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Horm Metab Res 2005; 37(2): 59-62
DOI: 10.1055/s-2005-861157
Review
© Georg Thieme Verlag KG Stuttgart · New York

RNA Interference-based Strategies for Metabolic Syndrome Treatment

A.  Barthel1 , S.  Herzig2 , H.-W.  Müller3 , J.  Harborth4 , S.  R.  Bornstein5
  • 1Department of Endocrinology, Diabetes and Rheumatology, University Hospital Duesseldorf, Germany
  • 2Department Molecular Metabolic Control, German Cancer Research Center, Heidelberg, Germany
  • 3Department of Nuclear Medicine, University Hospital Duesseldorf, Germany
  • 4Alnylam Pharmaceuticals, Cambridge, MA, USA
  • 5Department of Medicine, University of Dresden, Carl Gustav Carus, Dresden, Germany
Further Information

Publication History

Received 4 January 2005

Accepted after revision 4 January 2005

Publication Date:
21 March 2005 (online)

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Abstract

RNA interference is a naturally occurring cellular mechanism to inhibit the expression of specific gene products. The technical application of RNA interference offers great potential for the specific treatment of a huge variety of diseases including the metabolic syndrome, one of the most challenging threats to human health associated with our civilization. In order to develop novel and powerful strategies for the treatment of the metabolic syndrome, it is essential to define a set of specific gene products that may be targeted by RNA interference. Based on currently available in vitro and in vivo data, we discuss the feasibility of candidate genes involved in the pathophysiology of the metabolic syndrome as potential targets for a rational RNA interference based therapy in this review.

Key words

Metabolic syndrome - Insulin signaling - Hepatic glucose production - Adipose tissue - Renin-angiotensin-aldosterone system

