Profile of BKS.Cg-m +/+ Leprdb/Jcl Mice
- Homozygous Leprdb/Leprdb individuals develop obesity from around 3-4 weeks of age, making them distinguishable from normal mice. Elevated plasma insulin levels are observed from around 10-14 days of age, while increased blood glucose levels begin from 4-8 weeks of age. Body weight increases rapidly between 3 and 8 weeks, reaching a maximum of 45g before declining until death. The cause of obesity is hyperphagia accompanied by hyperglycemia, which progressively worsens and exceeds 500mg/dl at 12 weeks of age. When blood glucose levels surpass 250mg/dl, symptoms such as glycosuria, polydipsia, and polyuria appear.
- Blood glucose levels cannot be controlled, and pancreatic beta cells responsible for insulin production exhibit severe damage, leading to death before 10 months of age. Even with insulin administration, severely affected individuals cannot regulate their blood glucose levels, and an increase in the activity of gluconeogenic enzymes is observed.
- Although the pancreas of young individuals shows significant variability, it decreases to 25% of the normal value around 12 weeks of age and remains at this level until death. The elevated plasma insulin levels return to nearly normal values by 8 weeks of age.
- Due to a short lifespan of 6-8 months, pathological changes in the kidneys, lungs, heart, and eyes are less likely to occur, but degranulation and rapid degeneration of pancreatic beta cells are observed. While both male and female homozygous individuals are infertile, transplantation of ovaries from homozygous females into normal females restores fertility. The testes of homozygous males are small, and spermatogenesis is not observed.
- Proteinuria and rapid thickening of the glomerular basement membrane (Like et al., 1972), as well as the expression of large amounts of immunoglobulins and complement in the glomerular interstitium (Mauer et al., 1976) have been reported.
- Severe homozygous Leprdb/Leprdb individuals appear to have abnormalities in the immune system, exhibiting characteristic anti-pancreatic immune activity in pancreatic cells and serum from 10 days of age (Debray-Sachs et al., 1983).
- Pancreatic beta cells contain intrafollicular type A particles, and these particles express p73 protein as their nucleus. p73 acts as a neoantigen, inducing an autoimmune response (Trayhurn, P. 1979).
- Homozygous individuals exhibit an increase in metabolic efficiency, leading to a decrease in energy consumption for thermogenesis (Trayhurn, P. 1979).
- This increased metabolic efficiency is also observed in heterozygous Leprdb/+ individuals. Although body weight, blood glucose levels, and plasma insulin levels are normal, they live longer than control congenic (+/+) individuals under long-term fasting conditions. This is due to a significantly higher conversion rate of acetone to lactic acid in (Leprdb/+) compared to (+/+) individuals induced by fasting (Coleman, D. L. 1979, 1980).
- Parabiosis between homozygous individuals and normal mice results in the inability of normal mice to eat and death within two weeks. This suggests that homozygous individuals lack a response to circulating satiety factors, leading to hyperphagia and preventing normal mice from eating. Studies on the destruction of the ventromedial nucleus of the hypothalamus support the notion that (Leprdb) is caused by hypothalamic damage (Herberg et al., 1977).
- The infertility of female homozygous individuals, which exhibit impaired secretion of gonadotropins, is also thought to be related to hypothalamic damage (Johnson et al., 1979).
※Quoted and modified from Jcl NEWS No.1, issued October 1, 1989, by CLEA Japan, Inc., Development Division.
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