The genetics of obesity. Lessons for polycystic ovary syndrome

Both polycystic ovary syndrome (PCOS) and obesity are common disorders with a complex phenotype. Both are presumably heterogeneous in etiology. Understanding the genetics of obesity, which has a longer and richer history, may therefore illuminate the genetics of PCOS, where major projects are now underway. Obesity may be the penultimate condition in which the effects of heredity and environment will forever mingle. Most obesity mutations identified to date (with the exception of the Agouti mutation) are inherited in an autosomal recessive manner. Therefore, it is unlikely that such mutations, even when identified in a human population, could explain only a fraction of the cases that make up the high prevalence of both of these disorders. Although the mouse models of single gene defects causing obesity contain many similar aspects of the PCOS phenotype such as obesity and subfecundity, there is no mouse model that mimics all aspects of the syndrome, especially the circulating androgen excess. This elevation in circulating androgens may be the sine qua non of the syndrome as indicated by our findings in sisters of PCOS probands that hyperandrogenemia may be the distintinctive reproductive phenotype. Isolation of PCOS and obesity genes may allow the development of targeted interventions that will lead to effective and safe treatment of both obesity and PCOS.