Description

Strain Information

Type Mutant Stock; Targeted Mutation; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Mating System Homozygote x Homozygote         (Female x Male)   07-FEB-12 Species laboratory mouse Generation F?+F3 (29-JUN-11) Generation Definitions   Donating Investigator Dr. Frederick W. Alt,   Children's Hospital

Description
The targeted mutation deletes exon 2-3 of the mouse sirtuin (silent information regulator 2 (Sir2)) homolog 3, Sirt3, gene, abolishing gene function. Homozygous mice are viable, fertile, normal in size and do not display any gross physical or behavioral abnormalities. Sirt3^-/- mice exhibit hyperacetylation of mitochondrial enzymes, including glutamate dehydrogenase (GDH) and long-chain acyl co-enzyme A dehydrogenase (LCAD), leading to a decrease in the modulation of mitochondrial metabolism and fatty acid oxidation. They show reduced ATP production, cold intolerance, and hypoglycemia. These mice may be useful in studying the role of fatty acid oxidation in diabetes, cardiovascular disease, steatosis, fasting, cold exposure, and life span.

Development
A targeting vector was designed to replace exon 2-3 of the mouse sirtuin (silent information regulator 2 (Sir2)) homolog 3, Sirt3, gene with a neomycin (neo)-resistance cassette. Specifically, a loxP site was inserted upstream of exon 2, and a floxed neo cassette was inserted downstream of exon 3. This construct was electroporated into 129S6/SvEvTac-derived TC1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6J blastocysts and the resulting chimeric males were bred to 129/Sv females. Mice heterozygous for the Sirt3 mutant allele were crossed to EIIa-cre mice on a 129 background to remove the floxed exons and the neo cassette. These mice were then intercrossed to produce homozygous Sirt3^-/- mice. Upon arrival at The Jackson Laboratory, mice were bred to 129S1/SvImJ inbred mice (Stock No. 002448) for at least one generation to establish the colony.

Control Information

	Control
	002448 129S1/SvImJ	(approximate)
Considerations for Choosing Controls

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms provided by MGI

- Model with phenotypic similarity to human disease where etiologies are distinct. Human genes are associated with this disease. Orthologs of these genes do not appear in the mouse genotype(s).

