Correction of the sterility defect in homozygous obese female mice by treatment with the human recombinant leptin

Abstract

The sterility of male and female homozygous ob/ob mice is a recognized feature of the ob mutation¹. Whereas ob/ob males can occasionally reproduce if maintained on a restricted diet, ob/ob females are always sterile². Thinning of the ob/ob females to normal weight by diet-restriction failed to correct their sterility. Early sexual development is normal in ob/ob females; however, ovulation never follows and the mice remain prepuberal indefinitely with no occurrence of oestrus cycles. Reproductive hormones are reduced in ob/ob females³ demonstrating a functional defect from the hypothalamic-pituitary axis^4–6. The ovaries of ob/ob females are capable of producing viable eggs when transplanted into lean female recipients⁷. Reconstitution of reproductive functions in the ob/ob female necessitates delivery of hypothalamic extracts to the third ventricle⁸ and administration of pituitary extracts⁹, gonadotropic hormones¹⁰, progesterone¹¹ and relaxin¹². These previous findings demonstrate that the sterility of ob/ob females is caused by an insufficiency of hormones at the hypothalamic-pituitary level rather than physical hindrance of copulatory activity, pregnancy and parturition caused by excess adipose tissue. We show here that repeated administration of only the recombinant human ob protein, leptin, into homozygous female ob/ob mice can correct their sterility, thus resulting in ovulation, pregnancy and parturition.