References

  • 1 Zamore P D, Tuschl T, Sharp P A, Bartel D P. RNAi: double-stranded RNA directs the ATP-dependent cleavage of mRNA at 21 to 23 nucleotide intervals.  Cell. 2000;  101 25-33
    CrossrefPubMedSearch in Google Scholar
  • 2 Elbashir S M, Lendeckel W, Tuschl T. RNA interference is mediated by 21- and 22-nucleotide RNAs.  Genes Dev. 2001;  15 188-200
    CrossrefPubMedSearch in Google Scholar
  • 3 Caplen N J, Fleenor J, Fire A, Morgan R A. dsRNA-mediated gene silencing in cultured Drosophila cells: a tissue culture model for the analysis of RNA interference.  Gene. 2000;  252 95-105
    CrossrefPubMedSearch in Google Scholar
  • 4 Caplen N J, Parrish S, Imani F, Fire A, Morgan R A. Specific inhibition of gene expression by small double-stranded RNAs in invertebrate and vertebrate systems.  Proc Natl Acad Sci USA. 2001;  98 9742-9747
    CrossrefPubMedSearch in Google Scholar
  • 5 Elbashir S M, Harborth J, Lendeckel W, Yalcin A, Weber K, Tuschl T. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells.  Nature. 2001;  411 494-498
    CrossrefPubMedSearch in Google Scholar
  • 6 Song Y K, Liu F, Zhang G, Liu D. Hydrodynamics-based transfection: simple and efficient method for introducing and expressing transgenes in animals by intravenous injection of DNA.  Methods Enzymol. 2002;  346 92-105
    PubMedSearch in Google Scholar
  • 7 Zhang G, Budker V, Wolff J A. High levels of foreign gene expression in hepatocytes after tail vein injections of naked plasmid DNA.  Hum Gene Ther. 1999;  10 1735-1737
    CrossrefPubMedSearch in Google Scholar
  • 8 Lewis D L, Hagstrom J E, Loomis A G, Wolff J A, Herweijer H. Efficient delivery of siRNA for inhibition of gene expression in postnatal mice.  Nat Genet. 2002;  32 107-108
    PubMedSearch in Google Scholar
  • 9 McCaffrey A P, Meuse L, Pham T T, Conklin D S, Hannon G J, Kay M A. RNA interference in adult mice.  Nature. 2002;  418 38-39
    CrossrefPubMedSearch in Google Scholar
  • 10 Song E, Lee S K, Wang J, Ince N, Ouyang N, Min J, Chen J, Shankar P, Lieberman J. RNA interference targeting Fas protects mice from fulminant hepatitis.  Nat Med. 2003;  9 347-351
    PubMedSearch in Google Scholar
  • 11 Brummelkamp T R, Bernards R, Agami R. A system for stable expression of short interfering RNAs in mammalian cells.  Science. 2002;  296 550-553
    CrossrefPubMedSearch in Google Scholar
  • 12 Herzig S, Long F, Jhala U S, Hedrick S, Quinn R, Bauer A, Rudolph D, Schutz G, Yoon C, Puigserver P, Spiegelman B, Montminy M. CREB regulates hepatic gluconeogenesis through the coactivator PGC-1.  Nature. 2001;  413 179-183
    CrossrefPubMedSearch in Google Scholar
  • 13 Herzig S, Hedrick S, Morantte I, Koo S H, Galimi F, Montminy M. CREB controls hepatic lipid metabolism through nuclear hormone receptor PPAR-gamma.  Nature. 2003;  426 190-193
    CrossrefPubMedSearch in Google Scholar
  • 14 Koo S H, Satoh H, Herzig S, Lee C H, Hedrick S, Kulkarni R, Evans R M, Olefsky J, Montminy M. PGC-1 promotes insulin resistance in liver through PPAR-alpha-dependent induction of TRB-3.  Nat Med. 2004;  10 530-534
    PubMedSearch in Google Scholar
  • 15 Soutschek J, Akinc A, Bramlage B, Charisse K, Constien R, Donoghue M, Elbashir S, Geick A, Hadwiger P, Harborth J, John M, Kesavan V, Lavine G, Pandey R K, Racie T, Rajeev K G, Rohl I, Toudjarska I, Wang G, Wuschko S, Bumcrot D, Koteliansky V, Limmer S, Manoharan M, Vornlocher H P. Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs.  Nature. 2004;  432 173-178
    CrossrefPubMedSearch in Google Scholar
  • 16 Gray A, Clarke P, Farmer A, Holman R, United Kingdom Prospective Diabetes Study (UKPDS) Group. Implementing intensive control of blood glucose concentration and blood pressure in type2 diabetes in England: cost analysis (UKPDS 63).  BMJ. 2002;  325 860
    CrossrefPubMedSearch in Google Scholar
