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 Generation Definitions   Donating Investigator Robert E Hammer,   UT Southwestern 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
017560	B6.FVB-Tg(Fabp4-IKBKB*)49Hxu/J
018625	B6.FVB-Tg(Fabp4-lacZ)4Mosh/J
017321	C57BL/6-Tg(Fabp4-Dgat1)2Far/J

View Strains carrying other alleles of Fabp4     (4 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 provided by MGI

- Characteristics of this human disease are associated with transgenes and other mutation types in the mouse.

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

View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI

      assigned by genotype

Tg(aP2-SREBF1c)9884Reh/0

        involves: C57BL/6J * SJL

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

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 provided by MGI

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,   UT Southwestern 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 provided by MGI

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]

Herrero L; Shapiro H; Nayer A; Lee J; Shoelson SE. 2010. Inflammation and adipose tissue macrophages in lipodystrophic mice. Proc Natl Acad Sci U S A 107(1):240-5. [PubMed: 20007767]  [MGI Ref ID J:156490]

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]

Wu AL; Kolumam G; Stawicki S; Chen Y; Li J; Zavala-Solorio J; Phamluong K; Feng B; Li L; Marsters S; Kates L; van Bruggen N; Leabman M; Wong A; West D; Stern H; Luis E; Kim HS; Yansura D; Peterson AS; Filvaroff E; Wu Y; Sonoda J. 2011. Amelioration of type 2 diabetes by antibody-mediated activation of fibroblast growth factor receptor 1. Sci Transl Med 3(113):113ra126. [PubMed: 22174314]  [MGI Ref ID J:183639]

Health & husbandry

Health & Colony Maintenance Information

Animal Health Reports

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

Colony Maintenance

Diet Information	LabDiet® 5K52/5K67

Pricing and Purchasing

Pricing, Supply Level & Notes, Controls

General Supply Notes

• Genomic DNA is available for this strain from the Mouse DNA Resource.

Control Information

	Control
	Noncarrier
Considerations for Choosing Controls
Control Pricing Information for Genetically Engineered Mutant Strains.

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