Overview

Also Known As:ATGL-ko

In this ATGL-ko strain a NEO cassette replaces exon 1 of the Pnpla2 (patatin-like phospholipase domain containing 2) gene. Homozygotes exhibit a shortened lifespan, abnormal lipid homeostasis, glucose tolerance, and cardiovascular physiology and have applications in studies of impaired cardiac function, thermogenesis and lipid and energy homeostasis.

Donating Investigator

Rudolf Zechner, Karl Franzens University Graz

Genetic overview

Genetic Background	Generation

Pnpla2^tm1Rze

Allele Type	Gene Symbol	Gene Name
Targeted (Null/Knockout)	Pnpla2	patatin-like phospholipase domain containing 2

View Genetics

Research Applications

Cardiovascular Research
Metabolism Research
Neurobiology Research
Developmental Biology Research
Internal/Organ Research
Research Tools
Diabetes and Obesity Research

View All Research Applications

Base Price

Starting at:

$2,854.50 Domestic price Cryo Recovery

View Price List

Details

Detailed Description

Patatin-like phospholipase domain containing 2 (PNPLA2, ATGL) initiates lipolysis by catalyzing the hydrolysis of triacylglycerol to diacylglycerol in adipose tissue and non-adipose tissues. Mutations in human PNPLA2 have been associated with neutral lipids storage disorder with myopathy. These mice carry a targeted mutation of the Pnpla2 gene in which exon 1 (encoding the translational initiation codon and the lipase consensus sequence motif,) is replaced by a NEO cassette. Mice that are heterozygous for the targeted mutation are viable and fertile. Homozygotes die at about 14 to 16 weeks of age due to severe cardiac steatosis and lethal myopathy. Triacylglycerol hydrolase activity in homozygotes is decreased by more than 80% in white and brown adipose tissue, and reduced in cardiac muscle, skeletal muscle, testis, and in the liver. Levels of plasma free fatty acids are reduced in both fed and fasting homozygotes. Mice homozygous for this targeted mutation have 2 fold increased body mass, as well as increased gonadal and inguinal white adipose tissue. Intrascapular brown adipose tissue is increased more than 10-fold when compared to wildtype controls. Homozygotes exhibit increased levels of triacylglycerol also in most non-adipose tissues with a more than 10-fold increase in cardiac muscle. Following an overnight fast, homozygotes are hypoinsulinemic (ciruculating insulin levels reduced by 70%) and hypoglycemic (reduced approximately 40%). Fed homozygous mice exhibit a 40% reduction in circulating insulin compared to levels seen in controls. Homozygotes exhibit increased glucose tolerance and increased respiratory quotient during fasting. Homozygotes are sensitive to cold temperatures, experiencing severe hypothermia after 5 hours in 4 degrees celcius. Homozygous are protected against certain forms of cancer cachexia.

Development

A targeting vector containing a NEO cassette was used to disrupt exon 1, which encodes the translational initiation codon and the lipase consensus sequence motif (GXSXG). The construct was electroporated into 129P2/OlaHsd-Hprt^b-m3 derived HM-1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6J blastocysts. The resulting chimeric animals were crossed to C57BL/6J mice. The donating investigator reported that these mice were backcrossed to C57BL/6J for at least 10 generations (see SNP note below). Upon arrival at The Jackson Laboratory, the mice were crossed to C57BL/6J (Stock No. 000664) at least once to establish the colony.

A 32 SNP (single nucleotide polymorphism) panel analysis, with 27 markers covering all 19 chromosomes and the X chromosome, as well as 5 markers that distinguish between the C57BL/6J and C57BL/6N substrains, was performed on the rederived living colony at The Jackson Laboratory Repository. Three markers throughout the genome were segregating for 129, suggesting an incomplete backcross.

