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Am J Physiol Regul Integr Comp Physiol 274: R985-R990, 1998;
0363-6119/98 $5.00
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Vol. 274, Issue 4, R985-R990, April 1998

Heterozygosity for Lepob or Leprdb affects body composition and leptin homeostasis in adult mice

Wendy K. Chung1, Kristen Belfi2, Melvin Chua1, Jennifer Wiley2, Ronald Mackintosh2, Margery Nicolson3, Carol N. Boozer4, and Rudolph L. Leibel1

1 Department of Pediatrics, Division of Molecular Genetics, and 4 Department of Medicine, Institute of Human Nutrition, Columbia University College of Physicians and Surgeons, New York 10032; 2 Laboratory of Human Behavior and Metabolism, Rockefeller University, New York, New York 10021; and 3 Amgen, Thousand Oaks, California 91320

In an effort to understand the genetics of human obesity, we have studied the physiology and molecular genetics of rodent models with monogenetic forms of obesity including the leptin gene-defective (Lepob/Lepob) and leptin receptor gene-defective (Leprdb/Leprdb) mouse. In the experiments reported here, we investigated the effects of heterozygosity at Lepob and Leprdb on body composition and circulating leptin concentration in +/+, Leprdb/+, and Lepob/+ adult mice to identify possible gene dosage effects of these mutations that might elucidate their physiology. Adult mice heterozygous for the Lepob or Leprdb allele had equivalent fat mass and percentage body fat, which was increased 27-47% and 23-35%, respectively, relative to +/+ littermates. Plasma leptin concentrations adjusted for fat mass were 6.5 ng/ml in the Lepob /+, 9.6 ng/ml in the +/+, and 11.5 ng/ml in the Leprdb/+ mice. Sex had no effect on plasma leptin after controlling for fat mass. These data, and data from a small number of mice heterozygous at both Lepob and Leprdb (compound heterozygotes), suggest that leptin protein produced per mass of body fat is reduced in Lepob/+ mice and that body fat is increased in Lepob/+ mice until plasma leptin concentrations reach that of a normal +/+ mouse. The elevated plasma leptin concentration in the Leprdb/+ mice suggests that LEPR may mediate 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.

leptin receptor; fat mass; obesity; diabetes


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