| Phenotype Description |
Mice homozygous for the obese spontaneous mutation, (Lepob
commonly referred to as ob or ob/ob), are first recognizable
at about 4 weeks of age. Homozygous mutant mice increase in
weight rapidly and may reach three times the normal weight
of wildtype controls. In addition to obesity, mutant mice
exhibit hyperphagia, a diabetes-like syndrome of
hyperglycemia, glucose intolerance, elevated plasma insulin,
subfertility, impaired wound healing, and an increase in
hormone production from both pituitary and adrenal glands.
They are also hypometabolic and hypothermic. The obesity is
characterized by an increase in both number and size of
adipocytes. Although hyperphagia contributes to the obesity,
homozygotes gain excess weight and deposit excess fat even
when restricted to a diet sufficient for normal weight
maintenance in lean mice. Hyperinsulinemia does not develop
until after the increase body weight and is probably the
result of it. Homozygotes do have an abnormally low
threshold for stimulation of pancreatic islet insulin
secretion even in very young preobese animals. Female
homozygotes exhibit decreased uterine and ovarian weights,
decreased ovarian hormone production and hypercytolipidemia
in follicular granulosa and endometrial epithelial tissue
layers (Garris et al., 2004).
As is the case with mice carrying the diabetes mutation
(Leprdb), manifestation of the diabetic syndrome is
strikingly dependent on genetic background. Hyperglycemia is
only transient, (subsiding around 14 to 16 weeks) on the
C57BL/6J background. On the C57BLKS background, obese
homozygotes (Stock No. 000696) become severely diabetic with
regression of islets and early death. Cloning of the Lep
gene has made possible the production of recombinant leptin.
Injection of this protein into obese homozygotes sharply
reduces body weight, decreases food intake, increases energy
expenditure, and restores fertility in male mice.
Leptin can regulate bone mass through a central,
neuroendocrine signalling pathway. Similar to the effects of
aging in humans, homozygotes exhbit muscle hypoplasia
(quadriceps), increased marrow adipogenesis and decreased
bone mass in the hindlimbs (Hamrick et al., 2004).
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