Skip to main content

Advertisement

SpringerLink
Log in

Metabolic syndrome in mice induced by expressing a transcriptional activator in adipose tissue

  • Original Paper
  • Published:
Transgenic Research Aims and scope Submit manuscript

Abstract

Metabolic syndrome is a combination of medical disorders that increases the risk of developing cardiovascular disease and diabetes. Constitutive overexpression of 11β-HSD1 in adipose tissue in mice leads to metabolic syndrome. In the process of generating transgenic mice overexpressing 11β-HSD1 in an inducible manner, we found a metabolic syndrome phenotype in control, transgenic mice, expressing the reverse tetracycline-transactivator (rtTA) in adipose tissue. The control mice exhibited all four sequelae of metabolic syndrome (visceral obesity, insulin resistance, dyslipidemia, and hypertension), a pro-inflammatory state and marked hepatic steatosis. Gene expression profiling of the adipose tissue, muscle and liver of these mice revealed changes in expression of genes involved in lipid metabolism, insulin resistance, and inflammation. Transient transfection of rtTA, but not tTS, into 3T3-L1 cells resulted in lipid accumulation. We conclude that expression of rtTA in adipose tissue causes metabolic syndrome in mice.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Brinster RL, Chen HY, Warren R, Sarthy A, Palmiter RD (1982) Regulation of metallothionein–thymidine kinase fusion plasmids injected into mouse eggs. Nature 296:39–42

    Article  PubMed  CAS  Google Scholar 

  • Ford ES, Giles WH, Dietz WH (2002) Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA 287:356–359

    Article  PubMed  Google Scholar 

  • Frank DU, Elliott SA, Park EJ, Hammond J, Saijoh Y, Moon AM (2007) System for inducible expression of cre-recombinase from the Foxa2 locus in endoderm, notochord, and floor plate. Dev Dyn 236:1085–1092

    Article  PubMed  CAS  Google Scholar 

  • Govindarajan V, Harrison WR, Xiao N, Liang D, Overbeek PA (2005) Intracorneal positioning of the lens in Pax6-GAL4/VP16 transgenic mice. Mol Vis 11:876–886

    PubMed  CAS  Google Scholar 

  • Horobin RW, Kiernan J (2002) Conn’s biological stains. Oxford University Press, Oxford

    Google Scholar 

  • Hughes TR, Mao M, Jones AR, Burchard J, Marton MJ, Shannon KW, Lefkowitz SM, Ziman M, Schelter JM, Meyer MR, Kobayashi S, Davis C, Dai H, He YD, Stephaniants SB, Cavet G, Walker WL, West A, Coffey E, Shoemaker DD, Stoughton R, Blanchard AP, Friend SH, Linsley PS (2001) Expression profiling using microarrays fabricated by an ink-jet oligonucleotide synthesizer. Nat Biotechnol 19:342–347

    Article  PubMed  CAS  Google Scholar 

  • Hummel KP, Dickie MM, Coleman DL (1966) Diabetes, a new mutation in the mouse. Science 153:1127–1128

    Article  PubMed  CAS  Google Scholar 

  • Hunt CR, Ro JH, Dobson DE, Min HY, Spiegelman BM (1986) Adipocyte P2 gene: developmental expression and homology of 5′-flanking sequences among fat cell-specific genes. Proc Natl Acad Sci USA 83:3786–3790

    Article  PubMed  CAS  Google Scholar 

  • Ingalls AM, Dickie MM, Snell GD (1950) Obese, a new mutation in the house mouse. J Hered 41:317–318

    PubMed  CAS  Google Scholar 

  • Jaubert J, Patel S, Cheng J, Segre JA (2004) Tetracycline-regulated transactivators driven by the involucrin promoter to achieve epidermal conditional gene expression. J Invest Dermatol 123:313–318

    Article  PubMed  CAS  Google Scholar 

  • Knostman KA, Venkateswaran A, Zimmerman B, Capen CC, Jhiang SM (2007) Creation and characterization of a doxycycline-inducible mouse model of thyroid-targeted RET/PTC1 oncogene and luciferase reporter gene coexpression. Thyroid 17:1181–1188

    Article  PubMed  CAS  Google Scholar 

  • Kurtz TW, Morris RC, Pershadsingh HA (1989) The Zucker fatty rat as a genetic model of obesity and hypertension. Hypertension 13:896–901

    PubMed  CAS  Google Scholar 

  • Le YZ, Zheng W, Rao PC, Zheng L, Anderson RE, Esumi N, Zack DJ, Zhu M (2008) Inducible expression of cre recombinase in the retinal pigmented epithelium. Invest Ophthalmol Vis Sci 49:1248–1253

    Article  PubMed  Google Scholar 

  • McCloskey DT, Turnbull L, Swigart PM, Zambon AC, Turcato S, Joho S, Grossman W, Conklin BR, Simpson PC, Baker AJ (2005) Cardiac transgenesis with the tetracycline transactivator changes myocardial function and gene expression. Physiol Genomics 22:118–126

    Article  PubMed  CAS  Google Scholar 

  • Moller DE, Kaufman KD (2005) Metabolic syndrome: a clinical and molecular perspective. Annu Rev Med 56:45–62

    Article  PubMed  CAS  Google Scholar 

  • Morimoto M, Kopan R (2009) rtTA toxicity limits the usefulness of the SP-C-rtTA transgenic mouse. Dev Biol 325:171–178

    Article  PubMed  CAS  Google Scholar 

  • Naar AM, Beaurang PA, Zhou S, Abraham S, Solomon W, Tjian R (1999) Composite co-activator ARC mediates chromatin-directed transcriptional activation. Nature 398:828–832