Abdominal Obesity-Metabolic Syndrome

View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI

      assigned by genotype

Sirt3^tm1.1Fwa/Sirt3^tm1.1Fwa

        involves: 129S6/SvEvTac

• adipose tissue phenotype
• increased total body fat amount
  • increase in weight is due to increased adiposity   (MGI Ref ID J:178653)
• growth/size phenotype
• increased susceptibility to diet-induced obesity
  • mutants on a high-fat diet develop diet induced obesity at an accelerated rate compared to controls   (MGI Ref ID J:178653)
  • on a high-fat diet, mutants weight 7% more than wild-type mice by 18 weeks, 10% more by 33 weeks, and 15% more by 52 weeks   (MGI Ref ID J:178653)
• homeostasis/metabolism phenotype
• abnormal cytokine level
  • aged obese mutants fed a high-fat diet exhibit higher serum levels of inflammatory cytokines, but are unchanged in nonobese 3-month old mutants   (MGI Ref ID J:178653)
• • increased circulating interferon-gamma level
    • aged obese mutants fed a high-fat diet exhibit 3-fold higher interferon-gamma levels than wild-type mice   (MGI Ref ID J:178653)
  • increased circulating interleukin-10 level
    • aged obese mutants fed a high-fat diet exhibit 3-fold higher IL-10 levels than wild-type mice   (MGI Ref ID J:178653)
  • increased circulating interleukin-12 level
    • aged obese mutants fed a high-fat diet exhibit 12-fold higher IL-12p70 levels than wild-type mice   (MGI Ref ID J:178653)
  • increased circulating interleukin-6 level
    • aged obese mutants fed a high-fat diet exhibit 10-fold higher IL-6 levels than wild-type mice   (MGI Ref ID J:178653)
  • increased circulating tumor necrosis factor level
    • aged obese mutants fed a high-fat diet exhibit 1.7-fold higher TNF-alpha levels than wild-type mice   (MGI Ref ID J:178653)
• abnormal enzyme/ coenzyme level
  • mutants fed a standard diet exhibit a 53% reduction in LCAD enzymatic activity mutants fed a standard diet exhibit a 53% reduction in long-chain acyl-CoA dehydrogenase (LCAD) enzymatic activity   (MGI Ref ID J:178653)
• abnormal lipid homeostasis   (MGI Ref ID J:178653)
• • increased circulating cholesterol level
    • 12 month old mutants on a high-fat diet show a 141% increase in cholesterol levels compared to wild-type mice   (MGI Ref ID J:178653)
  • • increased circulating LDL cholesterol level
      • 12 month old mutants on a high-fat diet show a 60% increase in low-density lipoproteins compared to wild-type mice   (MGI Ref ID J:178653)
    • increased circulating VLDL cholesterol level
      • 12 month old mutants on a high-fat diet show a 100% increase in very-low-density lipoproteins compared to wild-type mice   (MGI Ref ID J:178653)
  • increased circulating triglyceride level
    • 12 month old mutants on a high-fat diet show a 97% increase in trigylcerides compared to wild-type mice   (MGI Ref ID J:178653)
  • increased liver cholesterol level
    • 3 month old mutants fed a high-fat diet have 41% more hepatic cholesterol esters   (MGI Ref ID J:178653)
  • increased liver triglyceride level
    • 3 month old mutants fed a high-fat diet have 38% more hepatic trigylcerides than wild-type mice   (MGI Ref ID J:178653)
• decreased carbon dioxide production
  • CO2 exhalation is 15% lower in mutants during light and 16% during dark cycles   (MGI Ref ID J:178653)
  • however, no differences in respiratory exchange ratio are seen   (MGI Ref ID J:178653)
• decreased oxygen consumption
  • oxygen consumption is 15% lower in mutants during light and 14% lower during dark cycles   (MGI Ref ID J:178653)
• hyperglycemia
  • obese mutants fed a high-fat diet exhibit hyperglycemia during glucose-tolerance testing   (MGI Ref ID J:178653)
  • non-obese mutants fed a standard diet show marked hyperglycemia upon intraperitoneal glucose injection   (MGI Ref ID J:178653)
• increased circulating insulin level
  • 12 month old mutants on a high-fat diet show a 285% increase in fasting insulin levels compared to wild-type mice   (MGI Ref ID J:178653)
  • however, leptin, adiponectin, and resistin are unchanged   (MGI Ref ID J:178653)
• increased susceptibility to diet-induced obesity
  • mutants on a high-fat diet develop diet induced obesity at an accelerated rate compared to controls   (MGI Ref ID J:178653)
  • on a high-fat diet, mutants weight 7% more than wild-type mice by 18 weeks, 10% more by 33 weeks, and 15% more by 52 weeks   (MGI Ref ID J:178653)
• insulin resistance
  • obese mutants fed a high-fat diet show insulin resistance in insulin tolerance testing   (MGI Ref ID J:178653)
  • non-obese mutants fed a standard diet show marked insulin resistance upon intraperitoneal insulin injection   (MGI Ref ID J:178653)
• immune system phenotype
• abnormal cytokine level
  • aged obese mutants fed a high-fat diet exhibit higher serum levels of inflammatory cytokines, but are unchanged in nonobese 3-month old mutants   (MGI Ref ID J:178653)
• • increased circulating interferon-gamma level
    • aged obese mutants fed a high-fat diet exhibit 3-fold higher interferon-gamma levels than wild-type mice   (MGI Ref ID J:178653)
  • increased circulating interleukin-10 level
    • aged obese mutants fed a high-fat diet exhibit 3-fold higher IL-10 levels than wild-type mice   (MGI Ref ID J:178653)
  • increased circulating interleukin-12 level
    • aged obese mutants fed a high-fat diet exhibit 12-fold higher IL-12p70 levels than wild-type mice   (MGI Ref ID J:178653)
  • increased circulating interleukin-6 level
    • aged obese mutants fed a high-fat diet exhibit 10-fold higher IL-6 levels than wild-type mice   (MGI Ref ID J:178653)
  • increased circulating tumor necrosis factor level
    • aged obese mutants fed a high-fat diet exhibit 1.7-fold higher TNF-alpha levels than wild-type mice   (MGI Ref ID J:178653)
• liver inflammation
  • aged mutants fed a high-fat diet exhibit more lobular lymphoplasmacytic inflammation, and more hepatocyte ballooning degeneration compared to wild-type mice   (MGI Ref ID J:178653)
• liver/biliary system phenotype
• hepatic steatosis
  • mutants fed a high-fat diet show higher lipid levels in the liver than in controls fed a high-fat diet   (MGI Ref ID J:178653)
  • mutants fed a high-fat diet show an increased accumulation of hepatic long-chain acylcarnitine species, but not organic acids or amino acids   (MGI Ref ID J:178653)
  • aged mutants fed a high-fat diet exhibit more macrovesicular steatosis   (MGI Ref ID J:178653)
• increased liver cholesterol level
  • 3 month old mutants fed a high-fat diet have 41% more hepatic cholesterol esters   (MGI Ref ID J:178653)
• increased liver triglyceride level
  • 3 month old mutants fed a high-fat diet have 38% more hepatic trigylcerides than wild-type mice   (MGI Ref ID J:178653)
• liver fibrosis
  • aged mutants fed a high-fat diet exhibit more hepatic fibrosis compared to wild-type mice   (MGI Ref ID J:178653)
• liver inflammation
  • aged mutants fed a high-fat diet exhibit more lobular lymphoplasmacytic inflammation, and more hepatocyte ballooning degeneration compared to wild-type mice   (MGI Ref ID J:178653)

