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 Mutant Stock; Transgenic; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Species laboratory mouse Generation N?+4F1N1p   Donating Investigator Robert Hammer,   U. of Texas, SW Medical Center at Dallas

Description
This transgenic mouse strain overexpresses human nuclear sterol regulatory element binding protein-1c in adipose tissue under the control of the adipocyte-specific aP2 promoter. The phenotype of transgenic mice resembles congenital generalized lipodystrophy (CGL), a rare autosomal recessive disorder in humans. CGL is characterized by an insufficiency of adipose tissue which is evident at birth and is accompanied by a severe insulin resistance leading to symptoms of type II diabetes mellitis, (hyperinsulinemia and hyperglycemia), and an enlarged fatty liver. Transgenic mice exhibit these symptoms showing defects in differentiation of white fat accompanied by an hypertrophy of brown fat that resembles immature white fat.

Development
A transgene was prepared encoding amino acids 1 - 436 of human SREBF1c driven by a 5.4 kb DNA fragment containing the adipose specific enhancer/promoter of the gene encoding aP2. The truncated SREBF1c lacks the membrane-attachment domain and enters the nucleus directly without a requirement for proteolysis. The Founder Line is 988-4, designated as 9884 as a "-" cannot be used in transgenic nomenclature.

Control Information

	Control
	Noncarrier
Considerations for Choosing Controls

Related Strains

Strains carrying other alleles of Fabp4

005069	B6.Cg-Tg(Fabp4-cre)1Rev/J
004100	FVB-Tg(AZIP/F)1Vsn/J

View Strains carrying other alleles of Fabp4     (2 strains)

Strains carrying other alleles of SREBF1

002840

B6SJL-Tg(SREBP1a)7343Reh/J

View Strains carrying other alleles of SREBF1     (1 strain)

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms

	Diabetes Mellitus, Noninsulin-Dependent; NIDDM -
	Lipodystrophy, Congenital Generalized, Type 2; CGL2 -

