Description

Strain Information

Type Coisogenic; Mutant Strain; Transgenic; Additional information on Genetically Engineered Mutant Mice. Species laboratory mouse   Donating Investigator Charles Vinson,   NCI, NIH

Description
Mice expressing the A-ZIP/F gene under the control of 7.6kB of the adipocyte specific Fabp4 promoter have virtually no white adipose tissue and a reduced amount of brown adipose tissue. Brown adipose is found in lesser amounts as the animal ages. These mutant mice are very sensitive to cold temperature. Hemizygotes suffer from poor fecundity; the donating investigator indicates that not all males breed and pregnant females lactate inadequately. At birth, mice appear normal, losing weight in the first post-natal week but reach or exceed wildtype weight by 8-11 weeks. Adult mice display polyphagia and polydypsia, eating and drinking several times more than wildtype mice. Urine output is greatly increased. Transgenic mice have a characteristic rough-appearing coat and increased abdominal girth attributed to enlarged viscera. Most notably affected is the liver. Histological examination of liver tissue reveals numerous lipid droplets. Pancreatic islets are hypertrophic and hyperplastic with large increases in beta cell numbers observed. Adult mice exhibit elevated levels of glucose, insulin, free fatty acids and triglycerides. Increased insulin levels are observed as early as 5 weeks of age. Circulating levels of free, active leptin are greatly diminished. This strain represents a model useful for studying lipoatrophicdiabetes and the contribution of fat tissue to metabolic equilibrium.

Development
A transgenic construct containing the A-ZIP/F gene under the direction of a fatty acid binding protein 4, adipocyte promoter/enhancer was injected into male pronuclei of FVB/N mice. Founder animals were obtained and mated with FVB/N mice.

Control Information

	Control
	Noncarrier
Considerations for Choosing Controls

Related Strains

Strains carrying other alleles of Fabp4

005069	B6.Cg-Tg(Fabp4-cre)1Rev/J
003393	B6;SJL-Tg(aP2-SREBF1c)9884Reh/J

View Strains carrying other alleles of Fabp4     (2 strains)

