Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

RNAi-based therapeutic strategies for metabolic disease

Abstract

RNA interference (RNAi) is a robust gene silencing mechanism that degrades mRNAs complementary to the antisense strands of double-stranded, short interfering RNAs (siRNAs). As a therapeutic strategy, RNAi has an advantage over small-molecule drugs, as virtually all genes are susceptible to targeting by siRNA molecules. This advantage is, however, counterbalanced by the daunting challenge of achieving safe, effective delivery of oligonucleotides to specific tissues in vivo. Lipid-based carriers of siRNA therapeutics can now target the liver in metabolic diseases and are being assessed in clinical trials for the treatment of hypercholesterolemia. For this indication, a chemically modified oligonucleotide that targets endogenous small RNA modulators of gene expression (microRNAs) is also under investigation in clinical trials. Emerging 'self-delivery' siRNAs that are covalently linked to lipophilic moieties show promise for the future development of therapies. Besides the liver, inflammation of the adipose tissue in patients with obesity and type 2 diabetes mellitus may be an attractive target for siRNA therapeutics. Administration of siRNAs encapsulated within glucan microspheres can silence genes in inflammatory phagocytic cells, as can certain lipid-based carriers of siRNA. New technologies that combine siRNA molecules with antibodies or other targeting molecules also appear encouraging. Although still at an early stage, the emergence of RNAi-based therapeutics has the potential to markedly influence our clinical future.

Key Points

  • RNA interference (RNAi) represents a therapeutic approach for targeting any expressed gene with a high degree of specificity

  • Chemical modifications of siRNAs enhance their potency, stability and efficacy, while reducing immunostimulatory effects

  • Targeting hepatic lipid synthesis with RNAi can alleviate hyperlipidemia and hepatic steatosis in patients with the metabolic syndrome

  • Clinical trials have shown that liposomal RNAi delivery systems are efficacious at lowering serum lipid profiles

  • The metabolic syndrome in patients with obesity is associated with adipose tissue inflammation

  • Targeting inflammation with RNAi may offer an exciting but challenging goal for the treatment of metabolic disease

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Major steps in the RNA interference (RNAi) pathway.
Figure 2: Physiological barriers to successful delivery of small RNA therapeutics in humans.
Figure 3: Modifications of small RNA therapeutics that enhance potency or decrease susceptibility to nucleases, innate immune responses and off-target effects.
Figure 4: Targets in hepatic signaling pathways in metabolic disease.
Figure 5: Obesity leads to inflammation and insulin resistance in adipose tissue.

References

  1. Jornayvaz, F. R., Samuel, V. T. & Shulman, G. I. The role of muscle insulin resistance in the pathogenesis of atherogenic dyslipidemia and nonalcoholic fatty liver disease associated with the metabolic syndrome. Annu. Rev. Nutr. 30, 273–290 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Reaven, G. M. The insulin resistance syndrome: definition and dietary approaches to treatment. Annu. Rev. Nutr. 25, 391–406 (2005).

    Article  CAS  PubMed  Google Scholar 

  3. Guilherme, A., Virbasius, J. V., Puri, V. & Czech, M. P. Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes. Nat. Rev. Mol. Cell Biol. 9, 367–377 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Ergens, R. & Yukhimenko, S. S. Gyrodactylus somnaensis sp. n (Monogenea: Gyrodactylidae), a new fish parasite from the basin of the River Amur. Folia Parasitol. (Praha) 37, 313–314 (1990).

    CAS  Google Scholar 

  5. Zheng, C. J. et al. Therapeutic targets: progress of their exploration and investigation of their characteristics. Pharmacol. Rev. 58, 259–279 (2006).

    Article  CAS  PubMed  Google Scholar 

  6. De, A. & DiMarchi, R. D. Synthesis and characterization of ester-based prodrugs of glucagon-like peptide 1. Biopolymers 94, 448–456 (2010).

