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 mutation (1). Whereas ob/ob males can occasionally reproduce if maintained on a restricted diet, ob/ob females are always sterile (2). 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 females (3) 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 recipients (7). Reconstitution of reproductive functions in the ob/ob female necessitates delivery of hypothalamic extracts to the third ventricle (8) and administration of pituitary extract (9), gonadotropic hormones (10), progesterone (11) and relaxin (12). 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.

Caloric restriction: Impact upon pituitary function and reproduction

“…Central application of leptin to animals that possess a fasting-disrupted GnRH/LH secretion profile was able to normalize this imbalance and re-instate reproductive function (Barash et al, 1996;Chehab et al, 1996;Nagatani et al, 1998). These findings suggest that the body can interpret circulating levels of leptin as an indicator of its metabolic state, which may then act as a gate to control the activity of the reproductive axis.…”

Effect of Central Antileptin Antibody on the Onset of Female Rat Puberty

“…One indication that leptin is involved in centrally regulated maturation of the reproductive system was the discovery that ob/ob females are always sterile [6], and weight loss induced by dietary restriction fails to correct their sterility. Importantly, their fertility can be reversed by leptin treatment in both sexes [7, 8]. The ob/ob leptin deficient and db/db leptin resistant mouse models have greatly advance our understanding regarding the pivotal role of leptin in reproduction [9, 10].…”

Relationship between metabolic syndrome and platelet responsiveness to leptin in overweight and obese patients

“…7 Although leptin's major role seems to be in the regulation of body weight and energy metabolism, several evidences suggest that this hormone could be involved in other pathophysiological mechanisms, such as immune function, angiogenesis, bone formation and fertility, and the expression of leptin receptor has been demonstrated in a variety of tissues. [8][9][10][11][12][13] The long form of leptin receptor (ObRb) has been found on platelet membrane, 14 and it has been demonstrated that leptin-deficient ob/ob mice, 15,16 and wild-type mice treated with a leptin-neutralizing antibody, 17 develop unstable thrombi and an attenuated thrombotic response to arterial injury, and they exhibit a defective platelet aggregation. Leptin also promotes thrombosis in the mouse, and it potentiates the aggregation of murine platelets in vitro in a leptin receptor-dependent manner.…”