HETEROZYGOSITY FOR LEP(OB) OR LEPR(DB) AFFECTS BODY-COMPOSITION AND LEPTIN HOMEOSTASIS IN ADULT MICE

In an effort to understand the genetics of human obesity, we have stud ied the physiology and molecular genetics of rodent models with monoge netic forms of obesity including the leptin gene-defective (Lepr(ob)/L epr(ob)) and leptin receptor gene-defective (Lepr(db)/Lepr(db)) mouse. In the experiments reported here, we investigated the effects of hete rozygosity at Lep(ob) and Lepr(db) on body composition and circulating leptin concentration in +/+, Lepr(db)/+, and Lep(ob)/+ adult mice to identify possible gene dosage effects of these mutations that might el ucidate their physiology. Adult mice heterozygous for the Lep(ob) or L epr(db) allele had equivalent fat mass and percentage body fat, which was increased 27-47% and 23-35%, respectively, relative to +/+ litterm ates. Plasma leptin concentrations adjusted for fat mass were 6.5 ng/m l in the Lep(ob)/+, 9.6 ng/ml in the +/+, and 11.5 ng/ml in the Lepr(d b)/+ mice. Sex had no effect on plasma leptin after controlling for fa t mass. These data, and data from a small number of mice heterozygous at both Lep(ob) and Lepr(db) (compound heterozygotes), suggest that le ptin protein produced per mass of body fat is reduced in Lep(ob)/+ mic e and that body fat is increased in Lep(ob)/+ mice until plasma leptin concentrations reach that of a normal +/+ mouse. The elevated plasma leptin concentration in the Lepr(db)/+ mice suggests that LEPR may med iate autocrine suppression of Lep expression. These results raise the possibility that human mutations that have even subtle effects on the leptin/leptin receptor system in either the homozygous or heterozygous state may have significant effects on adiposity.