    Article  CAS  PubMed  Google Scholar 

  7. Mello, C. C. & Conte, D. Jr. Revealing the world of RNA interference. Nature 431, 338–342 (2004).

    Article  CAS  PubMed  Google Scholar 

  8. Ghildiyal, M. & Zamore, P. D. Small silencing RNAs: an expanding universe. Nat. Rev. Genet. 10, 94–108 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Ambros, V. The functions of animal microRNAs. Nature 431, 350–355 (2004).

    Article  CAS  PubMed  Google Scholar 

  10. Guo, H., Ingolia, N. T., Weissman, J. S. & Bartel, D. P. Mammalian microRNAs predominantly act to decrease target mRNA levels. Nature 466, 835–840 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Bumcrot, D., Manoharan, M., Koteliansky, V. & Sah, D. W. RNAi therapeutics: a potential new class of pharmaceutical drugs. Nat. Chem. Biol. 2, 711–719 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Shabtai, M., Waltzer, W. C., Anaise, D., Miller, F. & Rapaport, F. T. Implication of IgA and complement in the alterations in renal blood flow associated with allograft rejection. Transplant Proc. 21, 352–353 (1989).

    CAS  PubMed  Google Scholar 

  13. Wolfrum, C. et al. Mechanisms and optimization of in vivo delivery of lipophilic siRNAs. Nat. Biotechnol. 25, 1149–1157 (2007).

    Article  CAS  PubMed  Google Scholar 

  14. Sioud, M. Recent advances in small interfering RNA sensing by the immune system. N. Biotechnol. 27, 236–242 (2010).

    Article  CAS  PubMed  Google Scholar 

  15. Kleinman, M. E. et al. Sequence- and target-independent angiogenesis suppression by siRNA via TLR3. Nature 452, 591–597 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Castanotto, D. & Rossi, J. J. The promises and pitfalls of RNA-interference-based therapeutics. Nature 457, 426–433 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Tiemann, K. & Rossi, J. J. RNAi-based therapeutics-current status, challenges and prospects. EMBO Mol. Med. 1, 142–151 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Jackson, A. L. & Linsley, P. S. Recognizing and avoiding siRNA off-target effects for target identification and therapeutic application. Nat. Rev. Drug Discov. 9, 57–67 (2010).

    Article  CAS  PubMed  Google Scholar 

  19. Vaishnaw, A. K. et al. A status report on RNAi therapeutics. Silence 1, 14 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Zimmermann, T. S. et al. RNAi-mediated gene silencing in non-human primates. Nature 441, 111–114 (2006).

    Article  CAS  PubMed  Google Scholar 

  21. Semple, S. C. et al. Rational design of cationic lipids for siRNA delivery. Nat. Biotechnol. 28, 172–176 (2010).

    Article  CAS  PubMed  Google Scholar 

  22. Schroeder, A., Levins, C. G., Cortez, C., Langer, R. & Anderson, D. G. Lipid-based nanotherapeutics for siRNA delivery. J. Intern. Med. 267, 9–21 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Rozema, D. B. et al. Dynamic PolyConjugates for targeted in vivo delivery of siRNA to hepatocytes. Proc. Natl Acad. Sci. USA 104, 12982–12987 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Sato, A., Takagi, M., Shimamoto, A., Kawakami, S. & Hashida, M. Small interfering RNA delivery to the liver by intravenous administration of galactosylated cationic liposomes in mice. Biomaterials 28, 1434–1442 (2007).

    Article  CAS  PubMed  Google Scholar 

  25. Morrissey, D. V. et al. Potent and persistent in vivo anti-HBV activity of chemically modified siRNAs. Nat. Biotechnol. 23, 1002–1007 (2005).

    Article  CAS  PubMed  Google Scholar 

  26. Nishina, K. et al. Efficient in vivo delivery of siRNA to the liver by conjugation of alpha-tocopherol. Mol. Ther. 16, 734–740 (2008).

