Is obesity our genetic legacy?

CONTEXT To design rational management regimes and identify novel therapeutic targets, it is essential to understand the biological drivers of the current epidemic of obesity. This review describes our current knowledge of genetic factors in obesity, drawing functional parallels in the underlying neuroendocrine mechanisms and suggesting promising new directions for research. EVIDENCE ACQUISITION Published literature, addressing both the current knowledge of genetics of monogenic and syndromic forms of extreme obesity, and the emerging literature on genetic factors associated with more common forms of obesity are analyzed. EVIDENCE SYNTHESIS The current genetic evidence in obesity underlines the importance of neuroendocrine mechanisms of appetite regulation. Monogenic forms of disease explain 6% of children with extreme obesity, having hyperphagia associated with defects in the leptin-melanocortin pathway, as a central feature. Candidate gene association studies indicate that more subtle variations of the same genes also contribute to common forms of obesity. Well-powered genome-wide association studies recently identified FTO as a strong contributor to both childhood and adult obesity, demonstrating the power of such hypothesis-free analysis to provide new insights into the underlying pathogenic mechanisms of a common complex disease. CONCLUSIONS Although there has been some very heartening recent progress in elucidating genetic mechanisms underlying obesity, we are still a long way from explaining the high heritability of adiposity. Investigations of different forms of variation, such as copy number polymorphism, may extend our understanding of this condition.