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

Sirt3^tm1.1Fwa/Sirt3^tm1.1Fwa

        involves: 129/Sv * FVB/N

• normal phenotype
• no abnormal phenotype detected
  • mice are phenotypically normal with unremarkable metabolism and adaptive thermogenesis   (MGI Ref ID J:129009)

View Research Applications

Research Applications

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

Diabetes and Obesity Research
Hypoglycemia

Metabolism Research
Lipid Metabolism
Low Body Temperature

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		Sirt3tm1.1Fwa
Allele Name		targeted mutation 1.1, Frederick W Alt
Allele Type		Targeted (knock-out)
Common Name(s)		SIRT3-;
Mutation Made By		Dr. Frederick Alt,   Children's Hospital
Strain of Origin		129S6/SvEvTac
Gene Symbol and Name		Sirt3, sirtuin 3 (silent mating type information regulation 2, homolog) 3 (S. cerevisiae)
Chromosome		7
Gene Common Name(s)		2310003L23Rik; AI848213; RIKEN cDNA 2310003L23 gene; SIR2L3; Sir2l3; expressed sequence AI848213; silent mating type information regulation 2, (S.cerevisiae, homolog)-like 3;
Molecular Note		A floxed neo cassette was inserted into intron 3 and an additional loxP site was inserted upstream of exon 2. Cre-mediated recombination was used to remove the neo cassette, exon 2 and exon 3. The absence of protein product was confirmed by western blot analysis on liver and brain extracts. [MGI Ref ID J:129009]

Genotyping

Genotyping Information

Genotyping Protocols

Sirt3^tm1.1Fwa, Standard PCR

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Additional References

Sirt3^tm1.1Fwa related

Finley LW; Carracedo A; Lee J; Souza A; Egia A; Zhang J; Teruya-Feldstein J; Moreira PI; Cardoso SM; Clish CB; Pandolfi PP; Haigis MC. 2011. SIRT3 Opposes Reprogramming of Cancer Cell Metabolism through HIF1alpha Destabilization. Cancer Cell 19(3):416-28. [PubMed: 21397863]  [MGI Ref ID J:169928]

Finley LW; Haas W; Desquiret-Dumas V; Wallace DC; Procaccio V; Gygi SP; Haigis MC. 2011. Succinate dehydrogenase is a direct target of sirtuin 3 deacetylase activity. PLoS One 6(8):e23295. [PubMed: 21858060]  [MGI Ref ID J:176493]

