Description

Strain Information

Type Mutant Stock; Targeted Mutation; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Mating System Heterozygote x Heterozygote         (Female x Male)   02-MAY-07 Species laboratory mouse Generation F?+N1F1pN1F3 (13-JAN-09) Generation Definitions   Donating Investigator Bradford Lowell,   Beth Israel Deaconess Med Cntr (Harvard)

Description
The mice have a loxp-flanked transcriptional blocking (loxTB) sequence that prevents normal endogenous gene transcription and translation from the endogenous locus. As such, homozygous mice are devoid of functional mRNA in all tested regions of the brain. Homozygous mice exhibit severe early-onset obesity, accompanied by hyperphagia, increased snout-anus length and hyperinsulinemia. The function of this disrupted allele can be restored by the enzymatic activity of Cre-recombinase. These mutant mice may be useful in studies of neurobiology, obesity, diabetes, hunger/appetite, and fat and energy metabolism.

When bred to a strain expressing Cre recombinase in the hypothalamus see Stock No. 006395 for example), this mutant mouse strain exhibits as intermediate phenotype in comparison to homozygous null mice.

Development
A targeting vector was designed to insert a loxp-flanked transcriptional blocker sequence (loxTB) between the transcriptional start site and ATG of the endogenous gene. The blocker sequence contains an SV40 enhancer, neomycin resistance gene, two HSV-TK polyA sequences, and an additional transcriptional pause signal from the pGL3-control vector. The construct was electroporated into 129S4/SvJae-derived embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6 blastocysts. Chimeric mice were bred to C57BL/6 mice. Mutant mice heterozygous for the "loxTB Mc4r" allele were bred together and maintained as such prior to arrival at The Jackson Laboratory.

Control Information

	Control
	Wild-type from the colony
	101043 B6129SF1/J	(approximate)
	101045 B6129SF2/J	(approximate)
Considerations for Choosing Controls

Related Strains

Strains carrying other alleles of Mc4r

008323

B6.Cg-Tg(Mc4r-MAPT/Sapphire)21Rck/J

View Strains carrying other alleles of Mc4r     (1 strain)

Additional Web Information

Introduction to Cre-lox technology

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms provided by MGI

Fatty Liver Disease, Nonalcoholic, Susceptibility to, 1; NAFLD1 - Models with phenotypic similarity to human disease where etiologies are distinct.2