    Article  CAS  PubMed  Google Scholar 

  27. Love, K. T. et al. Lipid-like materials for low-dose, in vivo gene silencing. Proc. Natl Acad. Sci. USA 107, 1864–1869 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  28. McCaffrey, A. P. et al. RNA interference in adult mice. Nature 418, 38–39 (2002).

    Article  CAS  PubMed  Google Scholar 

  29. 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. 32, 107–108 (2002).

    Article  CAS  PubMed  Google Scholar 

  30. Gomez-Valades, A. G. et al. Pck1 gene silencing in the liver improves glycemia control, insulin sensitivity, and dyslipidemia in db/db mice. Diabetes 57, 2199–2210 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Judge, A. D., Bola, G., Lee, A. C. & MacLachlan, I. Design of noninflammatory synthetic siRNA mediating potent gene silencing in vivo. Mol. Ther. 13, 494–505 (2006).

    Article  CAS  PubMed  Google Scholar 

  32. Kim, S. I. et al. Systemic and specific delivery of small interfering RNAs to the liver mediated by apolipoprotein A-I. Mol. Ther. 15, 1145–1152 (2007).

    Article  CAS  PubMed  Google Scholar 

  33. Giladi, H. et al. Small interfering RNA inhibits hepatitis B virus replication in mice. Mol. Ther. 8, 769–776 (2003).

    Article  CAS  PubMed  Google Scholar 

  34. Frank-Kamenetsky, M. et al. Therapeutic RNAi targeting PCSK9 acutely lowers plasma cholesterol in rodents and LDL cholesterol in nonhuman primates. Proc. Natl Acad. Sci. USA 105, 11915–11920 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  35. Akinc, A. et al. A combinatorial library of lipid-like materials for delivery of RNAi therapeutics. Nat. Biotechnol. 26, 561–569 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Akinc, A. et al. Targeted delivery of RNAi therapeutics with endogenous and exogenous ligand-based mechanisms. Mol. Ther. 18, 1357–1364 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Akinc, A. et al. Development of lipidoid-siRNA formulations for systemic delivery to the liver. Mol. Ther. 17, 872–879 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Watts, J. K., Deleavey, G. F. & Damha, M. J. Chemically modified siRNA: tools and applications. Drug Discov. Today 13, 842–855 (2008).

    Article  CAS  PubMed  Google Scholar 

  39. Behlke, M. A. Chemical modification of siRNAs for in vivo use. Oligonucleotides 18, 305–319 (2008).

    Article  CAS  PubMed  Google Scholar 

  40. Chernolovskaya, E. L. & Zenkova, M. A. Chemical modification of siRNA. Curr. Opin. Mol. Ther. 12, 158–167 (2010).

    CAS  PubMed  Google Scholar 

  41. Chiu, Y. L. & Rana, T. M. siRNA function in RNAi: a chemical modification analysis. RNA 9, 1034–1048 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Allerson, C. R. et al. Fully 2′-modified oligonucleotide duplexes with improved in vitro potency and stability compared to unmodified small interfering RNA. J. Med. Chem. 48, 901–904 (2005).

    Article  CAS  PubMed  Google Scholar 

  43. Judge, A. & MacLachlan, I. Overcoming the innate immune response to small interfering RNA. Hum. Gene Ther. 19, 111–124 (2008).

    Article  CAS  PubMed  Google Scholar 

  44. Veedu, R. N. & Wengel, J. Locked nucleic acids: promising nucleic acid analogs for therapeutic applications. Chem. Biodivers. 7, 536–542 (2010).

    Article  CAS  PubMed  Google Scholar 

  45. Gaglione, M. & Messere, A. Recent progress in chemically modified siRNAs. Mini Rev. Med. Chem. 10, 578–595 (2010).

    Article  CAS  PubMed  Google Scholar 

  46. Bennett, C. F. & Swayze, E. E. RNA targeting therapeutics: molecular mechanisms of antisense oligonucleotides as a therapeutic platform. Annu. Rev. Pharmacol. Toxicol. 50, 259–293 (2010).

