Molecular Mechanisms Associated with Metabolic Dysfunction: Contributions of Nutritional Genomics

Nutritional genomics has expanded our understanding of how dietary exposures interact with genetic and epigenetic mechanisms involved in metabolic dysfunction. In this context, metabolic dysfunction associated with excessive visceral adiposity arises from a multifaceted interaction between systemic inflammation, insulin resistance, and inter-individual biological susceptibility. Obesity, particularly when driven by diets rich in saturated fatty acids, disrupts intestinal homeostasis, thereby triggering metabolic endotoxemia and contributing to low-grade systemic inflammation and adipose tissue dysfunction. Advances following the Human Genome Project have broadened our understanding of the molecular mechanisms of metabolic diseases, highlighting the role of genetic variability and epigenetic regulation in obesity-related insulin resistance. In nutritional science, the integration of genomics and proteomics has further elucidated how dietary exposures interact with the biological pathways involved in this dysfunction. From a nutrigenomic perspective, this narrative review aims to discuss how genetic variability and diet-related molecular mechanisms contribute to obesity-related metabolic dysfunction, with emphasis on single-nucleotide polymorphisms in key genes, including FTO, MC4R, PPAR, APOA, and FADS, involved in the regulation of energy homeostasis and insulin secretion. Additionally, we analyze studies on epigenetic mechanisms, including DNA methylation and the action of microRNAs, which act as post-transcriptional regulators sensitive to nutritional and inflammatory stimuli. We also address how dietary patterns, such as the Mediterranean Diet, as well as nutrients and bioactive compounds, can influence epigenetic regulation. We conclude that integrating multiomics data may improve our understanding of the molecular mechanisms underlying metabolic dysfunction and may support the future development of personalized nutritional strategies and molecular biomarkers for obesity and cardiometabolic diseases.