e increased potency of leptin in lean mice receiving the protein via ICV infusion and those receiving subcutaneous injections shows that the central nervous system, in particular the hypothalamus, is an important site of leptin action," says Friedman. "Indeed, chronic ICV infusions of very low doses of leptin replicate the weight-reducing effects of much higher doses of leptin given by injection. The basis for this apparent difference is not clear, but may suggest that the transport of leptin across the blood-brain barrier, which allows leptin to enter the brain from the body's blood stream, may be an important step in the body's processing of leptin's signal."

Specifically, in normal, lean mice, injecting leptin subcutaneously at an infusion rate of 200 ng per hour, for example, led to an increase in blood levels, from 5 to 7 ng/milliliter, and resulted in a 5 percent reduction in weight. A doubling of leptin levels led to a 9 percent reduction in weight, while a five-fold increase in leptin levels yielded a 15 percent weight loss.

Other lean mice receiving leptin through ICV infusion rapidly lost fat, reaching their lowest weight by the eighth day of treatment and maintained it for the remainder of the 30-day infusion period. The mice reduced their food intake to its lowest level, a drop of more than 50 percent, by the third day, but their food intake crept back to original levels by the eighth day. After the 30 days of ICV, the researchers replaced the cerebrospinal fluid and the mice quickly recovered their weight by eating more food.

To compare leptin's affects via injection and ICV infusion among overweight mice, the researchers selected strains of mice with different types of obesity. One type, the Diet Induced Obese (DIO) mouse, is lean when fed regular mouse chow, but has an inherited predisposition to develop obesity when fed a diet in which 45 percent of the calories are from fat.

The second strain, the New Zeala
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Contact: Marion E. Glick
runews@rockvax.rockefeller.edu
212-327-7900
Rockefeller University
1-Aug-1997

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