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Strain Name:

NOD/ShiLtJ-Leprdb-5J/LtJ

Stock Number:

004939

Availability:

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General Terms and Conditions

Former Name      NOD-Leprdb-5J/Lt    (Changed: 07-MAR-07 )
Genes & Alleles   Lepr;   Leprdb-5J;

Product Information

Strain Details

Type JAX® GEMM® Strain - Coisogenic
Additional information on JAX® GEMM® Strains.
Type JAX® GEMM® Strain - Mutant Strain
Mating SystemHeterozygote x Heterozygote         (Female x Male)
Specieslaboratory mouse
Donating Investigator Edward Leiter,   The Jackson Laboratory
H2 Haplotypeg7
Generation[F105+4p]N1+F2 (10-DEC-07)

Appearance
albino
Related Genotype: A/A Tyrc/Tyrc

Strain Description
Co-isogenic, NOD/ShiLtJ- Leprdb-5J/LtJ (NOD- Leprdb-5J) homozygous mice develop juvenile onset obesity and type II diabetes coupled with suppression of spontaneous type I diabetes in which the NOD/ShiLtJ (NOD/Lt) strain is known. RT-PCR confirms the expression of the leptin receptor long isoform (Rb) in the hypothalamus. NOD/Lt mice homozygous for this mutation are viable and retain some fertility although the stock is maintained by heterozygous matings. By 5 weeks of age, homozygous mice are hyperphagic, eating twice the amount of mouse chow as lean controls and develop hyperglycemia not requiring insulin therapy for long tem survival (39+ weeks of age). Lean littermate mice (wildtype or heterozygotes) develop spontaneous type 1 diabetes in an age dependent (post-adolescent) manner. In contrast, Leprdb-5J homozygotes of both sexes develop hyperglycemia within 1-2 weeks of weaning. This is a type II diabetes based upon chronically elevated insulin and leptin levels maintained over periods up to 1 year. Pancreatic histopathology in most individuals shows islet hypertrophy with beta cell hyperplasia that is not restricted by insulitis. Insulitis, when present, is primarily peri-vascular/periductular and not intra-islet. Approximately 1/3 of mutants progress to an end-stage Type II diabetes with decreases in body weight and plasma insulin whereas 2/3 maintain obese body weight (35-45g) in association with a beta cell hypertrophy/hyperplasia phenotype (Lee et al., 2005). Originally, mutant males were reported as more severely affected than females, but current unpublished results show the same multiplicity of phenotypes in females. Serum lipid levels were not significantly increased in any of the Leprdb-5J homozygous mutant mice, current studies are showing an unexplained variability in this phenotype. No significant pathology was originally observed in the liver or kidney (Lee et al., 2005). Splenic leukocytes from young, hyperglycemic mutants transferred into NOD.Rag1 recipients did not transfer type I diabetes over 13 weeks; whereas wild-type donor cells did. However, widespread insulitis was transferred by Leprdb-5J donors, indicating that their splenocytes contained a less-activated effector population at the time of transfer. Reciprocal bone marrow transfers confirmed that Leprdb-5J marrow contained diabetogenic stem cells; however, the slower diabetes generated by either wildtype or mutant marrow transferred into irradiated Leprdb-5J recipients indicated that the disturbed metabolic milieu produced by the obesity mutation was the major reason for suppressing the diabetogenic potential of marrow precursors (Lee et al., 2006). Leptin has been reported to accelerate T1D onset in juvenile NOD females (Matarese et al., 2002). The leptin-resistant NOD- Leprdb-5J mouse is useful for dissecting the interaction between the endocrine and immune system in type 1 diabetes-prone mice; understanding the trophic factors generated to produce robust proliferation of B-cells; and studying the involvement of leptin signaling in cueing the cytopathic function of autoimmune T-effector cells.

Strain Development
The recessive Leprdb-5J mutation in the leptin receptor gene (Chr. 4) arose spontaneously in the NOD/ShiLtJ (Stock No. 1976) production colony at The Jackson Laboratory in 2003 (Lee et al., 2005). The mutation was eliminated from breeder stock in the production colony but Dr. Edward Leiter retained heterozygous breeders. The Leprdb-5J mutation present in this NOD/Lt strain contains a G-T transversion mutation at position 640 encoding a valine instead of a glycine; eliminates a Hae III restriction site present in the wild-type receptor and resides in the distal portion of the extra-cellular domain (Lee et al., 2005). Thus, unlike the commonly studied Leprdb-1J mutation that lacks the intracellular signaling domain, the Leprdb-5J molecule retains an intact intracellular domain. In 2006, the T1DR received this strain at generation F105+4.

