Effect of the genetic background on the reproduction of leptin-deficient obese mice

Obesity is often associated with an impairment of the hypothalamic-pituitar y-gonadal axis. The leptin-deficient ob/ob mouse model is characterized by a morbid obesity with a sterility in males and females that is corrected by continuous leptin treatment. Since ob/ob mice are maintained on the C57BL/ 6J inbred genetic background, we sought to determine whether their infertil ity can be corrected without leptin treatment but via the effect of modifie r genes brought into the obese-sterile phenotype by a different genetic bac kground. Thus, we generated via an F-2 intercross ob/ob mice on a mixed C57 BL/6J-BALB/cJ genetic background and assayed them for fertility by mating w ith wild-type C57BL/6J mice. Whereas genetically heterogeneous F-2 obese fe males remained sterile like male and female C57BL/6J ob/ob mice, 41% of F-2 C57BL/6J-BALB/cJ obese males were capable of reproducing despite a morbidl y obese state. Therefore, the sterility of the original C57BL/6J ob/ob mous e model was genetically corrected independently of its obese state via the effects of modifier genes. Unlike testosterone levels, triglyceride levels, and testes weight-to-body weight ratios, which were all higher in fertile vs. sterile mice, glucose levels were similar in both groups, indicating th at the underlying hyperglycemia of ob/ob mice was not an impediment to the onset of fertility. A genome-wide scan in F-2 ob/ob males resulted in the l ocalization of four modifier loci on chromosomes 1, 3, 5, and 14 with respe ctive quantitative traits consisting of number of pregnancies, testes weigh ts normalized to body weights, body weight at 8 weeks of age, and circulati ng testosterone. We conclude that the inheritance of modifier genes at the identified loci acts to promote fertility of otherwise sterile leptin-defic ient obese male mice.