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

Type Congenic; Targeted Mutation; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Additional information on Congenic nomenclature. Species laboratory mouse   Donating Investigator Martin G Myers,   University of Michigan Medical School

Description
Mice homozygous for the Lepr^Leu985 mutant allele (or l/l mice) are viable and fertile with a Tyr->Leu replacement at amino acid residue 985 of the leptin receptor long form (LRb)-specific exon 18b. The mutation specifically disrupts LRb-SHP2 and LRb-SOCS3 transcription factor signaling. The mutant protein, LRb^L985, is expressed normally and mediates other leptin signals normally, but fails to recruit SHP2 or SOCS3. Homozygous male and female mice are neuroendocrinologically normal, but homozygous females may exhibit decreased feeding, body weight, adipocity, circulating leptin, circulating insulin, expression of orexigenic neuropeptides, protection from high-fat diet-induced obesity, and increased leptin sensitivity depending upon diet and genetic background. Homozygous Lepr^Leu985 mutant mice may be useful for studying the influence of LRb-SHP2 and LRb-SOCS3 signaling in the physiological and metabolic function of leptin; specifically body energy homeostasis and neuroendocrine function, glucose homeostasis, melanocortin production, neuropeptide Y, obesity, diabetes, fertility and growth.

Development
A targeting vector was designed to replace the tyrosine residue at amino acid 985 of the leptin receptor long form (LRb)-specific exon 18b of the targeted gene with a leucine residue (generating a novel HindIII site and also inserting a neo cassette downstream of exon 18b). The donating investigator reports that the construct was electroporated into (129X1/SvJ x 129S1/Sv)F1-derived R1 embryonic stem (ES) cells and the resulting chimeric animals were bred with C57BL/6NCrl mice to generate Lepr^Leu985 mutant mice. These mice were then backcrossed to C57BL/6NCrl using a speed congenic approach for six generations prior to arrival at The Jackson Laboratory. Upon arrival, mutant mice were bred with C57BL/6NJ (Stock No. 005304) for at least one generation to establish the colony.

Control Information

	Control
	005304 C57BL/6NJ	(approximate)
Considerations for Choosing Controls

Related Strains

Strains carrying other alleles of Lepr

000709	129P3/J-Leprdb-3J/J
002048	B6 x C57BLKS-Dock7m Leprdb Myo15sh2-J/J
017527	B6.129(FVB)-Leprtm5Mgmj/J
008518	B6.129-Leprtm1Mgmj/J
008320	B6.129-Leprtm2(cre)Rck/J
008327	B6.129P2-Leprtm1Rck/J
000697	B6.BKS(D)-Leprdb/J
000699	B6.Cg-Dock7m Leprdb/+ +/J
000642	BKS.Cg-Dock7m +/+ Leprdb/J
000700	BKS.Cg-Dock7m Leprdb/+ +/J
008340	BKS.Cg-Leprdb Nos3tm1Unc/RhrsJ
001192	BKS.Cg-meaJ Leprdb +/+ + Dock7m/J
000707	CBA.Cg-Dock7m Leprdb/+ +/J
012666	D2.BKS(D)-Leprdb/J
006654	FVB.BKS(D)-Leprdb/ChuaJ
004939	NOD/ShiLtJ-Leprdb-5J/LtJ
006846	STOCK Leprdb-9J/Jgn
018989	STOCK Leprtm1Jke/J

View Strains carrying other alleles of Lepr     (18 strains)

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms provided by MGI

- Potential model based on gene homology relationships. Phenotypic similarity to the human disease has not been tested. Leptin Receptor Deficiency   (LEPR)

View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI

      assigned by genotype

Lepr^tm2Mgmj/Lepr⁺

        B6.Cg-Lepr^tm2Mgmj

• homeostasis/metabolism phenotype
• decreased circulating insulin level
  • in young females fed ad libitum or older females on a high fat diet   (MGI Ref ID J:122056)

Lepr^tm2Mgmj/Lepr^tm2Mgmj

        B6.Cg-Lepr^tm2Mgmj

• homeostasis/metabolism phenotype
• decreased circulating insulin level
  • in young females fed ad libitum or older females on a high fat diet   (MGI Ref ID J:122056)
• decreased circulating leptin level
  • in males and females   (MGI Ref ID J:122056)
• adipose tissue phenotype
• abnormal fat pad morphology
  • fat pads are decreased in females regardless of diet   (MGI Ref ID J:122056)
• • decreased gonadal fat pad weight
    • gonadal fat pad weight in older female mice is decreased   (MGI Ref ID J:122056)
• growth/size phenotype
• decreased body weight
  • female weight in older mice is decreased on a normal or high fat diet   (MGI Ref ID J:122056)

The following phenotype information may relate to a genetic background differing from this JAX^® Mice strain.

Lepr^tm2Mgmj/Lepr^tm2Mgmj

        Background Not Specified

• endocrine/exocrine gland phenotype
• decreased insulin secretion
  • leptin-treated islet cells exhibit decreased insulin secretion compared to similarly treated wild-type islets   (MGI Ref ID J:145998)
• homeostasis/metabolism phenotype
• decreased insulin secretion
  • leptin-treated islet cells exhibit decreased insulin secretion compared to similarly treated wild-type islets   (MGI Ref ID J:145998)

View Research Applications

Research Applications

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

Cardiovascular Research
Other
      altered fat metabolism
      altered lipoprotein profile

Cell Biology Research
Signal Transduction
Transcriptional Regulation

Diabetes and Obesity Research
Hypoinsulinemia
Impaired Insulin Processing
Obesity With Diabetes
Obesity Without Diabetes