Phenotype

Phenotype Information

View Mammalian Phenotype Terms

Mammalian Phenotype Terms

      assigned by genotype

Tg(AZIP/F)1Vsn/0

        involves: FVB/N

• lethality-postnatal
• postnatal lethality (MGI Ref ID J:50807)
  • normal numbers of transgenic pups are born however by weaning the percentage of transgenic pups is decreased to 30% (from 50%)
  • almost no pups from litters produced by hemizygous females survive until weaning
• life span-post-weaning/aging
• abnormal induced morbidity/mortality (MGI Ref ID J:50807)
  • transgenic mice are more sensitive to death after anesthesia than wild-type mice
• premature death (MGI Ref ID J:50807)
  • survival after weaning is reduced
• adipose tissue phenotype
• decreased brown adipose tissue amount (MGI Ref ID J:50807)
  • transgenic mice have decreased brown fat at birth which is primarily inactive and resembles white adipose tissue
• decreased white adipose tissue amount (MGI Ref ID J:50807)
  • transgenic mice have essentially no white fat as a result of a failure to generate white adipose tissue cells
• behavior/neurological phenotype
• polydipsia (MGI Ref ID J:50807)
  • transgenic mice drink 4 times more than wild-type mice
• digestive/alimentary phenotype
• islet cell hyperplasia (MGI Ref ID J:50807)
  • the islet cells are hyperplastic and hypertrophic with a large increase in the number of beta cells
• endocrine/exocrine gland phenotype
• islet cell hyperplasia (MGI Ref ID J:50807)
  • the islet cells are hyperplastic and hypertrophic with a large increase in the number of beta cells
• growth/size phenotype
• increased body weight (MGI Ref ID J:50807)
  • transgenic mice are heavier than wild-type mice at 8-11 weeks of age as a result of an increase in the weights of multiple organs including the liver, heart, kidneys, and spleen
  • transgenic mice have increased abdominal girth compared to wild-type mice
• postnatal growth retardation (MGI Ref ID J:50807)
  • transgenic mice grow slower than wild-type mice before weaning, weighing 50% and 80% of wild-type weight at 1 and 3 weeks of age, respectively
• weight loss (MGI Ref ID J:50807)
  • when fasted adult transgenic mice lose weight faster than non-transgenic mice
• homeostasis/metabolism phenotype
• abnormal glucose homeostasis (MGI Ref ID J:50807)
• hyperglycemia (MGI Ref ID J:50807)
  • serum glucose is increased about 3-fold compared to wild-type mice
  • elevated serum glucose is first detected 3 weeks after birth and reaches diabetic levels by 4 weeks
  • when fasted serum glucose levels drop to a much greater extent than in non-transgenic mice
• increased circulating insulin level (MGI Ref ID J:50807)
  • serum insulin levels are increased 58- and 442-fold in male and female transgenic mice
  • insulin levels are already elevated 30-fold by 1 week after birth
  • when fasted serum insulin levels drop to a much greater extent than in non-transgenic mice
• abnormal lipid homeostasis (MGI Ref ID J:50807)
• increased circulating free fatty acid level (MGI Ref ID J:50807)
  • circulating free fatty acid are increased 1.5- to 2.5 fold compared to wild-type mice however no signs of ketosis are detected
  • when fasted circulating free fatty acid levels drop rather than rise as in wild-type mice
• increased triglyceride level (MGI Ref ID J:50807)
  • the livers of transgenic mice contain 6.8-fold higher triglyceride levels compared to wild-type mice
• increased circulating triglyceride level (MGI Ref ID J:50807)
  • serum triglyceride levels are elevated 3- to 5-fold
• decreased circulating leptin level (MGI Ref ID J:50807)
  • free active leptin levels are about 5% of wild-type mice
• liver/biliary system phenotype
• hepatic steatosis (MGI Ref ID J:50807)
  • the liver is pale with lipid accumulation in a zone 3/centrilobular pattern
• increased liver weight (MGI Ref ID J:50807)
  • liver weight is increased 2.1-fold accounting for less than 50% of the total body weight increase in transgenic mice
• renal/urinary system phenotype
• polyuria (MGI Ref ID J:50807)
  • transgenic mice have a significantly higher urine output than normal
• reproductive system phenotype
• reduced female fertility (MGI Ref ID J:50807)
  • females have reduced fertility and litter size with almost no pups surviving until weaning
• reduced male fertility (MGI Ref ID J:50807)
  • male fertility is decreased but litters that are produced are of normal size
• respiratory system phenotype
• abnormal lung morphology (MGI Ref ID J:50807)
  • lipid loaded phagocytic cells are seen in the lungs of some transgenic mice
• skin/coat/nails phenotype
• rough hair (MGI Ref ID J:50807)

View Research Applications

Research Applications

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

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

Metabolism Research
Lipid Metabolism

Genes & Alleles

Gene & Allele Information

Allele Symbol		Tg(AZIP/F)1Vsn
Allele Name		transgene insertion 1, Charles Vincent
Allele Type		Transgenic (random, expressed)
Common Name(s)		A-ZIP/F-1;
Mutation Made By		Charles Vinson,   NCI, NIH
Strain of Origin		FVB/N
Expressed Gene		A-ZIP/F, flag epitope/leucine zipper, artificial
Promoter		Fabp4, fatty acid binding protein 4, adipocyte, mouse, laboratory
General Note		The A-ZIP/F-1 phenotype suggests a mouse model for the human disease lipoatrophic diabetes (Seip-Berardinelli syndrome).
Molecular Note		A 7.6 kb segment of the Fabp4 enhancer/promoter was used to drive expression of an artificially constructed cDNA encoding a dominant-negative protein to inhibit the DNA binding of both Cebpa and Jun family members. The protein is 104 amino acids long, with an amino-terminal 9 amino acid Flag epitope, a 13 amino acid linker, a 21 amino acid designed acidic amphipathic helix and a 61 amino acid designed leucine zipper (ZIP/F). The transgene also had an SV40 intron and a PolyA signal. [MGI Ref ID J:50807]

Genotyping

Genotyping Information

Genotyping Protocols

Tg(AZIP/F)1Vsn, STD PCR, vers. 1

Helpful Links

Optimizing PCR Protocols

References

References

Selected Reference(s)

Moitra J; Mason MM; Olive M; Krylov D; Gavrilova O; Marcus-Samuels B; Feigenbaum L; Lee E; Aoyama T; Eckhaus M; Reitman ML; Vinson C. 1998. Life without white fat: a transgenic mouse. Genes Dev 12(20):3168-81. [PubMed: 9784492]  [MGI Ref ID J:50807]

Additional References

Kim JK; Fillmore JJ; Gavrilova O; Chao L; Higashimori T; Choi H; Kim HJ; Yu C; Chen Y; Qu X; Haluzik M; Reitman ML; Shulman GI. 2003. Differential effects of rosiglitazone on skeletal muscle and liver insulin resistance in A-ZIP/F-1 fatless mice. Diabetes 52(6):1311-8. [PubMed: 12765938]  [MGI Ref ID J:83535]

