Heterozygosity for Lep(ob) or Lep(rdb) affects body composition and leptin homeostasis in adult mice.
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 (Lep(ob)/Lep(ob)) and leptin receptor gene-defective (Lep(rdb)/Lep(rdb)) mouse. In the experiments reported here, we investigated the effects of heterozygosity at Lep(ob) and Lep(rdb) on body composition and circulating leptin concentration in +/+, Lep(rdb)/+, and Lep(ob)/+ adult mice to identify possible gene dosage effects of these mutations that might elucidate their physiology. Adult mice heterozygous for the Lep(ob) or Lep(rdb) 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 Lep(ob)/+, 9.6 ng/ml in the +/+, and 11.5 ng/ml in the Lep(rdb)/+ 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 Lep(ob) and Lep(rdb) (compound heterozygotes), suggest that leptin protein produced per mass of body fat is reduced in Lep(ob)/+ mice 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 Lep(rdb)/+ 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.
Chung
W K
WK
Department of Pediatrics, Columbia University College of Physicians and Surgeons, New York 10032, USA.
Belfi
K
K
Chua
M
M
Wiley
J
J
Mackintosh
R
R
Nicolson
M
M
Boozer
C N
CN
Leibel
R L
RL
D000273:Adipose Tissue / Q000473:pathology; D000818:Animals; D001823:Body Composition / Q000502:physiology*; D015992:Body Mass Index; D002352:Carrier Proteins / Q000235:genetics*; D005260:Female; D018628:Gene Dosage; D005838:Genotype; D006579:Heterozygote; D006706:Homeostasis / Q000502:physiology*; D020738:Leptin; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL / Q000235:genetics; D009765:Obesity / Q000097:blood / Q000235:genetics* / Q000473:pathology; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D012727:Sex Characteristics
D002352:Carrier Proteins; C515448:LEPR protein, human; D020738:Leptin; D011506:Proteins; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; C515447:leptin receptor, mouse