  • 17 Clarke P, Gray A, Adler A, Stevens R, Raikou M, Cull C, Stratton I, Holman R, UKPDS Group. United Kingdom Prospective Diabetes Study. Cost-effectiveness analysis of intensive blood-glucose control with metformin in overweight patients with type II diabetes (UKPDS No. 51).  Diabetologia. 2001;  44 298-304
    CrossrefPubMedSearch in Google Scholar
  • 18 Elchebly M, Payette P, Michaliszyn E, Cromlish W, Collins S, Loy A L, Normandin D, Cheng A, Himms-Hagen J, Chan C C, Ramachandran C, Gresser M J, Tremblay M L, Kennedy B P. Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene.  Science. 1999;  283 1544-1548
    CrossrefPubMedSearch in Google Scholar
  • 19 Zinker B A, Rondinone C M, Trevillyan J M, Gum R J, Clampit J E, Waring J F, Xie N, Wilcox D, Jacobson P, Frost L, Kroeger P E, Reilly R M, Koterski S, Opgenorth T J, Ulrich R G, Crosby S, Butler M, Murray S F, McKay R A, Bhanot S, Monia B P, Jirousek M R. PTP1B antisense oligonucleotide lowers PTP1B protein, normalizes blood glucose, and improves insulin sensitivity in diabetic mice.  Proc Natl Acad Sci USA. 2002;  99 11 357-11 362
    PubMedSearch in Google Scholar
  • 20 Clement S, Krause U, Desmedt F, Tanti J F, Behrends J, Pesesse X, Sasaki T, Penninger J, Doherty M, Malaisse W, Dumont J E, Le Marchand-Brustel Y, Erneux C, Hue L, Schurmans S. The lipid phosphatase SHIP2 controls insulin sensitivity.  Nature. 2001;  409 92-97
    CrossrefPubMedSearch in Google Scholar
  • 21 Butler M, McKay R A, Popoff I J, Gaarde W A, Witchell D, Murray S F, Dean N M, Bhanot S, Monia B P. Specific inhibition of PTEN expression reverses hyperglycemia in diabetic mice.  Diabetes. 2002;  51 1028-1034
    CrossrefPubMedSearch in Google Scholar
  • 22 Ueki K, Kondo T, Tseng Y H, Kahn C R. Central role of suppressors of cytokine signaling proteins in hepatic steatosis, insulin resistance, and the metabolic syndrome in the mouse.  Proc Natl Acad Sci USA. 2004;  101 10 422-10 427
    PubMedSearch in Google Scholar
  • 23 Ueki K, Kondo T, Kahn C R. Suppressor of cytokine signaling 1 (SOCS-1) and SOCS-3 cause insulin resistance through inhibition of tyrosine phosphorylation of insulin receptor substrate proteins by discrete mechanisms.  Mol Cell Biol. 2004;  24 5434-5446
    CrossrefPubMedSearch in Google Scholar
  • 24 Kawazoe Y, Naka T, Fujimoto M, Kohzaki H, Morita Y, Narazaki M, Okumura K, Saitoh H, Nakagawa R, Uchiyama Y, Akira S, Kishimoto T. Signal Transducer and Activator of Transcription (STAT)-induced STAT Inhibitor 1 (SSI-1)/Suppressor of Cytokine Signaling 1 (SOCS1) Inhibits Insulin Signal Transduction Pathway through Modulating Insulin Receptor Substrate 1 (IRS-1) Phosphorylation.  J Exp Med. 2001;  193 263-270
    CrossrefPubMedSearch in Google Scholar
  • 25 Nordlie R C, Foster J D, Lange A J. Regulation of glucose production by the liver.  Annu Rev Nutr. 1999;  19 379-406
    PubMedSearch in Google Scholar
  • 26 Jeng C Y, Sheu W H, Fuh M M, Chen Y D, Reaven G M. Relationship between hepatic glucose production and fasting plasma concentration in patients with NIDDM.  Diabetes. 1994;  43 1440-1444
    PubMedSearch in Google Scholar
  • 27 Barthel A, Schmoll D. Novel concepts in insulin regulation of hepatic gluconeogenesis.  Am J Physiol Endocrinol Metab. 2003;  285 E685-E692
    PubMedSearch in Google Scholar
  • 28 Barthel A, Scherbaum W A, Bornstein S R. Novel aspects in the mechanisms of steroid diabetes and the regulation of hepatic glucose production by insulin and steroids.  Med Klin. 2003;  98 283-286
    CrossrefPubMedSearch in Google Scholar
  • 29 Sloop K W, Cao J X, Siesky A M, Zhang H Y, Bodenmiller D M, Cox A L, Jacobs S J, Moyers J S, Owens R A, Showalter A D, Brenner M B, Raap A, Gromada J, Berridge B R, Monteith D K, Porksen N, McKay R A, Monia B P, Bhanot S, Watts L M, Michael M D. Hepatic and glucagon-like peptide-1-mediated reversal of diabetes by glucagon receptor antisense oligonucleotide inhibitors.  J Clin Invest. 2004;  113 1571-1581
    CrossrefPubMedSearch in Google Scholar
