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

被引:93
作者
Chung, WK
Belfi, K
Chua, M
Wiley, J
Mackintosh, R
Nicolson, M
Boozer, CN
Leibel, RL
机构
[1] Columbia Univ Coll Phys & Surg, Dept Pediat, Div Mol Genet, New York, NY 10032 USA
[2] Columbia Univ Coll Phys & Surg, Dept Med, Inst Human Nutr, New York, NY 10032 USA
[3] Rockefeller Univ, Human Behav & Metab Lab, New York, NY 10021 USA
[4] Amgen, Thousand Oaks, CA 91320 USA
关键词
leptin receptor; fat mass; obesity; diabetes;
D O I
10.1152/ajpregu.1998.274.4.R985
中图分类号
Q4 [生理学];
学科分类号
071003 ;
摘要
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 (Lepr(ob)/Lepr(ob)) and leptin receptor gene-defective (Lepr(db)/Lepr(db)) mouse. In the experiments reported here, we investigated the effects of heterozygosity 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 elucidate their physiology. Adult mice heterozygous for the Lep(ob) or Lepr(db) 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 Lepr(db)/+ 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 Lepr(db) (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 Lepr(db)/+ 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.
引用
收藏
页码:R985 / R990
页数:6
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