2 Human genes are associated with this disease. Orthologs of those genes do not appear in the mouse genotype(s).

View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI

      assigned by genotype

Mc4r^tm1Lowl/Mc4r^tm1Lowl

        involves: 129S4/SvJae * C57BL/6J

• growth/size phenotype
• increased body length
  • at 12 weeks, homozygotes show increased snout-anus length   (MGI Ref ID J:115192)
• increased susceptibility to weight gain
  • mutants exhibit increased weight gain compared to wild-type mice when fed either the standard diet or a high-fat diet   (MGI Ref ID J:177386)
• • increased susceptibility to diet-induced obesity
    • mutants exhibit increased weight gain compared to wild-type mice when fed a high-fat diet   (MGI Ref ID J:177386)
• obese   (MGI Ref ID J:177386)
  • male and female homozygotes display severe early-onset obesity   (MGI Ref ID J:115192)
• homeostasis/metabolism phenotype
• abnormal oxygen consumption
  • mice do not show an increase in oxygen consumption from stimulation by MTII as wild-type mice do   (MGI Ref ID J:115192)
• • decreased oxygen consumption
    • oxygen consumption is reduced in the dark and light cycles compared to wild-type and is similar to mutants also expressing Tg(Sim1-cre)1Lowl   (MGI Ref ID J:115192)
• decreased adiponectin level
  • mutants fed the high-fat diet exhibit decreased serum adiponectin levels compared to wild-type mice on the same diet   (MGI Ref ID J:177386)
• increased circulating alanine transaminase level
  • mutants fed the high-fat diet show increased serum alanine aminotransferase concentrations compared to wild-type mice   (MGI Ref ID J:177386)
• increased circulating free fatty acid level
  • mutants fed the high-fat diet show an increase in serum free fatty acid concentrations relative to wild-type mice   (MGI Ref ID J:177386)
• increased circulating insulin level
  • hyperinsulinemia is displayed by homozygotes   (MGI Ref ID J:115192)
• increased circulating interleukin-6 level
  • mutants fed the high-fat diet exhibit increased serum IL-6 levels compared to wild-type mice on the same diet   (MGI Ref ID J:177386)
• increased circulating leptin level
  • mutants fed the high-fat diet exhibit increased serum leptin levels compared to wild-type mice on the same diet   (MGI Ref ID J:177386)
• increased liver triglyceride level
  • mutants exhibit increased hepatic triglyceride content compared to wild-type mice on either the standard or high-fat diet   (MGI Ref ID J:177386)
  • livers of mutants fed the high-fat diet exhibit increased triglyceride secretion compared to wild-type livers   (MGI Ref ID J:177386)
• increased susceptibility to diet-induced obesity
  • mutants exhibit increased weight gain compared to wild-type mice when fed a high-fat diet   (MGI Ref ID J:177386)
• behavior/neurological phenotype
• abnormal food intake
  • unlike wild-type mice, mutants do not exhibit a reduction in food intake after treatment with the Mc4r inhibitor, MTII   (MGI Ref ID J:115192)
• • polyphagia
    • obesity is accompanied by polyphagia   (MGI Ref ID J:115192)
• adipose tissue phenotype
• abnormal white adipose tissue morphology
  • white adipose tissue of mutants fed the high-fat diet for 8 weeks exhibits increased macrophage infiltration and pro-inflammatory cytokine expression compared to wild-type white adipose tissue   (MGI Ref ID J:177386)
• increased total body fat amount
  • mutants fed the standard diet exhibit increased adiposity compared to wild-type mice on the same diet   (MGI Ref ID J:177386)
  • mutants fed the high-fat diet also exhibit increased adiposity, but only up to 8 weeks of high-fat feeding with no further increase after 8 weeks   (MGI Ref ID J:177386)
• immune system phenotype
• increased circulating interleukin-6 level
  • mutants fed the high-fat diet exhibit increased serum IL-6 levels compared to wild-type mice on the same diet   (MGI Ref ID J:177386)
• liver inflammation
  • livers from mutants fed the high-fat diet exhibit ballooning degeneration and massive infiltration of inflammatory cells   (MGI Ref ID J:177386)
  • livers from mutants fed the high-fat diet exhibit increased inflammatory cell infiltration compared to wild-type livers   (MGI Ref ID J:177386)
• liver/biliary system phenotype
• hepatic steatosis
  • mutants fed the high-fat diet for 8 weeks exhibit massive microvesicular steatosis in the centrilobular and portal areas while wild-type mice only have minimal lipid accumulation in the liver   (MGI Ref ID J:177386)
  • mutants fed the high-fat diet develop liver steatosis faster (by 8 weeks of high-fat diet) than wild-type mice (by 20 weeks of high-fat diet)   (MGI Ref ID J:177386)
• increased liver triglyceride level
  • mutants exhibit increased hepatic triglyceride content compared to wild-type mice on either the standard or high-fat diet   (MGI Ref ID J:177386)
  • livers of mutants fed the high-fat diet exhibit increased triglyceride secretion compared to wild-type livers   (MGI Ref ID J:177386)
• increased liver weight
  • mutants exhibit increased liver weight compared to wild-type mice on either the standard or high-fat diet   (MGI Ref ID J:177386)
• liver fibrosis
  • livers from mutants fed the high-fat diet exhibit increased pericellular fibrosis compared to wild-type mice at 8 and 20 weeks of high-fat feeding   (MGI Ref ID J:177386)
• liver inflammation
  • livers from mutants fed the high-fat diet exhibit ballooning degeneration and massive infiltration of inflammatory cells   (MGI Ref ID J:177386)
  • livers from mutants fed the high-fat diet exhibit increased inflammatory cell infiltration compared to wild-type livers   (MGI Ref ID J:177386)
• tumorigenesis
• hepatocellular carcinoma
  • mutants fed the high-fat diet, but not the standard diet, for a year develop liver tumors   (MGI Ref ID J:177386)
  • tumors resemble hepatocellular carcinoma   (MGI Ref ID J:177386)

The following phenotype relates to a compound genotype created using this strain.
Contact JAX^® Services jaxservices@jax.org for customized breeding options.