  • 30 Nakae J, Biggs W H 3rd, Kitamura T, Cavenee W K, Wright C V, Arden K C, Accili D. Regulation of insulin action and pancreatic beta-cell function by mutated alleles of the gene encoding forkhead transcription factor Foxo1.  Nat Genet. 2002;  32 245-253
    PubMedSearch in Google Scholar
  • 31 Yoon J C, Puigserver P, Chen G, Donovan J, Wu Z, Rhee J, Adelmant G, Stafford J, Kahn C R, Granner D K, Newgard C B, Spiegelman B M. Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1.  Nature. 2001;  413 131-138
    CrossrefPubMedSearch in Google Scholar
  • 32 Du K, Herzig S, Kulkarni R N, Montminy M. TRB3: a tribbles homolog that inhibits Akt/PKB activation by insulin in liver.  Science. 2003;  300 1574-1577
    CrossrefPubMedSearch in Google Scholar
  • 33 Masuzaki H, Paterson J, Shinyama H, Morton N M, Mullins J J, Seckl J R, Flier J S. A transgenic model of visceral obesity and the metabolic syndrome.  Science. 2001;  294 2166-2170
    CrossrefPubMedSearch in Google Scholar
  • 34 Masuzaki H, Flier J S. Tissue-specific glucocorticoid reactivating enzyme, 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1)-a promising drug target for the treatment of metabolic syndrome.  Curr Drug Targets Immune Endocr Metabol Disord. 2003;  3 255-262
    CrossrefPubMedSearch in Google Scholar
  • 35 Saltiel A R, Kahn C R. Insulin signalling and the regulation of glucose and lipid metabolism.  Nature. 2001;  414 799-806
    CrossrefPubMedSearch in Google Scholar
  • 36 Kahn B B, Flier J S. Obesity and insulin resistance.  J Clin Invest. 2000;  106 473-481
    CrossrefPubMedSearch in Google Scholar
  • 37 Steppan C M, Bailey S T, Bhat S, Brown E J, Banerjee R R, Wright C M, Patel H R, Ahima R S, Lazar M A. The hormone resistin links obesity to diabetes.  Nature. 2001;  409 307-312
    CrossrefPubMedSearch in Google Scholar
  • 38 Moon B, Kwan J J, Duddy N, Sweeney G, Begum N. Resistin inhibits glucose uptake in L6 cells independently of changes in insulin signaling and GLUT4 translocation.  Am J Physiol Endocrinol Metab. 2003;  285 E106-E115
    PubMedSearch in Google Scholar
  • 39 Pravenec M, Kazdova L, Landa V, Zidek V, Mlejnek P, Jansa P, Wang J, Qi N, Kurtz T W. Transgenic and recombinant resistin impair skeletal muscle glucose metabolism in the spontaneously hypertensive rat.  J Biol Chem. 2003;  278 45 209-45 215
    PubMedSearch in Google Scholar
  • 40 Rajala M W, Obici S, Scherer P E, Rossetti L. Adipose-derived resistin and gut-derived resistin-like molecule-beta selectively impair insulin action on glucose production.  J Clin Invest. 2003;  111 225-230
    CrossrefPubMedSearch in Google Scholar
  • 41 Banerjee R R, Rangwala S M, Shapiro J S, Rich A S, Rhoades B, Qi Y, Wang J, Rajala M W, Pocai A, Scherer P E, Steppan C M, Ahima R S, Obici S, Rossetti L, Lazar M A. Regulation of fasted blood glucose by resistin.  Science. 2004;  303 1195-1198
    CrossrefPubMedSearch in Google Scholar
  • 42 Goodfriend T L, Egan B M, Kelley D E. Aldosterone in obesity.  Endocr Res. 1998;  24 789-796
    CrossrefPubMedSearch in Google Scholar
  • 43 Goodfriend T L, Kelley D E, Goodpaster B H, Winters S J. Visceral obesity and insulin resistance are associated with plasma aldosterone levels in women.  Obes Res. 1999;  7 355-362
    CrossrefPubMedSearch in Google Scholar
  • 44 Ehrhart-Bornstein M, Lamounier-Zepter V, Schraven A, Langenbach J, Willenberg H S, Barthel A, Hauner H, McCann S M, Scherbaum W A, Bornstein S R. Human adipocytes secrete mineralocorticoid-releasing factors.  Proc Natl Acad Sci USA. 2003;  100 14 211-14 216
    PubMedSearch in Google Scholar
  • 45 Rosenson R S, Reasner C A. Therapeutic approaches in the prevention of cardiovascular disease in metabolic syndrome and in patients with type 2 diabetes.  Curr Opin Cardiol. 2004;  19 480-487
    CrossrefPubMedSearch in Google Scholar

Dr. Andreas Barthel

Department of Endocrinology, Diabetology and Rheumatology, University Hospital Duesseldorf

Moorenstr. 5 · 40225 Düsseldorf · Germany

Phone: +49(211)811-78 10

Fax: +49(211)811-78 60

Email: Andreas.Barthel@uni-duesseldorf.de