Metabolism Research
Lipid Metabolism

Neurobiology Research
Metabolic Defects

Research Tools
Cardiovascular Research
Diabetes and Obesity Research
Metabolism Research
Neurobiology Research

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		Leprtm2Mgmj
Allele Name		targeted mutation 2, Martin G Myers, Jr
Allele Type		Targeted (knock-in)
Common Name(s)		LeprL985; LeprLeu985;
Mutation Made By		Martin Myers,   University of Michigan Medical School
Promoter		Lepr, leptin receptor, mouse, laboratory
Molecular Note		Tyr985 was converted to a leucine in exon 18b abrogating a phosphorylation site. A Southern blot was used to confirm the conversion. [MGI Ref ID J:122056]

Genotyping

Genotyping Information

Genotyping Protocols

Lepr^tm1Mgmj, Standard PCR

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Bjornholm M; Munzberg H; Leshan RL; Villanueva EC; Bates SH; Louis GW; Jones JC; Ishida-Takahashi R; Bjorbaek C; Myers MG Jr. 2007. Mice lacking inhibitory leptin receptor signals are lean with normal endocrine function. J Clin Invest 117(5):1354-60. [PubMed: 17415414]  [MGI Ref ID J:122056]

Leinninger GM; Myers MG Jr. 2008. LRb signals act within a distributed network of leptin-responsive neurones to mediate leptin action. Acta Physiol (Oxf) 192(1):49-59. [PubMed: 18171429]  [MGI Ref ID J:137518]

Additional References

Lepr^tm2Mgmj related

Bouret SG; Bates SH; Chen S; Myers MG Jr; Simerly RB. 2012. Distinct roles for specific leptin receptor signals in the development of hypothalamic feeding circuits. J Neurosci 32(4):1244-52. [PubMed: 22279209]  [MGI Ref ID J:180585]

Gerin I; Louis GW; Zhang X; Prestwich TC; Kumar TR; Myers MG Jr; Macdougald OA; Nothnick WB. 2009. Hyperphagia and obesity in female mice lacking tissue inhibitor of metalloproteinase-1. Endocrinology 150(4):1697-704. [PubMed: 19036876]  [MGI Ref ID J:158084]

Hinoi E; Gao N; Jung DY; Yadav V; Yoshizawa T; Myers MG Jr; Chua SC Jr; Kim JK; Kaestner KH; Karsenty G. 2008. The sympathetic tone mediates leptin's inhibition of insulin secretion by modulating osteocalcin bioactivity. J Cell Biol 183(7):1235-42. [PubMed: 19103808]  [MGI Ref ID J:145998]

Johnson JA; Calo S; Nair L; IglayReger HB; Greenwald-Yarnell M; Skorupski J; Myers MG Jr; Bodary PF. 2012. Testosterone interacts with the feedback mechanisms engaged by Tyr985 of the leptin receptor and diet-induced obesity. J Steroid Biochem Mol Biol 132(3-5):212-9. [PubMed: 22750459]  [MGI Ref ID J:190163]

Mancuso P; Myers MG Jr; Goel D; Serezani CH; O'Brien E; Goldberg J; Aronoff DM; Peters-Golden M. 2012. Ablation of leptin receptor-mediated ERK activation impairs host defense against Gram-negative pneumonia. J Immunol 189(2):867-75. [PubMed: 22685316]  [MGI Ref ID J:189551]

Robertson S; Ishida-Takahashi R; Tawara I; Hu J; Patterson CM; Jones JC; Kulkarni RN; Myers MG Jr. 2010. Insufficiency of Janus kinase 2-autonomous leptin receptor signals for most physiologic leptin actions. Diabetes 59(4):782-90. [PubMed: 20068132]  [MGI Ref ID J:164339]

Shi Y; Yadav VK; Suda N; Liu XS; Guo XE; Myers MG Jr; Karsenty G. 2008. Dissociation of the neuronal regulation of bone mass and energy metabolism by leptin in vivo. Proc Natl Acad Sci U S A 105(51):20529-33. [PubMed: 19074282]  [MGI Ref ID J:142673]

Tom RZ; Sjogren RJ; Vieira E; Glund S; Iglesias-Gutierrez E; Garcia-Roves PM; Myers MG Jr; Bjornholm M. 2011. Increased hepatic insulin sensitivity in mice lacking inhibitory leptin receptor signals. Endocrinology 152(6):2237-46. [PubMed: 21521753]  [MGI Ref ID J:174819]

Villanueva EC; Munzberg H; Cota D; Leshan RL; Kopp K; Ishida-Takahashi R; Jones JC; Fingar DC; Seeley RJ; Myers MG Jr. 2009. Complex regulation of mammalian target of rapamycin complex 1 in the basomedial hypothalamus by leptin and nutritional status. Endocrinology 150(10):4541-51. [PubMed: 19628573]  [MGI Ref ID J:157328]

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

Animal Health Reports

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200.

Colony Maintenance

Breeding & Husbandry	When maintaining a live colony, homozygous mice may be bred together.

Pricing and Purchasing

Pricing, Supply Level & Notes, Controls

Control Information

	Control
	005304 C57BL/6NJ	(approximate)
Considerations for Choosing Controls
Control Pricing Information for Genetically Engineered Mutant Strains.

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Terms are granted by individual review and stated on the customer invoice(s) and account statement. These transactions are payable in U.S. currency within the granted terms. Payment for services, products, shipping containers, and shipping costs that are rendered are expected within the payment terms indicated on the invoice or stated by contract. Invoices and account balances in arrears of stated terms may result in The Jackson Laboratory pursuing collection activities including but not limited to outside agencies and court filings.

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The Jackson Laboratory's Genotype Promise

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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