Control Suggestions

Wild-type from the colony

Approximate Controls

000664 C57BL/6J

Additional Information

Considerations for Choosing Controls

Selected References

Kaneko T; Maeda A; Takefuji M; Aoyama H; Nakayama M; Kawabata S; Kawano Y; Iwamatsu A; Amano M; Kaibuchi K. 2005. Rho mediates endocytosis of epidermal growth factor receptor through phosphorylation of endophilin A1 by Rho-kinase. Genes Cells 10(10):973-87PubMed: 16164598 MGI: J:108456

View All References

Genetics

Pnpla2^tm1Rze

Allele Symbol: Pnpla2^tm1Rze

Allele Name	targeted mutation 1, Rudolf Zechner
Allele Type	Targeted (Null/Knockout)
Allele Synonym(s)	ATGL^-; ATGL-ko
Gene Symbol and Name	Pnpla2, patatin-like phospholipase domain containing 2
Gene Synonym(s)
Strain of Origin	129P2/OlaHsd-Hprt^b-m3
Chromosome	7
Molecular Note	A neomycin resistance cassette replaced the first exon including the translational start codon and the lipase consensus sequence motif (GXSXG). Northern analysis of white adipose tissue did not detect transcript in white adipose tissue from homozygous mutant mice. Similarly, western blot analysis of white adipose tissue from homozygous mutant mice did not detect protein.
Mutations Made By	Rudolf Zechner, Karl Franzens University Graz

Disease/Phenotype

Disease Terms

Research Areas By Phenotype

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

Cardiovascular Research
- Other
  - altered fat metabolism
Metabolism Research
- Enzyme Deficiency
- Lipid Metabolism
Neurobiology Research
- Metabolic Defects
Developmental Biology Research
- Postnatal Lethality
  - Homozygous
Internal/Organ Research
- Adipose Defects
Research Tools
- Diabetes and Obesity Research
Diabetes and Obesity Research
- Hypoinsulinemia
- Hypoglycemia

Mammalian Phenotype Terms by Genotype

The following phenotype information is associated with a similar, but not exact match to this JAX^® Mice strain

Genotype: Pnpla2^tm1Rze/Pnpla2^tm1Rze
involves: 129P2/OlaHsd

adipose tissue phenotype

increased brown adipose tissue amount

increased white adipose tissue amount

cellular phenotype

abnormal mitochondrial morphology
- cardiomyocytes exhibit increased mitochondria size with decreased mitochondrial DNA compared to in wild-type muscles
- Normal - however, treatment with Wy14643 (PPARA agonist) restores mitochondrial size and membrane potential

growth/size/body region phenotype

cardiac hypertrophy
- concentric hypertrophy

increased left ventricle weight
- Normal - however, treatment with Wy14643 (PPARA agonist) restores normal left ventricle weight

homeostasis/metabolism phenotype

abnormal enzyme/coenzyme activity
- mouse embryonic fibroblasts exhibit decreased triglyceride hydrolase activity compared with wild-type cells
- Normal - however, epidermal triglyceride hydrolase activity is normal
- liver and skin triglyceride hydrolase activity is decreased compared to in wild-type mice

abnormal respiratory quotient
- during the light period or food deprivation, mice exhibit less of a decrease in respiratory quotient compared with wild-type mice

decreased oxygen consumption
- Normal - however, treatment with Wy14643 (PPARA agonist) restores oxygen consumptions
- in heart homogenate mitochondria under basal and succinate-stimulated conditions

increased liver triglyceride level
- 4.6-fold in the livers of newborn mice
- Normal - however, treatment with Wy14643 or fenofibrate (PPARA agonists) reduces triglyceride levels

increased triglyceride level
- 4.6-fold higher in older mice than in younger mice
- Normal - however, treatment with Wy14643 or fenofibrate (PPARA agonists) restores normal triglyceride levels
- in cardiac and liver muscles
- 1.6-fold in the dermal
- 4.6-fold in the livers of newborn mice
- 1.3-fold in epidermis

abnormal metabolism
- treatment with GW501516 or GW0742 (PPARG agonists) fail to improve cardiometabolic defects
- Normal - however, treatment with Wy14643 (PPARA agonist) rescues cardiometabolic defects

impaired lipolysis
- Normal - however, epidermal triglyceride hydrolase activity is normal
- mouse embryonic fibroblasts exhibit decreased triglyceride hydrolase activity compared with wild-type cells
- liver and skin triglyceride hydrolase activity is decreased compared to in wild-type mice

increased cardiac muscle glycogen level

abnormal lipid homeostasis
- mouse embryonic fibroblasts treated with oleic acid to induce lipogenesis exhibit a 1.9-fold increase in triglyceride accumulation compared with similarly treated wild-type cells

increased fatty acids level
- mice exhibit a 53% increase in total intracellular concentration of unesterified fatty acid in the heart compared with wild-type mice

