Strain Name:

NOD/ShiLtJ-Leprdb-5J/LtJ

Stock Number:

004939

Availability:

Cryopreserved - Ready for recovery

Description

The genotypes of the animals provided may not reflect those discussed in the strain description or the mating scheme utilized by The Jackson Laboratory prior to cryopreservation. Please inquire for possible genotypes for this specific strain.

Strain Information

Former Names NOD-Leprdb-5J/Lt    (Changed: 07-MAR-07 )
Type Coisogenic; Mutant Strain;
Additional information on Genetically Engineered and Mutant Mice.
Visit our online Nomenclature tutorial.
Specieslaboratory mouse
H2 Haplotypeg7
GenerationF105+4pN1
 
Donating Investigator Edward Leiter,   The Jackson Laboratory

Appearance
albino
Related Genotype: A/A Tyrc/Tyrc

Description
Coisogenic, 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/ShiLt) strain is known. RT-PCR confirms the expression of the leptin receptor long isoform (Rb) in the hypothalamus. NOD/ShiLt mice homozygous for this mutation are viable and retain some fertility although the stock is maintained by heterozygous matings. By five 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 (wild-type 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 one to two weeks of weaning. This is a type II diabetes based upon chronically elevated insulin and leptin levels maintained over periods up to one 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 one third of mutants progress to an end-stage Type II diabetes with decreases in body weight and plasma insulin whereas two thirds maintain obese body weight (35-45g) in association with a beta cell hypertrophy/hyperplasia phenotype (Lee et all., 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 Originally, mutant males were reported as more severely affected than females, but current unpublished results show the same multiplicity of phenotypes in females.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 wild-type 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.

Development
The recessive Leprdb-5J mutation in the leptin receptor gene (Chromosome 4) arose spontaneously in the NOD/ShiLtJ (Stock No. 001976) 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/ShiLt 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.

Control Information

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

Related Strains

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

View Strains carrying other alleles of Lepr     (15 strains)

Phenotype

Phenotype Information

View Mammalian Phenotype Terms

Mammalian Phenotype Terms
      assigned by genotype

Leprdb-5J/Leprdb-5J

        NOD/ShiLtJ
  • digestive/alimentary phenotype
  • degranulated pancreatic beta cells (MGI Ref ID J:87061)
    • beta-degranulation in the islets of Langerhans
  • pancreatic islet hyperplasia (MGI Ref ID J:87061)
  • endocrine/exocrine gland phenotype
  • degranulated pancreatic beta cells (MGI Ref ID J:87061)
    • beta-degranulation in the islets of Langerhans
  • pancreatic islet hyperplasia (MGI Ref ID J:87061)
  • 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 pancreatic islet 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
    • degranulated pancreatic beta cells (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 pancreatic islet 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
    • degranulated pancreatic beta cells (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
View Research Applications

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

Genes & Alleles

Gene & Allele Information

 
Allele Symbol Leprdb-5J
Allele Name diabetes 5 Jackson
Allele Type Spontaneous
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]

Genotyping

Genotyping Information

Genotyping Protocols

Leprdb-5J, Pyrosequencing
Leprdb-5J, Restriction Enzyme Digest

Helpful Links

Genotyping resources and troubleshooting

References

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]

Health & husbandry

The genotypes of the animals provided may not reflect those discussed in the strain description or the mating scheme utilized by The Jackson Laboratory prior to cryopreservation. Please inquire for possible genotypes for this specific strain.

Health & Colony Maintenance Information

Colony Maintenance

Breeding & HusbandryHomozygotes of both sexes breed. However, homozygote x homozygote crosses are often unproductive.

Purchasing information

Pricing, Supply Level & Notes, Controls, General Terms & Conditions

Pricing

Pricing for USA, Canada and Mexico shipping destinations View International pricing
Price (US dollars $)
Cryorecovery Fee $1900.00
Animals Provided

At least two mice that carry the mutation (if it is a mutant strain) will be provided. Their genotypes may not reflect those discussed in the strain description. Please inquire for possible genotypes and see additional details below.

Additional Supply Details

Pricing for International shipping destinations View USA Canada and Mexico pricing
Price (US dollars $)
Cryorecovery Fee $2470.00
Animals Provided

At least two mice that carry the mutation (if it is a mutant strain) will be provided. Their genotypes may not reflect those discussed in the strain description. Please inquire for possible genotypes and see additional details below.

Additional Supply Details

Supply Details

Standard SupplyCryopreserved. Ready for recovery. Please refer to pricing and supply notes for further information.
Supply Notes
  • Cryorecovery - Standard.
    We will fulfill your order by providing at least two pair of mice, at least one animal of each pair carrying the mutation of interest. The total number of animals provided, their gender and genotype will vary. Please inquire if larger numbers of animals with specific genotype and genders are needed. Animals typically ship between 13 and 16 weeks from the date of your order. If a second cryorecovery is needed in order to provide the minimum number of animals, animals will ship within 25 weeks. IMPORTANT NOTE: The genotypes of animals provided may not reflect the mating scheme utilized by The Jackson Laboratory prior to cryopreservation, or that discussed in the strain description. Please inquire about possible genotypes which will be recovered for this specific strain. The Jackson Laboratory cannot guarantee the reproductive success of mice shipped to your facility. If the mice are lost after the first three days (post-arrival) or do not produce progeny at your facility, a new order and fee will be necessary.

    Cryorecovery to establish a Dedicated Supply for greater quantities of mice.
    Mice recovered can be used to establish a dedicated colony to contractually supply you mice according to your requirements. Price by quotation. For more information on Dedicated Supply, please contact JAX® Services, Tel: 1-800-422-6423 (from U.S.A., Canada or Puerto Rico only) or 1-207-288-5845 (from any location).

  • This strain is included in the Type 1 Diabetes Repository collection.
  • Genomic DNA is available for this strain from the Mouse DNA Resource.

Control Information

  Control
   Wild-type from the colony
   001976 NOD/ShiLtJ
 
  Considerations for Choosing Controls
  USA, Canada and Mexico - Control Pricing Information for Genetically Engineered Mutant Strains.
  International - Control Pricing Information for Genetically Engineered Mutant Strains.

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