Mice homozygous for the fat spontaneous mutation (Cpefat) on a C57BLKS/J genetic background (N10) have a diabetes phenotype that is primarily restricted to males and is more severe than what is seen on the original HRS/J or C57BLKS/J (N5) genetic backgrounds. At weaning both males and female homozygous mutant mice were significantly lighter than wildtype or heterozygous littermates. Obesity develops between 6 and 8 weeks of age and mutant mice can be distinguished from wildtype littermates between 8 and 12 weeks of age. By 18 weeks fat mutant mice will reach 45-55 g and may reach 60-70 g by 6 months of age. Thus, the obesity is thus slower to develop than in the obese (Lepob) and diabetes (Leprdb) mutant mice. The excess adiposity is distributed throughout the body's fat stores, in contrast to the largely axial and inguinal fat deposition of the obese and diabetes mutant mice. Hyperinsulinemia is severe by 4 weeks of age and continues throughout life; it is associated with hypertrophy and hyperplasia of the islets of Langerhans. Male homozygotes backcrossed 10 generations to C57BLKS/J develop severe hyperglycemia after the development of gross obesity compared to a milder diabetic syndrome seen in males on a HRS/J or 5th generation backcross to C57BLKS. In contrast to obese and diabetes mutant mice on a C57BLKS background, glucose levels do not continue to rise but plateau around 400 - 600 mg/dL After 30 weeks of age plasma glucose levels of most male mutant mice are below 300 mg/dL despite continued weight gain and obesity. Most female mutant mice are resistant to development of hyperglycemia. Hyperglycemia is not associated with significant beta-cell necrosis or islet atrophy, occurs primarily in males. Homozygous fat mutant mice do not exhibit the hypercorticism characteristic of both obese and diabetes mutant mice. Proopiomelanocortin (POMC), the precursor of several neuroendocrine peptides that are ordinarily secreted in a regulated fashion, is misassorted to the constitutive secretory pathway in the pituitary intermediate lobe of fat mutant mice. Naggert et al. (1995) proposed that the obesity of fat homozygous mutant mice may reflect "defects in processing of prohormone forms of a variety of neuropeptides associated with the control of energy balance, nutrient partitioning and satiety."
The fat spontaneous mutation arose spontaneously on the HRS/J strain and was backcrossed 5 generations (N5) to C57BLKS/J by Drs. Coleman and Eicher. Backcrossing was later continued to N10 by Dr. Edward Leiter.
|Gene Symbol and Name||Cpe, carboxypeptidase E|
|Strain of Origin||HRS/J|
|Molecular Note||The molecular mutation responsible for the phenotype in the fat mouse is a T to C transition at coding nucleotide 730 of the mRNA. The codon of this nucleotide corresponds to amino acid 244 of the unprocessed preproenzyme or amino acid 202 of the mature peptidase. The mutation alters a conserved serine to a proline residue in the encoded protein (p.S244P). Enzymatic activity of the mutant protein was shown to be abolished in fluorometric assays in vitro.|
This strain is maintained by mating heterozygous siblings as fat homozygous mutant mice are generally infertile. The genotype of progeny are determine by an allele specific PCR protocol (see Genetic Typing). Mice are maintained on a NIH-31 6% fat diet.
When using the fat mouse strain in a publication, please cite the originating article(s) and include JAX stock #002391 in your Materials and Methods section.
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