Hafner AV; Dai J; Gomes AP; Xiao CY; Palmeira CM; Rosenzweig A; Sinclair DA. 2010. Regulation of the mPTP by SIRT3-mediated deacetylation of CypD at lysine 166 suppresses age-related cardiac hypertrophy. Aging (Albany NY) 2(12):914-23. [PubMed: 21212461]  [MGI Ref ID J:178585]

Hirschey MD; Shimazu T; Goetzman E; Jing E; Schwer B; Lombard DB; Grueter CA; Harris C; Biddinger S; Ilkayeva OR; Stevens RD; Li Y; Saha AK; Ruderman NB; Bain JR; Newgard CB; Farese RV Jr; Alt FW; Kahn CR; Verdin E. 2010. SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. Nature 464(7285):121-5. [PubMed: 20203611]  [MGI Ref ID J:157979]

Hirschey MD; Shimazu T; Jing E; Grueter CA; Collins AM; Aouizerat B; Stancakova A; Goetzman E; Lam MM; Schwer B; Stevens RD; Muehlbauer MJ; Kakar S; Bass NM; Kuusisto J; Laakso M; Alt FW; Newgard CB; Farese RV Jr; Kahn CR; Verdin E. 2011. SIRT3 deficiency and mitochondrial protein hyperacetylation accelerate the development of the metabolic syndrome. Mol Cell 44(2):177-90. [PubMed: 21856199]  [MGI Ref ID J:178653]

Lombard DB; Alt FW; Cheng HL; Bunkenborg J; Streeper RS; Mostoslavsky R; Kim J; Yancopoulos G; Valenzuela D; Murphy A; Yang Y; Chen Y; Hirschey MD; Bronson RT; Haigis M; Guarente LP; Farese RV Jr; Weissman S; Verdin E; Schwer B. 2007. Mammalian Sir2 homolog SIRT3 regulates global mitochondrial lysine acetylation. Mol Cell Biol 27(24):8807-14. [PubMed: 17923681]  [MGI Ref ID J:129009]

Lu Z; Bourdi M; Li JH; Aponte AM; Chen Y; Lombard DB; Gucek M; Pohl LR; Sack MN. 2011. SIRT3-dependent deacetylation exacerbates acetaminophen hepatotoxicity. EMBO Rep 12(8):840-6. [PubMed: 21720390]  [MGI Ref ID J:174774]

Nakagawa T; Lomb DJ; Haigis MC; Guarente L. 2009. SIRT5 Deacetylates carbamoyl phosphate synthetase 1 and regulates the urea cycle. Cell 137(3):560-70. [PubMed: 19410549]  [MGI Ref ID J:148769]

Qiu X; Brown K; Hirschey MD; Verdin E; Chen D. 2010. Calorie restriction reduces oxidative stress by SIRT3-mediated SOD2 activation. Cell Metab 12(6):662-7. [PubMed: 21109198]  [MGI Ref ID J:168111]

Shimazu T; Hirschey MD; Hua L; Dittenhafer-Reed KE; Schwer B; Lombard DB; Li Y; Bunkenborg J; Alt FW; Denu JM; Jacobson MP; Verdin E. 2010. SIRT3 deacetylates mitochondrial 3-hydroxy-3-methylglutaryl CoA synthase 2 and regulates ketone body production. Cell Metab 12(6):654-61. [PubMed: 21109197]  [MGI Ref ID J:168112]

Sundaresan NR; Gupta M; Kim G; Rajamohan SB; Isbatan A; Gupta MP. 2009. Sirt3 blocks the cardiac hypertrophic response by augmenting Foxo3a-dependent antioxidant defense mechanisms in mice. J Clin Invest 119(9):2758-71. [PubMed: 19652361]  [MGI Ref ID J:152721]

Health & husbandry

Health & Colony Maintenance Information

Animal Health Reports

Room Number           AX11

Colony Maintenance

Breeding & Husbandry	When maintaining a live colony, homozygous mice may be bred together.
Mating System	Homozygote x Homozygote         (Female x Male)   07-FEB-12
Diet Information	LabDiet® 5K52/5K67

Pricing and Purchasing

Pricing, Supply Level & Notes, Controls

Control Information

	Control
	002448 129S1/SvImJ	(approximate)
Considerations for Choosing Controls
Control Pricing Information for Genetically Engineered Mutant Strains.

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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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