View Mammalian Phenotype Terms

Mammalian Phenotype Terms

      assigned by genotype

Tg(aP2-SREBF1c)9884Reh/0

        involves: C57BL/6J * SJL

• lethality-postnatal
• postnatal lethality (MGI Ref ID J:50770)
  • ~20% of mice fail to thrive and die within the first 3 weeks of life
• growth/size phenotype
• decreased body size (MGI Ref ID J:50770)
  • mice appear slightly runted during the first week of life
  • although most mice consuming a chow diet gain weight and reach a similar weight to that of control littermates by P40, a few remain runted throughout life
• distended abdomen (MGI Ref ID J:50770)
  • during the first week of life mice exhibit a distended abdomen due to liver enlargement
• adipose tissue phenotype
• *normal* adipose tissue phenotype (MGI Ref ID J:125992)
  • despite adipose tissue defects, adipogenesis is normal in embryonic fibroblasts
• abnormal brown adipose tissue morphology (MGI Ref ID J:50770)
  • brown fat is hypertrophic and contains fat-laden cells that resemble immature white fat
• abnormal brown fat cell morphology (MGI Ref ID J:50770)
  • at P8, the cytoplasm of mutant brown adipocytes displays large unilocular vacuoles similar to those of immature white adipocytes but unlike the small multilocular vacuoles observed in wild-type brown adipocytes
• increased brown fat cell lipid droplet size (MGI Ref ID J:50770)
  • at P40, most mutant brown adipocytes contain a prominent unilocular fat droplet
• increased brown fat cell size (MGI Ref ID J:50770)
  • at P8, mutant brown adipocytes are dramatically enlarged and stain palely
  • at P40, most mutant brown adipocytes remain significantly enlarged
• increased brown adipose tissue amount (MGI Ref ID J:50770)
  • at P7, mice display enlarged interscapular and submandibular brown fat depots relative to control mice
• abnormal epididymal fat pad morphology (MGI Ref ID J:50770)
  • at P8, the mutant epididymal fat pad consists predominantly of small immature adipocytes with brightly eosinophilic cytoplasm and a distinct unilocular vacuole
  • at P40, the mutant epididymal white fat contains a mixture of mature and immature adipocytes with significant size heterogeneity; immature adipocytes with bright eosinophilic cytoplasm, a round nucleus, and a distinct unilocular vacuole are observed
  • at P40, some epididymal fat pads exhibit histological evidence of mild inflammation and fibrosis
• decreased epididymal fat pad weight (MGI Ref ID J:50770)
  • at 12 weeks of age, the mutant epididymal fat pad weighs only ~35% of the wild-type fat pad (160 mg versus 510 mg, respectively)
• abnormal interscapular fat pad morphology (MGI Ref ID J:50770)
  • at P7, all mice exhibit enlarged interscapular brown fat pads, manifested as bilobed interscapular humps
  • at 7-12 weeks of age, mutant interscapular fat pads appear significantly enlarged, very firm, and white
  • at P40, mutant interscapular brown fat consists of enlarged adipocytes containing large unilocular fat droplets; the interstitium shows signs of mild chronic inflammation
• increased interscapular fat pad weight (MGI Ref ID J:50770)
  • at 12 weeks of age, mutant interscapular fat weighs nearly twice as much as wild-type (110 mg versus 58 mg, respectively)
• abnormal white adipose tissue morphology (MGI Ref ID J:50770)
  • white fat fails to differentiate fully, and the size of white fat depots is significantly reduced
• decreased white adipose tissue amount (MGI Ref ID J:50770)
  • at 7-12 weeks of age, mutant white adipose tissue is atrophic
  • at P40, epididymal, omental and perinephric white fat deposits are significantly reduced
• homeostasis/metabolism phenotype
• hyperglycemia (MGI Ref ID J:50770)
  • mice exhibit a significant increase in nonfasting plasma glucose levels, with a mean value 305 mg/dl
• increased circulating cholesterol level (MGI Ref ID J:50770)
  • at 7 weeks of age, plasma cholesterol levels are mildly, but significantly, increased
• increased circulating insulin level (MGI Ref ID J:50770)
  • mice exhibit a 60-fold increase in nonfasting plasma insulin levels relative to control littermates
• increased circulating triglyceride level (MGI Ref ID J:50770)
  • at 7 weeks of age, plasma triglyceride levels are mildly, but significantly, increased
  • at 9-11 months of age, plasma triglyceride levels are significantly higher (mean of 450 mg/dl; range, 367-565) than those of control littermates (mean of 97 mg/dl; range, 75-147)
• increased liver triglyceride level (MGI Ref ID J:50770)
  • at 7 weeks of age, the hepatic content of triglycerides is significantly increased
• insulin resistance (MGI Ref ID J:50770)
  • all mice are significantly resistant to the glucose-lowering effect of exogenous insulin
  • however, there is no evidence for insulin resistance in skeletal muscle
• liver/biliary system phenotype
• abnormal liver lobule morphology (MGI Ref ID J:50770)
  • at P8, mutant livers display uniform vacuolar changes throughout the hepatic lobule
• abnormal hepatocyte morphology (MGI Ref ID J:50770)
  • at P8, mutant hepatocytes are dramatically swollen; the cytoplasm stains palely eosinophilic and contains numerous microvesicular vacuoles which, in rare cases, coalesce to form a unilocular vacuole that displaces the nucleus peripherally
  • at P40, hepatocellular swelling is less severe than at P8, and it is confined to the centrolobular zone; no hepatitis or fibrosis is observed
• enlarged liver (MGI Ref ID J:50770)
  • at P7, mutant livers are massively enlarged
  • mutant livers remain enlarged at 7-12 weeks of age
• increased liver weight (MGI Ref ID J:50770)
  • at 12 weeks of age, mutant liver weighs twice as much as wild-type liver (3.9 g versus 1.5 g, respectively)
• hepatic steatosis (MGI Ref ID J:50770)
  • as early as P8, mutant livers are overloaded with fat
  • despite a markedly fatty liver, plasma levels of albumin, aspartate aminotransferase, and bilirubin remain normal at 7 weeks of age
• pale liver (MGI Ref ID J:50770)
  • at P7, mutant livers are markedly pale
  • mutant livers remain pale at 7-12 weeks of age
• digestive/alimentary phenotype
• enlarged pancreas (MGI Ref ID J:50770)
  • at 7-12 weeks of age, mutant pancreata are significantly enlarged
• endocrine/exocrine gland phenotype
• enlarged pancreas (MGI Ref ID J:50770)
  • at 7-12 weeks of age, mutant pancreata are significantly enlarged
• hematopoietic system phenotype
• enlarged spleen (MGI Ref ID J:50770)
  • at 7-12 weeks of age, mutant spleens are significantly enlarged
• immune system phenotype
• abnormal abdominal lymph node morphology (MGI Ref ID J:50770)
  • at 7-12 weeks of age, mutant abdominal lymph nodes are significantly enlarged
• enlarged spleen (MGI Ref ID J:50770)
  • at 7-12 weeks of age, mutant spleens are significantly enlarged

View Research Applications

Research Applications

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

Diabetes and Obesity Research
Hyperglycemia
Hyperinsulinemia
Insulin Resistance
Type 2 Diabetes (NIDDM)