    Article  PubMed  CAS  Google Scholar 

  • Phan J, Reue K (2005) Lipin, a lipodystrophy and obesity gene. Cell Metab 1:73–83

    Article  PubMed  CAS  Google Scholar 

  • Rao P, Monks DA (2009) A tetracycline-inducible and skeletal muscle-specific Cre recombinase transgenic mouse. Dev Neurobiol 69:401–406

    Article  PubMed  CAS  Google Scholar 

  • Rico-Bautista E, Flores-Morales A, Fernandez-Perez L (2006) Suppressor of cytokine signaling (SOCS) 2, a protein with multiple functions. Cytokine Growth Factor Rev 17:431–439

    Article  PubMed  CAS  Google Scholar 

  • Sisson TH, Hansen JM, Shah M, Hanson KE, Du M, Ling T, Simon RH, Christensen PJ (2006) Expression of the reverse tetracycline-transactivator gene causes emphysema-like changes in mice. Am J Respir Cell Mol Biol 34:552–560

    Article  PubMed  CAS  Google Scholar 

  • 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. Nat Genet 25:87–90

    Article  PubMed  CAS  Google Scholar 

  • Sprengel R, Hasan MT (2007) Tetracycline-controlled genetic switches. Handb Exp Pharmacol 178:49–72

    Article  PubMed  CAS  Google Scholar 

  • Takaya K, Ogawa Y, Isse N, Okazaki T, Satoh N, Masuzaki H, Mori K, Tamura N, Hosoda K, Nakao K (1996) Molecular cloning of rat leptin receptor isoform complementary DNAs—identification of a missense mutation in Zucker fatty (fa/fa) rats. Biochem Biophys Res Commun 225:75–83

    Article  PubMed  CAS  Google Scholar 

  • Tartaglia LA, Dembski M, Weng X, Deng N, Culpepper J, Devos R, Richards GJ, Campfield LA, Clark FT, Deeds J, Muir C, Sanker S, Moriarty A, Moore KJ, Smutko JS, Mays GG, Wool EA, Monroe CA, Tepper RI (1995) Identification and expression cloning of a leptin receptor, OB-R. Cell 83:1263–1271

    Article  PubMed  CAS  Google Scholar 

  • Thomas MK, Devon ON, Lee JH, Peter A, Schlosser DA, Tenser MS, Habener JF (2001) Development of diabetes mellitus in aging transgenic mice following suppression of pancreatic homeoprotein IDX-1. J Clin Invest 108:319–329

    PubMed  CAS  Google Scholar 

  • Traykova-Brauch M, Schonig K, Greiner O, Miloud T, Jauch A, Bode M, Felsher DW, Glick AB, Kwiatkowski DJ, Bujard H, Horst J, von Knebel DM, Niggli FK, Kriz W, Grone HJ, Koesters R (2008) An efficient and versatile system for acute and chronic modulation of renal tubular function in transgenic mice. Nat Med 14:979–984

    Article  PubMed  CAS  Google Scholar 

  • Weng L, Dai H, Zhan Y, He Y, Stepaniants SB, Bassett DE (2006) Rosetta error model for gene expression analysis. Bioinformatics 22:1111–1121

    Article  PubMed  CAS  Google Scholar 

  • Yang VW, Christy RJ, Cook JS, Kelly TJ, Lane MD (1989) Mechanism of regulation of the 422(aP2) gene by cAMP during preadipocyte differentiation. Proc Natl Acad Sci USA 86:3629–3633

    Article  PubMed  CAS  Google Scholar 

  • Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372:425–432

    Article  PubMed  CAS  Google Scholar 

  • Zhu Z, Zheng T, Lee CG, Homer RJ, Elias JA (2002) Tetracycline-controlled transcriptional regulation systems: advances and application in transgenic animal modeling. Semin Cell Dev Biol 13:121–128

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank the Rosetta Gene Expression Laboratories for processing the samples, and the anonymous reviewer for improving the manuscript.

Conflict of interest

All authors in this manuscript worked, at the time the research was carried out, at Merck Research Laboratories.

Author information

Authors and Affiliations

  1. Department of Cardiovascular Diseases, Merck Research Laboratories, Rahway, NJ, 07065, USA

    Liwen Zhang, Yuchen Zhou, Amber Ying Zhu, Steven S. Mundt, Ling Gao, Melba Hernandez, Magdalena Alonso-Galicia, Martin S. Springer & Bruce L. Daugherty

  2. Laboratory Animal Resources, Merck Research Laboratories, Rahway, NJ, 07065, USA

    Xiang-qing Li

  3. In Vitro Sciences, Merck Research Laboratories, Rahway, NJ, 07065, USA

    JeanMarie Lisnock

  4. Global Scientific and Medical Publications, Merck Sharp & Dohme Corp., Whitehouse Station, NJ, 08889, USA

    Edward A. O’Neill

  5. Exploratory and Translational Sciences, Merck Research Laboratories, Rahway, NJ, 07065, USA

    Oscar Puig

Authors
  1. Liwen Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yuchen Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Amber Ying Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xiang-qing Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Steven S. Mundt
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ling Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. JeanMarie Lisnock
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Melba Hernandez
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Magdalena Alonso-Galicia
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Martin S. Springer
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Edward A. O’Neill
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Bruce L. Daugherty
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Oscar Puig
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Oscar Puig.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhang, L., Zhou, Y., Zhu, A.Y. et al. Metabolic syndrome in mice induced by expressing a transcriptional activator in adipose tissue. Transgenic Res 21, 633–644 (2012). https://doi.org/10.1007/s11248-011-9562-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11248-011-9562-2

Keywords

Search

Navigation