increased respiratory quotient

decreased circulating free fatty acids level

decreased circulating triglyceride level

liver/biliary system phenotype

increased liver triglyceride level
- Normal - however, treatment with Wy14643 or fenofibrate (PPARA agonists) reduces triglyceride levels
- 4.6-fold in the livers of newborn mice

mammalian phenotype

integument phenotype
- Normal - mice exhibit normal skin barrier function

mortality/aging

premature death
- Normal - however, treatment with Wy14643 exhibit increased survival

muscle phenotype

abnormal myocardial fiber morphology
- cardiomyocytes exhibit increased mitochondria size with decreased mitochondrial DNA compared to in wild-type muscles
- cardiomyocytes exhibit increased size and number of lipid droplets and glycogen granules compared to in wild-type muscles
- Normal - however, treatment with Wy14643 (PPARA agonist) restores mitochondrial size and membrane potential

increased cardiac muscle glycogen level

decreased ventricle muscle contractility
- Normal - however, treatment with Wy14643 (PPARA agonist) restores fractional shortening and ejection fraction
- mice exhibit reduced ventricular fractional shortening and ejection fraction compared with wild-type mice

cardiovascular system phenotype

abnormal heart ventricle morphology
- thickened posterior wall
- lower left ventricular end-diastolic dimensions

increased heart rate
- Normal - however, treatment with Wy14643 (PPARA agonist) reduces heart rate

abnormal myocardial fiber physiology
- cardiomyocytes exhibit reduced oxidative capacity compared with wild-type mice

cardiac hypertrophy
- concentric hypertrophy

increased left ventricle weight
- Normal - however, treatment with Wy14643 (PPARA agonist) restores normal left ventricle weight

abnormal myocardial fiber morphology
- cardiomyocytes exhibit increased size and number of lipid droplets and glycogen granules compared to in wild-type muscles
- cardiomyocytes exhibit increased mitochondria size with decreased mitochondrial DNA compared to in wild-type muscles
- Normal - however, treatment with Wy14643 (PPARA agonist) restores mitochondrial size and membrane potential

increased cardiac muscle glycogen level

abnormal cardiovascular system morphology
- Normal - however, treatment with Wy14643 (PPARA agonist) rescues cardiometabolic defects
- treatment with GW501516 or GW0742 (PPARG agonists) fail to improve cardiometabolic defects

thick interventricular septum
- Normal - however, treatment with Wy14643 (PPARA agonist) reduces interventricular septum thickness

decreased ventricle muscle contractility
- Normal - however, treatment with Wy14643 (PPARA agonist) restores fractional shortening and ejection fraction
- mice exhibit reduced ventricular fractional shortening and ejection fraction compared with wild-type mice

Genotype: Pnpla2^tm1Rze/Pnpla2^tm1Rze
involves: 129P2/OlaHsd * C57BL/6

cellular phenotype

abnormal cardiomyocyte apoptosis
- in mutants there is a moderate induction of apoptosis

growth/size/body region phenotype

increased heart weight
- mutant hearts have a 1.4x heart weight because of the excess triglycerides (193 mg for mutant vs 131 mg wild-type)

increased body weight
- homozygotes are heavier than wild-type

increased body mass index
- homozygotes display a 2-fold increase in body fat mass

homeostasis/metabolism phenotype

abnormal circulating insulin level

decreased circulating glucose level
- after a 6-hour fast, mice have significantly lower basal glucose values compared to wild-type

increased triglyceride level
- in non-cardiac tissue the most pronounced accumulation of triglycerides is a >10-fold increase seen in the testis and kidney; smaller (1.5-4-fold) increases are seen in all tissues including the liver
- there is a 20-fold increase in triglyceride content in cardiac muscle by 12 weeks of age in mutants

abnormal circulating glucose level

abnormal glucose tolerance

impaired adaptive thermogenesis
- after 5 hours of cold exposure, mutant body temperature is only 25 degrees C
- after 18 hours of fasting, body temperature drops to 28.4 degrees C vs 35.4 degrees in wild-type with prolonged fasting
- when mutants are exposed to cold for 5 hours, they suffer from life-threatening hypothermia as a result of impaired catabolism to triglycerides to brown adipose tissue

abnormal lipid homeostasis

decreased circulating HDL cholesterol level
- total cholesterol (due to decreased HDL levels ) is reduced by 22%