Mc4r^tm1Lowl/Mc4r^tm1Lowl Tg(Nes-cre)1Kln/0

        involves: 129S4/SvJae * C57BL/6 * SJL   (conditional)

• normal phenotype
• no abnormal phenotype detected
  • mice homozygous for reactivated Mc4r in neurons show normal body weights and rescue of the increased snout-anus length observed in Mc4r homozygotes   (MGI Ref ID J:115192)

Mc4r^tm1Lowl/Mc4r^tm1Lowl Tg(Sim1-cre)1Lowl/0

        involves: 129S4/SvJae * C57BL/6J * FVB   (conditional)

• growth/size phenotype
• *normal* growth/size phenotype
  • at 12 weeks, transgenic mice and wild-type littermates have the same snout-anus length, compared to increased length observed in nontransgenic Mc4r^tm1Lowl mice   (MGI Ref ID J:115192)
• • increased body weight
    • transgenic mice have increased fat mass compared with wild-type littermates, but significantly decreased fat mass compared to Mc4r^tm1Lowl littermates   (MGI Ref ID J:115192)
  • • obese
      • at 12 weeks of age, male and female mutants have only 37% and 46% respectively, of the obesity observed in mice homozygous for Mc4r disruption   (MGI Ref ID J:115192)
  • increased lean body mass
    • transgenic mice have increased lean mass compared with wild-type littermates, but significantly decreased lean mass compared to Mc4r^tm1Lowl littermates   (MGI Ref ID J:115192)
• homeostasis/metabolism phenotype
• abnormal oxygen consumption
  • mice do not show an increase in oxygen consumption from stimulation by MTII as wild-type mice do   (MGI Ref ID J:115192)
• • decreased oxygen consumption
    • oxygen consumption is reduced in the dark and light cycles compared to wild-type and is similar to Mc4r^tm1Lowl homozygotes   (MGI Ref ID J:115192)
• behavior/neurological phenotype
• *normal* behavior/neurological phenotype
  • transgenic mice are obese, yet show food intake comparable to wild-type mice at 11 weeks of age   (MGI Ref ID J:115192)
• • abnormal food intake
    • when treated with MTII an Mc4r inhibitor, wild-type mice show a 50% reduction in food intake, while transgenic mice display no effect on intake   (MGI Ref ID J:115192)

Mc4r^tm1Lowl/Mc4r^tm1Lowl Tg(Zp3-cre)3Mrt/0

        involves: 129S4/SvJae * C57BL/6J * FVB/N   (conditional)

• normal phenotype
• no abnormal phenotype detected
  • mice homozygous for reactivated Mc4r in neurons show normal body weights and rescue of the increased snout-anus length observed in Mc4r homozygotes mice homozygous for reactivated Mc4r in the germline show normal body weights and rescue of the increased snout-anus length observed in Mc4r homozygotes   (MGI Ref ID J:115192)

View Research Applications

Research Applications

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

Diabetes and Obesity Research
Hyperinsulinemia
Obesity With Diabetes
Obesity Without Diabetes

Neurobiology Research
Metabolic Defects

Research Tools
Cre-lox System
      loxP-flanked Sequences
Diabetes and Obesity Research
      loxP
Metabolism Research
Neurobiology Research

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		Mc4rtm1Lowl
Allele Name		targeted mutation 1, Bradford B Lowell
Allele Type		Targeted (Floxed/Frt)
Common Name(s)		loxTB Mc4r;
Mutation Made By		Bradford Lowell,   Beth Israel Deaconess Med Cntr (Harvard)
Strain of Origin		129S4/SvJae
ES Cell Line Name		J1
ES Cell Line Strain		129S4/SvJae
Gene Symbol and Name		Mc4r, melanocortin 4 receptor
Chromosome		18
Gene Common Name(s)		Fatboy; Glu3; glucose 3;
Molecular Note		A loxP flanked PGK-neomycin selection marker inserted in the 5' UTR created a null allele. Cre recombinase deletes the selection marker, restoring normal activity of the allele. Mice fail to respond to MC4R agonist MTII. This is a null allele that canbe "reactivated" by cre recombinase. [MGI Ref ID J:115192]