    Article  CAS  PubMed  Google Scholar 

  47. Elmen, J. et al. LNA-mediated microRNA silencing in non-human primates. Nature 452, 896–899 (2008).

    Article  CAS  PubMed  Google Scholar 

  48. Krutzfeldt, J. et al. Specificity, duplex degradation and subcellular localization of antagomirs. Nucleic Acids Res. 35, 2885–2892 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Esau, C. C. Inhibition of microRNA with antisense oligonucleotides. Methods 44, 55–60 (2008).

    Article  CAS  PubMed  Google Scholar 

  50. Visser, M. E., Kastelein, J. J. & Stroes, E. S. Apolipoprotein B synthesis inhibition: results from clinical trials. Curr. Opin. Lipidol. 21, 319–323 (2010).

    Article  CAS  PubMed  Google Scholar 

  51. Unger, R. H. & Orci, L. Paracrinology of islets and the paracrinopathy of diabetes. Proc. Natl Acad. Sci. USA 107, 16009–16012 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  52. Cheung, N., Mitchell, P. & Wong, T. Y. Diabetic retinopathy. Lancet 376, 124–136 (2010).

    Article  PubMed  Google Scholar 

  53. Boulton, A. J. What you can't feel can hurt you. J. Am. Podiatr. Med. Assoc. 100, 349–352 (2010).

    Article  PubMed  Google Scholar 

  54. Wu, S. C., Marston, W. & Armstrong, D. G. Wound care: the role of advanced wound-healing technologies. J. Am. Podiatr. Med. Assoc. 100, 385–394 (2010).

    Article  PubMed  Google Scholar 

  55. van Dieren, S., Beulens, J. W., van der Schouw, Y. T., Grobbee, D. E. & Neal, B. The global burden of diabetes and its complications: an emerging pandemic. Eur. J. Cardiovasc. Prev. Rehabil. 17 (Suppl. 1), S3–S8 (2010).

    PubMed  Google Scholar 

  56. Postic, C. & Girard, J. The role of the lipogenic pathway in the development of hepatic steatosis. Diabetes Metab. 34, 643–648 (2008).

    Article  CAS  PubMed  Google Scholar 

  57. Brown, M. S. & Goldstein, J. L. Selective versus total insulin resistance: a pathogenic paradox. Cell Metab. 7, 95–96 (2008).

    Article  CAS  PubMed  Google Scholar 

  58. Abdelmalek, M. F. & Diehl, A. M. Nonalcoholic fatty liver disease as a complication of insulin resistance. Med. Clin. North Am. 91, 1125–1149, ix (2007).

    Article  CAS  PubMed  Google Scholar 

  59. Brown, M. S. & Goldstein, J. L. A receptor-mediated pathway for cholesterol homeostasis. Science 232, 34–47 (1986).

    Article  CAS  PubMed  Google Scholar 

  60. Baigude, H., McCarroll, J., Yang, C. S., Swain, P. M. & Rana, T. M. Design and creation of new nanomaterials for therapeutic RNAi. ACS Chem. Biol. 2, 237–241 (2007).

    Article  CAS  PubMed  Google Scholar 

  61. Seidah, N. G. et al. The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation. Proc. Natl Acad. Sci. USA 100, 928–933 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Bassi, D. E., Fu, J., Lopez de Cicco, R. & Klein-Szanto, A. J. Proprotein convertases: “master switches” in the regulation of tumor growth and progression. Mol. Carcinog. 44, 151–161 (2005).

    Article  CAS  PubMed  Google Scholar 

  63. Horton, J. D., Cohen, J. C. & Hobbs, H. H. Molecular biology of PCSK9: its role in LDL metabolism. Trends Biochem. Sci. 32, 71–77 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Allard, D. et al. Novel mutations of the PCSK9 gene cause variable phenotype of autosomal dominant hypercholesterolemia. Hum. Mutat. 26, 497 (2005).

