Recombinant leptin exchanges between parabiosed mice but does not reach equilibrium

Parabiosis experiments suggest that ob/ob mice are deficient in a circulating ''lipostatic'' signal but respond to such a signal when it is delivered in the cross circulation from their parabiotic partner. Identification of leptin as the mutation in ob/ob mice leads to the assumption that leptin is the lipostatic signal. The objective of these experiments was to determine the circulating half-life of leptin and to demonstrate whether it exchanged between parabiosed mice. Measurement of disappearance of recombinant leptin from serum in SWRJ mice indicated a circulating half-life of similar to 36 min. Single ob/ob mice or one member of a parabiosed pair of ob/ob mice received 50 mu g recombinant murine leptin in two intraperitoneal injections a day for 10 days, starting 40 days after parabiosis surgery. Control mice and pairs received equivalent injections of vehicle. In single mice. leptin significantly reduced food intake, body weight, serum insulin, and pancreatic and liver weight. Leptin treatment of one member of a parabiosed pair of ob/ob mice reduced serum insulin, gut content (an index of food intake), and body fat in both partners. The injected parabiont lost more fat than its partner, and body temperature was increased only in the injected mouse, indicating that leptin did not reach equilibrium in the two animals. This was confirmed by Western blot analysis of serum leptin measured 2 h after injection. Therefore, although leptin can exchange between parabionts, its half-life is inadequate to allow equilibrium when a large concentration gradient exists between partners.