴于难以直接获取与代谢稳态直接相关的组织，外周血表观遗传生物标志物为肥胖这些代谢合并症的发病机制提供了见解，并可能预测它们未来的发展。肥胖相关表观遗传变化的动态和可逆性质突出了它们的治疗潜力。未来的研究应应对组织特异性、与基因变异的相互作用以及表观遗传改变的功能影响等挑战。扩大对代际遗传、RNA修饰的研究以及表观遗传疗法的开发有望减轻肥胖相关代谢合并症的影响，并为临床实践中的精准干预提供依据。
