The pathogenesis of obesity from a genomic and systems biology perspective.

The recent obesity epidemic has imposed significant health, economical, and societal concerns. However, effective preventive and therapeutic strategies are currently lacking, primarily due to a lack of comprehensive understanding of the underlying molecular mechanisms. Recent genome-wide scans of genetic variants, transcriptome, and epigenome have uncovered >50 genetic loci that predispose individuals to obesity and revealed hundreds of genes with altered transcriptional activity and/or epigenetic variations in obesity-related tissues upon various environmental challenges such as high caloric diets, lack of physical activity, and environmental chemicals. These discoveries highlight the importance of genes involved in the control of energy homeostasis and food intake by the central nervous system, as well as genes contributing to lipid metabolism, adipogenesis, fat cell differentiation, and immune response in peripheral tissues, in obesity development. Future studies that are directed to obtain a more comprehensive, systems-level understanding of disease mechanisms and that test novel therapeutic strategies aiming at systems-level normalization of the obesity-related molecular alterations are warranted.