Internal/Organ Research
Adipose Defects
Liver Defects

SREBF1 related

Metabolism Research
Lipid Metabolism

Genes & Alleles

Gene & Allele Information

Allele Symbol		Tg(aP2-SREBF1c)9884Reh
Allele Name		transgene insertion 9884, Robert E Hammer
Allele Type		Transgenic (random, expressed)
Common Name(s)		aP2-SREBP-1c436;
Mutation Made By		Robert Hammer,   U. of Texas, SW Medical Center at Dallas
Strain of Origin		(C57BL/6J x SJL)F2
Expressed Gene		SREBF1, sterol regulatory element binding transcription factor 1, human
Promoter		Fabp4, fatty acid binding protein 4, adipocyte, mouse, laboratory
General Note		This line was generated from founder number 988-4.
Molecular Note		Sequence encoding residues 1 through 436 of human nuclear sterol regulatory element binding protein-1c (SREBF1c) was adjoined to 5.4 kb of the mouse adipose-specific enhancer/promoter of aP2. SREBF1c sequence encoding the membrane-attachment domain was not included in the construct, permitting the expressed componen to enter the nucleus without a requirement for proteolysis. [MGI Ref ID J:50770]

Genotyping

Genotyping Information

Genotyping Protocols

Tg(aP2-SREBF1c), Standard PCR

Helpful Links

Genotyping resources and troubleshooting

References

References

Selected Reference(s)

Shimomura I; Hammer RE; Richardson JA; Ikemoto S; Bashmakov Y; Goldstein JL; Brown MS. 1998. Insulin resistance and diabetes mellitus in transgenic mice expressing nuclear SREBP-1c in adipose tissue: model for congenital generalized lipodystrophy. Genes Dev 12(20):3182-94. [PubMed: 9784493]  [MGI Ref ID J:50770]

Additional References

Shimomura I; Hammer RE; Ikemoto S; Brown MS; Goldstein JL. 1999. Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy. Nature 401(6748):73-6. [PubMed: 10485707]  [MGI Ref ID J:57251]

Tg(aP2-SREBF1c)9884Reh related

Akpinar P; Kuwajima S; Krutzfeldt J; Stoffel M. 2005. Tmem27: a cleaved and shed plasma membrane protein that stimulates pancreatic beta cell proliferation. Cell Metab 2(6):385-97. [PubMed: 16330324]  [MGI Ref ID J:129667]

Asilmaz E; Cohen P; Miyazaki M; Dobrzyn P; Ueki K; Fayzikhodjaeva G; Soukas AA; Kahn CR; Ntambi JM; Socci ND; Friedman JM. 2004. Site and mechanism of leptin action in a rodent form of congenital lipodystrophy. J Clin Invest 113(3):414-24. [PubMed: 14755338]  [MGI Ref ID J:87590]

Kim S; Huang LW; Snow KJ; Ablamunits V; Hasham MG; Young TH; Paulk AC; Richardson JE; Affourtit JP; Shalom-Barak T; Bult CJ; Barak Y. 2007. A mouse model of conditional lipodystrophy. Proc Natl Acad Sci U S A 104(42):16627-32. [PubMed: 17921248]  [MGI Ref ID J:125992]

Nakayama H; Otabe S; Ueno T; Hirota N; Yuan X; Fukutani T; Hashinaga T; Wada N; Yamada K. 2007. Transgenic mice expressing nuclear sterol regulatory element-binding protein 1c in adipose tissue exhibit liver histology similar to nonalcoholic steatohepatitis. Metabolism 56(4):470-5. [PubMed: 17379003]  [MGI Ref ID J:121430]

Shimomura I; Bashmakov Y; Horton JD. 1999. Increased levels of nuclear SREBP-1c associated with fatty livers in two mouse models of diabetes mellitus. J Biol Chem 274(42):30028-32. [PubMed: 10514488]  [MGI Ref ID J:58018]

Shimomura I; Hammer RE; Ikemoto S; Brown MS; Goldstein JL. 1999. Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy. Nature 401(6748):73-6. [PubMed: 10485707]  [MGI Ref ID J:57251]

Shimomura I; Matsuda M; Hammer RE; Bashmakov Y; Brown MS; Goldstein JL. 2000. Decreased IRS-2 and increased SREBP-1c lead to mixed insulin resistance and sensitivity in livers of lipodystrophic and ob/ob mice. Mol Cell 6(1):77-86. [PubMed: 10949029]  [MGI Ref ID J:63895]

Health & husbandry

Health & Colony Maintenance Information

Colony Maintenance

Diet Information	LabDiet® 5K52/5K67

Purchasing information

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

Pricing

Supply Details

Standard Supply

Cryopreserved. Ready for recovery. Please refer to pricing and supply notes for further information.

Supply Notes

Cryopreserved Embryos This strain is also available as cryopreserved embryos. Orders for cryopreserved embryos may be placed with our Customer Service Department. Experienced technicians at The Jackson Laboratory have recovered frozen embryos of this strain successfully. We will provide you enough embryos to perform two embryo transfers. The Jackson Laboratory does not guarantee successful recovery at your facility. For complete information on purchasing embryos, please visit our Cryopreserved Embryos web page. 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 Induced Mutant Resource Colony collection. Genomic DNA is available for this strain from the Mouse DNA Resource.

Control Information

	Control
	Noncarrier
Considerations for Choosing Controls
USA, Canada and Mexico - 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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