Tg(AZIP/F)1Vsn related

Ablamunits V; Cohen Y; Brazee IB; Gaetz HP; Vinson C; Klebanov S. 2006. Susceptibility to Induced and Spontaneous Carcinogenesis Is Increased in Fatless A-ZIP/F-1 but not in Obese ob/ob Mice. Cancer Res 66(17):8897-902. [PubMed: 16951207]  [MGI Ref ID J:112412]

Colombo C; Haluzik M; Cutson JJ; Dietz KR; Marcus-Samuels B; Vinson C; Gavrilova O; Reitman ML. 2003. Opposite Effects of Background Genotype on Muscle and Liver Insulin Sensitivity of Lipoatrophic Mice. ROLE OF TRIGLYCERIDE CLEARANCE. J Biol Chem 278(6):3992-9. [PubMed: 12456680]  [MGI Ref ID J:81689]

Couldrey C; Moitra J; Vinson C; Anver M; Nagashima K; Green J. 2002. Adipose tissue: a vital in vivo role in mammary gland development but not differentiation. Dev Dyn 223(4):459-68. [PubMed: 11921335]  [MGI Ref ID J:135867]

Duan SZ; Ivashchenko CY; Whitesall SE; D'Alecy LG; Duquaine DC; Brosius FC rd; Gonzalez FJ; Vinson C; Pierre MA; Milstone DS; Mortensen RM. 2007. Hypotension, lipodystrophy, and insulin resistance in generalized PPARgamma-deficient mice rescued from embryonic lethality. J Clin Invest 117(3):812-22. [PubMed: 17304352]  [MGI Ref ID J:120750]

Ducy P; Amling M; Takeda S; Priemel M; Schilling AF; Beil FT; Shen J; Vinson C; Rueger JM; Karsenty G. 2000. Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass. Cell 100(2):197-207. [PubMed: 10660043]  [MGI Ref ID J:60001]

Ebihara K; Ogawa Y; Masuzaki H; Shintani M; Miyanaga F; Aizawa-Abe M; Hayashi T; Hosoda K; Inoue G; Yoshimasa Y; Gavrilova O; Reitman ML; Nakao K. 2001. Transgenic overexpression of leptin rescues insulin resistance and diabetes in a mouse model of lipoatrophic diabetes. Diabetes 50(6):1440-8. [PubMed: 11375346]  [MGI Ref ID J:69591]

Gavrilova O; Haluzik M; Matsusue K; Cutson JJ; Johnson L; Dietz KR; Nicol CJ; Vinson C; Gonzalez FJ; Reitman ML. 2003. Liver peroxisome proliferator-activated receptor gamma contributes to hepatic steatosis, triglyceride clearance, and regulation of body fat mass. J Biol Chem 278(36):34268-76. [PubMed: 12805374]  [MGI Ref ID J:85313]

Gavrilova O; Leon LR; Marcus-Samuels B; Mason MM; Castle AL; Refetoff S; Vinson C; Reitman ML. 1999. Torpor in mice is induced by both leptin-dependent and -independent mechanisms. Proc Natl Acad Sci U S A 96(25):14623-8. [PubMed: 10588755]  [MGI Ref ID J:58946]

Gavrilova O; Marcus-Samuels B; Reitman ML. 2000. Lack of responses to a beta3-adrenergic agonist in lipoatrophic A-ZIP/F-1 mice Diabetes 49(11):1910-6. [PubMed: 11078459]  [MGI Ref ID J:65483]

Haluzik M; Dietz KR; Kim JK; Marcus-Samuels B; Shulman GI; Gavrilova O; Reitman ML. 2002. Adrenalectomy improves diabetes in A-ZIP/F-1 lipoatrophic mice by increasing both liver and muscle insulin sensitivity. Diabetes 51(7):2113-8. [PubMed: 12086940]  [MGI Ref ID J:107194]

Kim JK; Fillmore JJ; Gavrilova O; Chao L; Higashimori T; Choi H; Kim HJ; Yu C; Chen Y; Qu X; Haluzik M; Reitman ML; Shulman GI. 2003. Differential effects of rosiglitazone on skeletal muscle and liver insulin resistance in A-ZIP/F-1 fatless mice. Diabetes 52(6):1311-8. [PubMed: 12765938]  [MGI Ref ID J:83535]