Genotyping

Genotyping Information

Genotyping Protocols

Mc4r^tm1Lowl, Standard PCR

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Balthasar N; Dalgaard LT; Lee CE; Yu J; Funahashi H; Williams T; Ferreira M; Tang V; McGovern RA; Kenny CD; Christiansen LM; Edelstein E; Choi B; Boss O; Aschkenasi C; Zhang CY; Mountjoy K; Kishi T; Elmquist JK; Lowell BB. 2005. Divergence of melanocortin pathways in the control of food intake and energy expenditure. Cell 123(3):493-505. [PubMed: 16269339]  [MGI Ref ID J:115192]

Additional References

Mc4r^tm1Lowl related

Itoh M; Suganami T; Nakagawa N; Tanaka M; Yamamoto Y; Kamei Y; Terai S; Sakaida I; Ogawa Y. 2011. Melanocortin 4 receptor-deficient mice as a novel mouse model of nonalcoholic steatohepatitis. Am J Pathol 179(5):2454-63. [PubMed: 21906580]  [MGI Ref ID J:177386]

Kawahara Y; Grimberg A; Teegarden S; Mombereau C; Liu S; Bale TL; Blendy JA; Nishikura K. 2008. Dysregulated editing of serotonin 2C receptor mRNAs results in energy dissipation and loss of fat mass. J Neurosci 28(48):12834-44. [PubMed: 19036977]  [MGI Ref ID J:142503]

Nogueiras R; Wiedmer P; Perez-Tilve D; Veyrat-Durebex C; Keogh JM; Sutton GM; Pfluger PT; Castaneda TR; Neschen S; Hofmann SM; Howles PN; Morgan DA; Benoit SC; Szanto I; Schrott B; Schurmann A; Joost HG; Hammond C; Hui DY; Woods SC; Rahmouni K; Butler AA; Farooqi IS; O'Rahilly S; Rohner-Jeanrenaud F; Tschop MH. 2007. The central melanocortin system directly controls peripheral lipid metabolism. J Clin Invest 117(11):3475-88. [PubMed: 17885689]  [MGI Ref ID J:127528]

Pillot B; Duraffourd C; Begeot M; Joly A; Luquet S; Houberdon I; Naville D; Vigier M; Gautier-Stein A; Magnan C; Mithieux G. 2011. Role of hypothalamic melanocortin system in adaptation of food intake to food protein increase in mice. PLoS One 6(4):e19107. [PubMed: 21544212]  [MGI Ref ID J:172374]

Rossi J; Balthasar N; Olson D; Scott M; Berglund E; Lee CE; Choi MJ; Lauzon D; Lowell BB; Elmquist JK. 2011. Melanocortin-4 receptors expressed by cholinergic neurons regulate energy balance and glucose homeostasis. Cell Metab 13(2):195-204. [PubMed: 21284986]  [MGI Ref ID J:169562]

Vella KR; Ramadoss P; Lam FS; Harris JC; Ye FD; Same PD; O'Neill NF; Maratos-Flier E; Hollenberg AN. 2011. NPY and MC4R signaling regulate thyroid hormone levels during fasting through both central and peripheral pathways. Cell Metab 14(6):780-90. [PubMed: 22100407]  [MGI Ref ID J:179670]

Voss-Andreae A; Murphy JG; Ellacott KL; Stuart RC; Nillni EA; Cone RD; Fan W. 2007. Role of the central melanocortin circuitry in adaptive thermogenesis of brown adipose tissue. Endocrinology 148(4):1550-60. [PubMed: 17194736]  [MGI Ref ID J:129583]

Xu Y; Jones JE; Lauzon DA; Anderson JG; Balthasar N; Heisler LK; Zinn AR; Lowell BB; Elmquist JK. 2010. A serotonin and melanocortin circuit mediates D-fenfluramine anorexia. J Neurosci 30(44):14630-4. [PubMed: 21048120]  [MGI Ref ID J:166702]