Mammalian Phenotype Terms assigned by genotype

Leprdb-5J/Leprdb-5J

        NOD/ShiLtJ
  • digestive/alimentary phenotype
  • abnormal islet of Langerhans morphology (MGI Ref ID J:87061)
    • abnormal pancreatic beta cell morphology (MGI Ref ID J:87061)
      • hyperplasticity and beta-degranulation of the islets of Langerhans
  • endocrine/exocrine gland phenotype
  • abnormal islet of Langerhans morphology (MGI Ref ID J:87061)
    • abnormal pancreatic beta cell morphology (MGI Ref ID J:87061)
      • hyperplasticity and beta-degranulation of the islets of Langerhans
  • growth/size phenotype
  • obese (MGI Ref ID J:87061)
    • both males and females are obese by weaning age
  • homeostasis/metabolism phenotype
  • hyperglycemia (MGI Ref ID J:87061)
    • age of onset by 5 weeks
  • increased circulating insulin level (MGI Ref ID J:87061)

Leprdb-5J/Leprdb-5J

        NOD/ShiLt-Leprdb-5J
  • life span-post-weaning/aging
  • premature death (MGI Ref ID J:118305)
    • 3/6 males showing weight loss with severe hyperglycemia die by 41-49 weeks of age
    • mice with juvenile-onset hyperglycemia did not require insulin therapy to survive to >39 weeks, whereas wild type NOD littermates developed adult onset hyperglycemia, rapidly lost weight, and were euthanized
  • growth/size phenotype
  • increased weight gain (MGI Ref ID J:118305)
    • within 1 week of weaning, mice gain 6-10 grams more than wild type littermates
    • females show rapid weight gain up ~15 weeks of age to a ~stable weight of 40 grams
    • males also show marked weight gain after weaning; in 64.7% of males (11/17), postpubertal (from 7 weeks of age) weight gain continues
  • weight loss (MGI Ref ID J:118305)
    • 35.3% (6/17) homozygous males show a persistent decrease in weight beginning at 7-9 weeks and continuing to 39 weeks of age
  • homeostasis/metabolism phenotype
  • *normal* homeostasis/metabolism phenotype (MGI Ref ID J:118304)
    • plasmacorticosterone levels in mutants and NOD controls are similar
    • abnormal circulating glucose level (MGI Ref ID J:118305)
      • hyperglycemia in all females and subset of males remits to normoglycemia with increasing age, while lean littermates show progression to type I diabetes
      • 4/11 males showing maintained elevated body weight become normoglycemic (glucose 145 mg/dl at 39 weeks); remaining 7 males in this group are still hyperglycemic but exhibit lower mean blood glucose level (386 mg/dl) at 39 weeks
      • hyperglycemia (MGI Ref ID J:118305)
        • develops in most obese mice withing 2 weeks of weaning
        • the males (6/17) showing decrease in body weight display severe hyperglycemia (glucose 581 mg/dl at 39 weeks)
        • by 5-7 weeks of age, 4/5 females and 11/17 males are hyperglycemic (glucose >200 mg/dl) and most remain hyperglycemic through the peripubertal period (253-686 mg/dl at 13 weeks)
    • increased circulating insulin level (MGI Ref ID J:118305)
      • levels increase markedly above lean controls with age
      • females remitting to normoglycemia still exhibit elevated insulin levels; males showing weight loss display reduced insulin levels (~nondiabetic control), while males maintaining elevated weight still show elevated levels
    • increased circulating leptin level (MGI Ref ID J:118305)
      • levels increase markedly above lean controls with age
      • females remitting to normoglycemia still exhibit elevated leptin levels
  • endocrine/exocrine gland phenotype
  • abnormal islet of Langerhans morphology (MGI Ref ID J:118305)
    • animals that maintained high body weight with or without remission from intermediate levels of hyperglycemia have extremely hyperplastic islets with well-granulated beta cells; islets display peri-insulitis
    • males exhibiting unrestrained hyperglycemia and weight loss have islets reduced in size and number of granulated beta cells, but showing minimal intraislet insulitis
    • abnormal pancreatic beta cell morphology (MGI Ref ID J:118305)
      • islets are normal-sized with markedly degranulated beta cells
  • pancreas inflammation (MGI Ref ID J:118305)
    • perivascular/periductular infiltrates are present but nor intraislet infiltrates are observed
  • digestive/alimentary phenotype
  • abnormal islet of Langerhans morphology (MGI Ref ID J:118305)
    • animals that maintained high body weight with or without remission from intermediate levels of hyperglycemia have extremely hyperplastic islets with well-granulated beta cells; islets display peri-insulitis
    • males exhibiting unrestrained hyperglycemia and weight loss have islets reduced in size and number of granulated beta cells, but showing minimal intraislet insulitis
    • abnormal pancreatic beta cell morphology (MGI Ref ID J:118305)
      • islets are normal-sized with markedly degranulated beta cells
  • pancreas inflammation (MGI Ref ID J:118305)
    • perivascular/periductular infiltrates are present but nor intraislet infiltrates are observed
  • behavior/neurological phenotype
  • polyphagia (MGI Ref ID J:118305)
    • early weight gain is associated with hyperphagia; at 5 weeks, mice consume twice as much as lean controls
  • adipose tissue phenotype
  • increased percent body fat (MGI Ref ID J:118305)
    • at 15 weeks, females have 40.5% carcass fat vs 19.9% in lean littermates; males show 33% body fat vs 14.7% in lean males
  • immune system phenotype
  • abnormal CD4-positive T cell morphology (MGI Ref ID J:118304)
    • CD4+ CD25+ T cells are slightly reduced in percentage compared to control NOD/LtJ mice (8.0 vs 9.5%)
  • abnormal CD8-positive T cell morphology (MGI Ref ID J:118304)
    • beta cell autoreactive CD8+ T cell clonotypes are decreased in mutants compared to NOD controls; IGRP and insulin-reactive CD8+ clonotypes are 5.7- and 1.7-fold lower in spleens of female mutants compared to controls
  • pancreas inflammation (MGI Ref ID J:118305)
    • perivascular/periductular infiltrates are present but nor intraislet infiltrates are observed
  • hematopoietic system phenotype
  • abnormal CD4-positive T cell morphology (MGI Ref ID J:118304)
    • CD4+ CD25+ T cells are slightly reduced in percentage compared to control NOD/LtJ mice (8.0 vs 9.5%)
  • abnormal CD8-positive T cell morphology (MGI Ref ID J:118304)
    • beta cell autoreactive CD8+ T cell clonotypes are decreased in mutants compared to NOD controls; IGRP and insulin-reactive CD8+ clonotypes are 5.7- and 1.7-fold lower in spleens of female mutants compared to controls

