Description

Strain Information

Former Names B6.129S4-Dgattm1Far    (Changed: 15-DEC-04 ) Type Congenic; Mutant Strain; Targeted Mutation; Additional information on Genetically Engineered Mutant Mice. Species laboratory mouse Generation N10F?+4+N1p (10-OCT-04)   Donating Investigator Bob Farese,   Gladstone Inst of Cardiovascular Disease

Description
Mice homozygous for the Dgat1^tm1Far targeted mutation are viable, fertile, normal in size and do not display any gross physical or behavioral abnormalities however, homozygous mutant females exhibit a complete absence of milk production, necessitating the use of foster mothers. Dgat1 mRNA is undetectable by Northern blot analysis, and DGAT enzyme activity in a variety of tissues is either absent or shows only residual levels. Surprisingly, in DGAT deficient mice triglyceride levels and fasting serum triglycerides levels are similar to wildtype controls. Although homozygotes do not differ in body weight compared to age- and sex-matched controls, total fat pad weight is reduced. Tissue triglyceride levels are reduced 30-40% in white adipose tissue and muscle. Liver triglyceride levels tend to be lower in chow-fed DGAT-deficient mice, but high-fat feeding leads to significantly lower liver triglycerides. Changes in tissue triglyceride levels are associated with increased sensitivity to insulin and leptin. Additionally, infusion of leptin suppresses weight gain significantly more in DGAT-deficient mice compared to controls. Dry fur and hair loss in mutant mice are evident by 6-8 weeks, resulting from sebaceous gland atrophy and abnormal fur lipid production (especially type 2 wax diesters). DGAT-deficient mice also exhibit impaired water repulsion and hypothermia after water immersion. Interestingly, leptin modulates the fur and skin effects seen with DGAT deficiency. Homozygotes that are maintained on a high fat diet (21% fat by weight) are resistant to obesity. Resistance to diet-induced obesity is attributed to increased energy expenditure in Dgat1-null mice. This mutant strain is a suitable tool for use in studies examining mechanisms of triglyceride synthesis and the relationship between triglyceride synthesis and obesity, leptin, and insulin resistance. DGAT-deficient mice also provide a useful model to study the role of DGAT in fur and sebaceous gland physiology.

Development
A targeting vector containing a neomycin resistance gene was used to disrupt a portion of the Dgat1 gene that enocdes the carboxy-terminal 27% of the protein product. The construct was transfected into 129S4/SvJae derived RF8 embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6J blastocysts. The resulting chimeric animals were backcrossed to C57BL/6J mice.

Control Information

	Control
	Wild-type from the colony
	000664 C57BL/6J
Considerations for Choosing Controls