Health & husbandry

Health & Colony Maintenance Information

Animal Health Reports

Room Number           AX12

Colony Maintenance

Breeding & Husbandry	Although homozygous mice are viable and fertile, the donating investigator breeds heterozygous mice together to generate homozygous, heterozygous, and wildtype mice.
Mating System	Heterozygote x Heterozygote         (Female x Male)   02-MAY-07
Diet Information	LabDiet® 5K52/5K67

Purchasing information

Pricing, Supply Level & Notes, Controls

General Supply Notes

• This strain is included in the Induced Mutant Resource Colony collection.

Control Information

	Control
	Wild-type from the colony
	101043 B6129SF1/J	(approximate)
	101045 B6129SF2/J	(approximate)
Considerations for Choosing Controls
Control Pricing Information for Genetically Engineered Mutant Strains.

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.

See Terms of Use tab for General Terms and Conditions

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.

---

Ordering Information
JAX^® Mice
Surgical and Preconditioning Services
JAX^® Services
Customer Services and Support
Tel: 1-800-422-6423 or 1-207-288-5845
Fax: 1-207-288-6150
Technical Support Email Form

Terms of Use

Terms of Use

General Terms and Conditions

For Licensing and Use Restrictions view the link(s) below:
- Use of MICE by companies or for-profit entities requires a license prior to shipping.

Contact information

General inquiries

Contracts Administration

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

JAX^® Mice, Products & Services Conditions of Use

"MICE" means mouse strains, their progeny derived by inbreeding or crossbreeding, unmodified derivatives from mouse strains or their progeny supplied by The Jackson Laboratory ("JACKSON"). "PRODUCTS" means biological materials supplied by JACKSON, and their derivatives. "RECIPIENT" means each recipient of MICE, PRODUCTS, or services provided by JACKSON including each institution, its employees and other researchers under its control. MICE or PRODUCTS shall not be: (i) used for any purpose other than the internal research, (ii) sold or otherwise provided to any third party for any use, or (iii) provided to any agent or other third party to provide breeding or other services. Acceptance of MICE or PRODUCTS from JACKSON shall be deemed as agreement by RECIPIENT to these conditions, and departure from these conditions requires JACKSON's prior written authorization.

In case of dissatisfaction for a valid reason and claimed in writing by a purchaser within ninety (90) days of receipt of mice, products or services, JACKSON will, at its option, provide credit or replacement for the mice or product received or the services provided.

No Liability

In no event shall JACKSON, its trustees, directors, officers, employees, and affiliates be liable for any causes of action or damages, including any direct, indirect, special, or consequential damages, arising out of the provision of MICE, PRODUCTS or services, including economic damage or injury to property and lost profits, and including any damage arising from acts or negligence on the part of JACKSON, its agents or employees. Unless prohibited by law, in purchasing or receiving MICE, PRODUCTS or services from JACKSON, purchaser or recipient, or any party claiming by or through them, expressly releases and discharges JACKSON from all such causes of action or damages, and further agrees to defend and indemnify JACKSON from any costs or damages arising out of any third party claims.

MICE and PRODUCTS are to be used in a safe manner and in accordance with all applicable governmental rules and regulations.

The foregoing represents the General Terms and Conditions applicable to JACKSON’s MICE, PRODUCTS or services. In addition, special terms and conditions of sale of certain MICE, PRODUCTS or services may be set forth separately in JACKSON web pages, catalogs, price lists, contracts, and/or other documents, and these special terms and conditions shall also govern the sale of these MICE, PRODUCTS and services by JACKSON, and by its licensees and distributors.

Acceptance of delivery of MICE, PRODUCTS or services shall be deemed agreement to these terms and conditions. No purchase order or other document transmitted by purchaser or recipient that may modify the terms and conditions hereof, shall be in any way binding on JACKSON, and instead the terms and conditions set forth herein, including any special terms and conditions set forth separately, shall govern the sale of MICE, PRODUCTS or services by JACKSON.