Kim JK; Gavrilova O; Chen Y; Reitman ML; Shulman GI. 2000. Mechanism of insulin resistance in A-ZIP/F-1 fatless mice. J Biol Chem 275(12):8456-60. [PubMed: 10722680]  [MGI Ref ID J:61383]

Lamounier-Zepter V; Bornstein SR; Kunes J; Zicha J; Krsek M; Ehrhart-Bornstein M; Ziegler CG; Kiessling A; Funk RH; Haluzik M. 2008. Adrenocortical changes and arterial hypertension in lipoatrophic A-ZIP/F-1 mice. Mol Cell Endocrinol 280(1-2):39-46. [PubMed: 18045774]  [MGI Ref ID J:131946]

Minn AH; Lan H; Rabaglia ME; Harlan DM; Peculis BA; Attie AD; Shalev A. 2005. Increased insulin translation from an insulin splice-variant overexpressed in diabetes, obesity, and insulin resistance. Mol Endocrinol 19(3):794-803. [PubMed: 15550470]  [MGI Ref ID J:96491]

Mir AA; Myakishev MV; Polesskaya OO; Moitra J; Petersen D; Miller L; Orosz A; Vinson C. 2003. A search for candidate genes for lipodystrophy, obesity and diabetes via gene expression analysis of A-ZIP/F-1 mice. Genomics 81(4):378-90. [PubMed: 12676562]  [MGI Ref ID J:82973]

Nunez NP; Oh WJ; Rozenberg J; Perella C; Anver M; Barrett JC; Perkins SN; Berrigan D; Moitra J; Varticovski L; Hursting SD; Vinson C. 2006. Accelerated tumor formation in a fatless mouse with type 2 diabetes and inflammation. Cancer Res 66(10):5469-76. [PubMed: 16707476]  [MGI Ref ID J:109048]

Reitman ML; Gavrilova O. 2000. A-ZIP/F-1 mice lacking white fat: a model for understanding lipoatrophic diabetes. Int J Obes Relat Metab Disord 24 Suppl 4:S11-4. [PubMed: 11126232]  [MGI Ref ID J:65989]

Suganami T; Mukoyama M; Mori K; Yokoi H; Koshikawa M; Sawai K; Hidaka S; Ebihara K; Tanaka T; Sugawara A; Kawachi H; Vinson C; Ogawa Y; Nakao K. 2005. Prevention and reversal of renal injury by leptin in a new mouse model of diabetic nephropathy. FASEB J 19(1):127-9. [PubMed: 15496495]  [MGI Ref ID J:128255]

Takemori K; Gao YJ; Ding L; Lu C; Su LY; An WS; Vinson C; Lee RM. 2007. Elevated blood pressure in transgenic lipoatrophic mice and altered vascular function. Hypertension 49(2):365-72. [PubMed: 17200435]  [MGI Ref ID J:128031]

Health & husbandry

Health & Colony Maintenance Information

Colony Maintenance

Breeding & Husbandry	These mice originated on an FVB/N background and have been maintained as hemizygotes by breeding to FVB mice. Hemizygotes suffer from poor fecundity; the donating investigator indicates that not all males breed and pregnant females lactate inadequately. Use of nestlets recommended due to cold sensitivity and extra absorbent bedding due to excessive urination.
Diet Information	LabDiet® 5K52/5K67

Purchasing information

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

Pricing

Supply Details

Standard Supply

Repository-Cryopreserved. Must Be Recovered. Please refer to pricing and supply notes for further information.

Supply Notes

Cryorecovery - Standard. The recovery process begins when a signed agreement form is returned to the Customer Service Department after order placement. Although results vary by strain, at least two males and two females (two pairs) will be provided, typically within 15 weeks of our receipt of the signed agreement form. If the first recovery attempt is unsuccessful or only one pair is recovered, a second recovery will be done, extending the delivery time to approximately 25 weeks. At least one member of each pair will be of known genotype and will carry the mutation if it is a mutant strain. Please note that pairs may not reflect the mating scheme utilized by The Jackson Laboratory prior to cryopreservation of the strain. Mating schemes are sometimes modified for successful cryopreservation. Price represents a repository maintenance fee, which includes the cost of recovery of the strain from the cryopreservation resource and the periodic replacement of the frozen embryos used for recovery. Cryorecovery to establish a Dedicated Supply for greater quantities of mice. One to two pairs will be recovered to establish a Dedicated Supply of mice. Price by quotation. For more information on Dedicated Supply, please contact JAX® Services, Tel: 1-800-422-6423 or 1-207-288-5845. This strain is included in the Induced Mutant Resource Colony collection.

Control Information

	Control
	Noncarrier
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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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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