impaired lipolysis
- in mutants there is decreased lipolytic activities in white (-82%) and brown (-85%) adipose tissues, cardiac muscle (-31%), skeletal muscle (-44%), testis (-69%) and liver (-73%)

increased circulating leptin level
- plasma leptin levels are elevated by 2.1-fold in fed mutants and by 4.4-fold in fasted mutant mice

abnormal gas homeostasis

decreased circulating triglyceride level
- levels are decreased by 66%

abnormal homeostasis

abnormal respiratory quotient
- RQ in mutants deviates from wild-type during fasting; RQ remains constant whereas in wild-type, it decreases with increasing fasting time

decreased circulating insulin level
- in the fed state, plasma insulin levels are reduced by 42% in mutants compared to wild-type

improved glucose tolerance
- after a 6-hour fast, null mice show improved glucose tolerance compared to wild-type

increased insulin sensitivity
- maximal decline of blood glucose levels is more pronounced (34 mg/dl vs 53 mg/dl in wild-type) in Pnpla-deficient mice and persists for the entire 3 hour observation period

abnormal circulating hormone level

decreased oxygen consumption
- oxygen consumption decreases to 25% of that of wild-type after 18 hours of fasting

decreased circulating free fatty acids level
- in mutants, levels are reduced by 30% in the fed state and by 62% in the fasted state

decreased circulating VLDL triglyceride level
- reduced VLDL levels are found in mutants

cardiac edema
- at death

liver/biliary system phenotype

hepatic steatosis

mortality/aging

premature death
- pronounced cardiac dysfunction results in premature death for male and female homozygotes; the first mice die around 12 weeks of age
- heterozygous mice have normal life spans
- male mice (50% after 16 weeks) die earlier than female (50% after 20 weeks)

muscle phenotype

abnormal myocardium layer morphology
- in homozygotes there is severe triglyceride accumulation in cardiac muscle; at 12 weeks of age, mutants have a 20-fold higher triglyceride content in myocytes compared to wild-type

decreased ventricle muscle contractility
- ejection fraction from left ventricle is drastically reduced compared to wild-type (40.2% vs 80.5% in wild-type)

abnormal myocardial fiber morphology
- lipid droplets show an age-dependent increase in size and number in cardiomyocytes of mutants beginning with microvesicular droplets at 6 weeks and progressing to large droplets by 18 weeks

abnormal cardiomyocyte apoptosis
- in mutants there is a moderate induction of apoptosis

respiratory system phenotype

pulmonary vascular congestion
- congestion is observed in pulmonary vessels at death; not observed in mice before 14 weeks of age

adipose tissue phenotype

increased interscapular fat pad weight
- mutants have an 8.5 fold increase in wet weight of intracapsular brown adipose tissue

increased inguinal fat pad weight
- homozygotes display a 2.1 fold increase in wet weight of inguinal white adipose tissue compared to controls

increased gonadal fat pad weight
- homozygotes display a 1.6 fold increase in wet weight of gonadal white adipose tissue compared to controls

abnormal brown adipose tissue morphology
- mutant mice have enlarged lipid droplets (1395 micrometer vs 67 micrometer in wild-type) in brown adipocytes

increased brown adipose tissue amount
- mutants have an 8.5 fold increase in wet weight of intracapsular brown adipose tissue

abnormal white adipose tissue morphology
- mutant mice have enlarged lipid droplets (4690 micrometer vs 3382 micrometer in wild-type) in white adipocytes

cardiovascular system phenotype

abnormal cardiovascular system physiology
- at death, cardiac edema and pleural as well as cardiac effusions are observed; these are not observed in mice before 14 weeks of age
- massive lipid buildup causes severe cardiac insufficiency in mutants

abnormal myocardial fiber morphology
- lipid droplets show an age-dependent increase in size and number in cardiomyocytes of mutants beginning with microvesicular droplets at 6 weeks and progressing to large droplets by 18 weeks

increased heart weight
- mutant hearts have a 1.4x heart weight because of the excess triglycerides (193 mg for mutant vs 131 mg wild-type)

abnormal cardiomyocyte apoptosis
- in mutants there is a moderate induction of apoptosis

abnormal myocardium layer morphology
- in homozygotes there is severe triglyceride accumulation in cardiac muscle; at 12 weeks of age, mutants have a 20-fold higher triglyceride content in myocytes compared to wild-type