Additional Web Information

Congenic Nomenclature

Phenotype

Phenotype Information

View Mammalian Phenotype Terms

Mammalian Phenotype Terms

      assigned by genotype

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

Dgat1^tm1Far/Dgat1^tm1Far

        involves: 129S4/SvJae * C57BL/6J

• homeostasis/metabolism phenotype
• decreased cholesterol level (MGI Ref ID J:111346)
  • after receiving a high-fat diet for 20 weeks, hepatic cholesterol ester levels are markedly reduced vs controls
• decreased circulating glucose level (MGI Ref ID J:111346)
  • after high-fat diet for 8 weeks, mice have decreased blood glucose after an overnight fast vs controls
• decreased circulating leptin level (MGI Ref ID J:111346)
  • serum leptin levels are significantly lower than in Dgat1-sufficient animals regardless of Adipoq genotype (4.2 ng/ml vs ~17.7 ng/ml in Dgat1-suffcient)
• decreased triglyceride level (MGI Ref ID J:111346)
  • after receiving a high-fat diet for 20 weeks, hepatic triglyceride levels are markedly reduced vs controls
• improved glucose tolerance (MGI Ref ID J:111346)
  • after glucose challenge, improved glucose tolerance compared to wild-type controls is seen; Dgat1-deficiency improves glucose tolerance by ~30-35% vs controls
• increased insulin sensitivity (MGI Ref ID J:61885)
  • tended to have lower glucose and insulin levels after a glucose tolerance test
• increased oxygen consumption (MGI Ref ID J:111346)
  • mice fed a higher fat diet have higher levels of oxygen consumption than Dgat1-sufficient mice
• increased resistance to diet-induced obesity (MGI Ref ID J:61885)
  • when fed a high-fat diet, mutant mice were resistant to obesity
  • mice fed a chow diet had similar body weights, but the weight of the total fat pads in mutant mice was lower than control
  • mutant mice has higher metabolic rates both on a chow diet and on a high-fat diet
• behavior/neurological phenotype
• hyperactivity (MGI Ref ID J:61885)
  • on the high-fat diet, mutant mice were twice as active as wild-type mice
• endocrine/exocrine gland phenotype
• abnormal lactation (MGI Ref ID J:61885)
  • females had a complete absence of milk production
• reproductive system phenotype
• abnormal lactation (MGI Ref ID J:61885)
  • females had a complete absence of milk production
• adipose tissue phenotype
• decreased percent body fat (MGI Ref ID J:111346)
  • lower than Dgat1-sufficient mice
• growth/size phenotype
• decreased body weight (MGI Ref ID J:111346)
  • when Dgat1-deficient, Adipoq-sufficient mice are weaned onto a high-fat diet, they show decreased body weight over 20 weeks vs wild-type controls
• increased resistance to diet-induced obesity (MGI Ref ID J:61885)
  • when fed a high-fat diet, mutant mice were resistant to obesity
  • mice fed a chow diet had similar body weights, but the weight of the total fat pads in mutant mice was lower than control
  • mutant mice has higher metabolic rates both on a chow diet and on a high-fat diet
• liver/biliary system phenotype
• increased resistance to hepatic steatosis (MGI Ref ID J:111346)
  • when fed a high fat diet for 20 weeks, mice show significantly less hepatic steatosis vs wild-type controls

View Research Applications

Research Applications

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

Dgat1^tm1Far related

Cardiovascular Research
Hypotriglyceridemia

Developmental Biology Research
Skin and Hair Texture Defects

Diabetes and Obesity Research
Obesity With Diabetes (diet-induced, resistant)

Internal/Organ Research
Adipose Defects

Metabolism Research
Lipid Metabolism

Genes & Alleles

Gene & Allele Information

Allele Symbol		Dgat1tm1Far
Allele Name		targeted mutation 1, Bob Farese
Allele Type		Targeted (knock-out)
Mutation Made By		Bob Farese,   Gladstone Inst of Cardiovascular Disease
Gene Symbol and Name		Dgat1, diacylglycerol O-acyltransferase 1
Chromosome		15
Gene Common Name(s)		ARGP1; C75990; D15Ertd23e; DGAT; DNA segment, Chr 15, ERATO Doi 23, expressed; expressed sequence C75990;
Molecular Note		A genomic fragment containing sequences encoding the carboxy-terminus of the protein was replaced by a neomycin cassette. Northern blot analysis did not detect a full length transcript produced from this allele in homozygous mice. Tissue DGAT activity was absent ot severely reduced in homozygous mice. [MGI Ref ID J:61885]

Genotyping

Genotyping Information

Genotyping Protocols

Dgat1^tm1Far, HRM, vers. 4
Dgat1^tm1Far, SEP PCR, vers. 3
Dgat1^tm1Far, STD PCR, vers. 1
Dgat1^tm1Far, STD PCR, vers. 2

Helpful Links

Optimizing PCR Protocols

References

References

Selected Reference(s)

Smith SJ; Cases S; Jensen DR; Chen HC; Sande E; Tow B; Sanan DA; Raber J; Eckel RH; Farese RV Jr. 2000. Obesity resistance and multiple mechanisms of triglyceride synthesis in mice lacking Dgat [see comments] Nat Genet 25(1):87-90. [PubMed: 10802663]  [MGI Ref ID J:61885]

Additional References

Dgat1^tm1Far related

Buhman KK; Smith SJ; Stone SJ; Repa JJ; Wong JS; Knapp FF Jr; Burri BJ; Hamilton RL; Abumrad NA; Farese RV Jr. 2002. DGAT1 is not essential for intestinal triacylglycerol absorption or chylomicron synthesis. J Biol Chem 277(28):25474-9. [PubMed: 11959864]  [MGI Ref ID J:120436]

Cases S; Zhou P; Shillingford JM; Wiseman BS; Fish JD; Angle CS; Hennighausen L; Werb Z; Farese RV Jr. 2004. Development of the mammary gland requires DGAT1 expression in stromal and epithelial tissues. Development 131(13):3047-55. [PubMed: 15163627]  [MGI Ref ID J:128259]

