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Our knowledge of the potential genetic link between fat metabolism and the reproductive axis dates back to the 1950s when the obese (ob/ob) mouse strain was first described. These mice were not only distinctly hyperphagic and rapidly developed obesity associated with hyperglycaemia and insulin resistance, but they were also infertile.1 It was not until 1994 when the leptin (ob) gene was postionally cloned and a mutation was identified in the coding sequence of murine leptin in ob/ob mice that the cause of their obesity was recognised.2 As predicted from the phenotype of ob/ob mice, leptin, which is principally expressed in adipocytes, had potent actions to suppress appetite and stimulate energy expenditure. It rapidly became clear that leptin could also influence the reproductive system. The sterility of male and femaleob/ob mice could be reversed when recombinant leptin was administered.3 4
In humans, initial studies focused on the possible role that leptin may play in obesity. The hypothesis that leptin deficiency may contribute to common human obesity was soon rejected. An exponential relation between serum leptin concentration and body mass index or percentage body fat was described,5 implying that, as a person became fatter, so insensitivity to the anorexigenic action of leptin developed. However, the relation between body fat and reproductive ability in humans has long been recognised. Both anorexia nervosa and intense physical training are associated with reduced gonadotrophin levels,6 while Frisch had proposed that a certain amount of body fat must be accrued to achieve regular menstruation.7 There is therefore a clear link between peripheral energy stores (in fat) and central regulation of physical development and reproductive capacity. Studies in animals and humans over the last four years have provided compelling evidence that leptin may be a neurohumoral mediator capable of signalling between …
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