abnormal heart morphology

decreased ventricle muscle contractility
- ejection fraction from left ventricle is drastically reduced compared to wild-type (40.2% vs 80.5% in wild-type)

dilated heart left ventricle
- at death; this is not observed in mice before 14 weeks of age

cardiac fibrosis
- there is a marked change in cardiac texture and increase in fibrosis

pulmonary vascular congestion
- congestion is observed in pulmonary vessels at death; not observed in mice before 14 weeks of age

thick interventricular septum
- the interventricular septum in mutant hearts is significantly thickened and increases in thickness with age

congestive heart failure
- at death, mutants display typical features of congestive heart failure

dilated heart right ventricle
- at death; this is not observed in mice before 14 weeks of age

References

Kaneko T; Maeda A; Takefuji M; Aoyama H; Nakayama M; Kawabata S; Kawano Y; Iwamatsu A; Amano M; Kaibuchi K. 2005. Rho mediates endocytosis of epidermal growth factor receptor through phosphorylation of endophilin A1 by Rho-kinase. Genes Cells 10(10):973-87PubMed: 16164598 MGI: J:108456

Additional - Pnpla2^tm1Rze related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Standard PCR:Pnpla2Alternate1
- Genotyping resources and troubleshooting
Breeding Considerations

When maintaining a live colony, these mice can be bred as heterozygotes. Homozygotes die at about 14 to 16 weeks of age.
- Additional Breeding and Husbandry Support
Citation
When using the ATGL-ko mouse strain in a publication, please cite the originating article(s) and include JAX stock #019003 in your Materials and Methods section.

Animal Health Reports

Facility Barrier Level Descriptions

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

Pricing & Availability

Cryo Recovery

Domestic
International

Live Mouse

Age

Genotype

Price

weeks

Cryorecovery - Pricing

Service/Product	Description	Price
	Heterozygous or wildtype for Pnpla2<tm1Rze>

Related Products and Services

Frozen Mouse Embryo	B6;129P2-Pnpla2<tm1Rze>/J	$2595.00
Frozen Mouse Embryo	B6;129P2-Pnpla2<tm1Rze>/J	$2595.00
Frozen Mouse Embryo	B6;129P2-Pnpla2<tm1Rze>/J	$3373.50
Frozen Mouse Embryo	B6;129P2-Pnpla2<tm1Rze>/J	$3373.50

Payment Terms and Conditions

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.

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. We do not guarantee breeding performance and therefore suggest that investigators order more than one breeding pair to avoid delays in their research.

Terms Of Use

General Terms and Conditions

Questions about Terms of Use

Licensing Information

Phone: 207-288-6470

Email: TechTran@jax.org

Also Known As:ATGL-ko

Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Control Suggestions

Approximate Controls

Additional Information

Selected References

Pnpla2tm1Rze

Allele Symbol: Pnpla2tm1Rze

Disease Terms

Research Areas By Phenotype

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

Mammalian Phenotype Terms by Genotype

Genotype: Pnpla2tm1Rze/Pnpla2tm1Rzeinvolves: 129P2/OlaHsd

adipose tissue phenotype

cellular phenotype

growth/size/body region phenotype

homeostasis/metabolism phenotype

liver/biliary system phenotype

mammalian phenotype

mortality/aging

muscle phenotype

cardiovascular system phenotype

Genotype: Pnpla2tm1Rze/Pnpla2tm1Rzeinvolves: 129P2/OlaHsd * C57BL/6

cellular phenotype

growth/size/body region phenotype

homeostasis/metabolism phenotype

liver/biliary system phenotype

mortality/aging

muscle phenotype

respiratory system phenotype

adipose tissue phenotype

cardiovascular system phenotype

References

Additional - Pnpla2tm1Rze related

Genotyping Protocols

Breeding Considerations

Citation

Animal Health Reports

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

Live Mouse

Cryorecovery - Pricing

Related Products and Services

Payment Terms and Conditions

The Jackson Laboratory's Genotype Promise

Terms Of Use

Licensing Information

Pnpla2^tm1Rze

Allele Symbol: Pnpla2^tm1Rze

Genotype: Pnpla2^tm1Rze/Pnpla2^tm1Rze
involves: 129P2/OlaHsd

Genotype: Pnpla2^tm1Rze/Pnpla2^tm1Rze
involves: 129P2/OlaHsd * C57BL/6

Additional - Pnpla2^tm1Rze related