Gene & Allele Details

Allele Symbol Leprdb-5J
Allele Name diabetes 5 Jackson
Mutation Made By Edward Leiter,   The Jackson Laboratory
Strain of OriginNOD/ShiLtJ
Gene Symbol and Name Lepr, leptin receptor
Chromosome 4
Gene Common Name(s) CD295; Fa; LEPROT; Leprb; Modb1; OB-RGRP; OBR; db; diabetes; leptin receptor gene-related protein; obese-like; obl;
Molecular Note A G to T transversion mutation was found in exon 13 effecting a glycine640valine change in the receptor. [MGI Ref ID J:87061]

Control Information

  Control
   Wild-type from the colony
   001976 NOD/ShiLtJ
 
  Considerations for Choosing Controls

Genotyping Protocols

Leprdb

Colony Maintenance

Breeding & HusbandryHomozygotes of both sexes breed. However, homozygote x homozygote crosses are often unproductive.
Diet Information LabDiet® 5K52/5K67

Related Strains

NOD Strains
001976   NOD/ShiLtJ
View NOD Strains     (1 strain)

View Strains carrying other alleles of Lepr     (11 strains)

Animal Health Reports

Room Number           AX11

Research Applications

This mouse can be used to support research in many areas including:

Diabetes and Obesity Research
Hyperglycemia
Hyperinsulinemia

Leprdb-5J related

Diabetes and Obesity Research
Hyperglycemia
Hyperinsulinemia

References

Selected Reference(s)

Lee CH; Chen YG; Chen J; Reifsnyder PC; Serreze DV; Clare-Salzler M; Rodriguez M; Wasserfall C; Atkinson MA; Leiter EH. 2006. Novel leptin receptor mutation in NOD/LtJ mice suppresses type 1 diabetes progression: II. Immunologic analysis. Diabetes 55(1):171-8. [PubMed: 16380490]  [MGI Ref ID J:118304]

Lee CH; Reifsnyder PC; Naggert JK; Wasserfall C; Atkinson MA; Chen J; Leiter EH. 2005. Novel leptin receptor mutation in NOD/LtJ mice suppresses type 1 diabetes progression: I. Pathophysiological analysis. Diabetes 54(9):2525-32. [PubMed: 16123339]  [MGI Ref ID J:118305]

Leiter EH; Lee C-H; Reifsnyder PC; Naggert JK. 2004. Leptin receptor deficiency in NOD/LtJ mice produces a type 2 diadetes syndrome with suppressed autoimmunity MGI Direct Data Submission :.  [MGI Ref ID J:87061]

Price and Supply Information

Strain Name: NOD/ShiLtJ-Leprdb-5J/LtJ
Stock Number: 004939

Price Details

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Supply Details

Standard SupplyRepository-Live. A collection of over 1000 strains maintained as live colonies. Individual colonies are sized to meet current customer demand. Delivery for orders of 10 mice or less ranges on average from one to eight weeks; mice are generally shipped between four to six weeks of age with a maximum shipping age of ~nine weeks. Colony sizes do not generally support stringent age specifications for large volumes of mice; however custom orders and larger quantities of mice are easily arranged. Estimated ship dates for all orders provided within 48 hours of order placement.
Supply Notes Usually shipped between four and eight weeks of age.
This strain is included in the Type 1 Diabetes Repository collection.
LicensingSee General Terms and Conditions below  
Control InformationView Control Information in Strain Details.

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The Jackson Laboratory has rigorous genetic quality control and mutant gene genotyping programs to ensure the genetic background of JAX® Mice strains as well as the genotypes of strains with identified molecular mutations. JAX® Mice strains are only made available to researchers after meeting our standards. However, the phenotype of each strain may not be fully characterized and/or captured in the strain data sheets. Therefore, we cannot guarantee a strain's phenotype will meet all expectations. To ensure that JAX® Mice will meet the needs of individual research projects or when requesting a strain that is new to your research, we suggest ordering and performing tests on a small number of mice to determine suitability for your particular project.
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