Chen HC; Ladha Z; Farese RV Jr. 2002. Deficiency of acyl coenzyme a:diacylglycerol acyltransferase 1 increases leptin sensitivity in murine obesity models. Endocrinology 143(8):2893-8. [PubMed: 12130553]  [MGI Ref ID J:78337]

Chen HC; Ladha Z; Smith SJ; Farese RV Jr. 2003. Analysis of energy expenditure at different ambient temperatures in mice lacking DGAT1. Am J Physiol Endocrinol Metab 284(1):E213-8. [PubMed: 12388146]  [MGI Ref ID J:107764]

Chen HC; Rao M; Sajan MP; Standaert M; Kanoh Y; Miura A; Farese RV Jr; Farese RV. 2004. Role of adipocyte-derived factors in enhancing insulin signaling in skeletal muscle and white adipose tissue of mice lacking Acyl CoA:diacylglycerol acyltransferase 1. Diabetes 53(6):1445-51. [PubMed: 15161747]  [MGI Ref ID J:90374]

Chen HC; Smith SJ; Ladha Z; Jensen DR; Ferreira LD; Pulawa LK; McGuire JG; Pitas RE; Eckel RH; Farese RV Jr. 2002. Increased insulin and leptin sensitivity in mice lacking acyl CoA:diacylglycerol acyltransferase 1. J Clin Invest 109(8):1049-55. [PubMed: 11956242]  [MGI Ref ID J:76091]

Chen HC; Smith SJ; Tow B; Elias PM; Farese RV Jr. 2002. Leptin modulates the effects of acyl CoA:diacylglycerol acyltransferase deficiency on murine fur and sebaceous glands. J Clin Invest 109(2):175-81. [PubMed: 11805129]  [MGI Ref ID J:74340]

Liu L; Zhang Y; Chen N; Shi X; Tsang B; Yu YH. 2007. Upregulation of myocellular DGAT1 augments triglyceride synthesis in skeletal muscle and protects against fat-induced insulin resistance. J Clin Invest 117(6):1679-89. [PubMed: 17510710]  [MGI Ref ID J:122086]

Liu Y; Millar JS; Cromley DA; Graham M; Crooke R; Billheimer JT; Rader DJ. 2008. Knockdown of acyl-CoA:diacylglycerol acyltransferase 2 with antisense oligonucleotide reduces VLDL TG and ApoB secretion in mice. Biochim Biophys Acta 1781(3):97-104. [PubMed: 18252207]  [MGI Ref ID J:133527]

Paglialunga S; Fisette A; Yan Y; Deshaies Y; Brouillette JF; Pekna M; Cianflone K. 2008. Acylation-stimulating protein deficiency and altered adipose tissue in alternative complement pathway knockout mice. Am J Physiol Endocrinol Metab 294(3):E521-9. [PubMed: 18160458]  [MGI Ref ID J:133454]

Streeper RS; Koliwad SK; Villanueva CJ; Farese RV Jr. 2006. Effects of DGAT1 deficiency on energy and glucose metabolism are independent of adiponectin. Am J Physiol Endocrinol Metab 291(2):E388-94. [PubMed: 16595853]  [MGI Ref ID J:111346]

Wongsiriroj N; Piantedosi R; Palczewski K; Goldberg IJ; Johnston TP; Li E; Blaner WS. 2008. The molecular basis of retinoid absorption: a genetic dissection. J Biol Chem 283(20):13510-9. [PubMed: 18348983]  [MGI Ref ID J:137102]

Health & husbandry

Health & Colony Maintenance Information

Colony Maintenance

Breeding & Husbandry	This strain originated on a B6;129S4 background and has been backcrossed to C57BL/6J for ten generations. If homozygous females are used for breeding, foster mothers are necessary, as homozygous females are unable to nurse. The donating investigator maintained this mutant strain by crossing homozygous males with heterozygous females. Coat color expected from breeding:Black
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

Cryopreserved Embryos This strain is also available as cryopreserved embryos from our Repository. Orders for cryopreserved embryos are supplied subject to a signed agreement that must be returned to the Customer Service Department after order placement. 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 from our repository, please visit our Cryopreserved Embryos web page. 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. Genomic DNA is available for this strain from the Mouse DNA Resource.

Control Information

	Control
	Wild-type from the colony
	000664 C57BL/6J
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.

General Terms and Conditions

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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.

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Terms of Use

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phone:	207-288-6470
fax:	207-288-6655

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