    Article  PubMed  Google Scholar 

  65. Abifadel, M. et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat. Genet. 34, 154–156 (2003).

    Article  CAS  PubMed  Google Scholar 

  66. Rashid, S. et al. Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9. Proc. Natl Acad. Sci. USA 102, 5374–5379 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Graham, M. J. et al. Antisense inhibition of proprotein convertase subtilisin/kexin type 9 reduces serum LDL in hyperlipidemic mice. J. Lipid Res. 48, 763–767 (2007).

    Article  CAS  PubMed  Google Scholar 

  68. Capeau, J. Insulin resistance and steatosis in humans. Diabetes Metab. 34, 649–657 (2008).

    Article  CAS  PubMed  Google Scholar 

  69. Meshkani, R. & Adeli, K. Hepatic insulin resistance, metabolic syndrome and cardiovascular disease. Clin. Biochem. 42, 1331–1346 (2009).

    Article  CAS  PubMed  Google Scholar 

  70. Fabbrini, E., Sullivan, S. & Klein, S. Obesity and nonalcoholic fatty liver disease: biochemical, metabolic, and clinical implications. Hepatology 51, 679–689 (2010).

    Article  CAS  PubMed  Google Scholar 

  71. Liang, G. et al. Diminished hepatic response to fasting/refeeding and liver X receptor agonists in mice with selective deficiency of sterol regulatory element-binding protein-1c. J. Biol. Chem. 277, 9520–9528 (2002).

    Article  CAS  PubMed  Google Scholar 

  72. Iizuka, K., Bruick, R. K., Liang, G., Horton, J. D. & Uyeda, K. Deficiency of carbohydrate response element-binding protein (ChREBP) reduces lipogenesis as well as glycolysis. Proc. Natl Acad. Sci. USA 101, 7281–7286 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Moore, K. J., Rayner, K. J., Suárez, Y. & Fernández-Hernando, C. microRNAs and cholesterol metabolism. Trends Endocrinol. Metab. 21, 699–706 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Lagos-Quintana, M. et al. Identification of tissue-specific microRNAs from mouse. Curr. Biol. 12, 735–739 (2002).

    Article  CAS  PubMed  Google Scholar 

  75. Xu, H. et al. Liver-enriched transcription factors regulate microRNA-122 that targets CUTL1 during liver development. Hepatology 52, 1431–1442 (2010).

    Article  CAS  PubMed  Google Scholar 

  76. Esau, C. et al. miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting. Cell Metab. 3, 87–98 (2006).

    Article  CAS  PubMed  Google Scholar 

  77. Elmén, J. et al. Antagonism of microRNA-122 in mice by systemically administered LNA-antimiR leads to up-regulation of a large set of predicted target mRNAs in the liver. Nucleic Acids Res. 36, 1153–1162 (2008).

    Article  CAS  PubMed  Google Scholar 

  78. Krützfeldt, J. et al. Silencing of microRNAs in vivo with 'antagomirs'. Nature 438, 685–689 (2005).

    Article  CAS  PubMed  Google Scholar 

  79. Gómez-Valadés, A. G. et al. Overcoming diabetes-induced hyperglycemia through inhibition of hepatic phosphoenolpyruvate carboxykinase (GTP) with RNAi. Mol. Ther. 13, 401–410 (2006).

    Article  CAS  PubMed  Google Scholar 

  80. Bosi, E. Metformin—the gold standard in type 2 diabetes: what does the evidence tell us? Diabetes Obes. Metab. 11 (Suppl. 2), 3–8 (2009).

    Article  CAS  PubMed  Google Scholar 

  81. Elbashir, S. M. et al. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 411, 494–498 (2001).

    Article  CAS  PubMed  Google Scholar 

  82. McCaffrey, A. P. et al. Inhibition of hepatitis B virus in mice by RNA interference. Nat.Biotechnol. 21, 639–644 (2003).

    Article  PubMed  Google Scholar 

  83. Song, E. et al. RNA interference targeting Fas protects mice from fulminant hepatitis. Nat. Med. 9, 347–351 (2003).

    Article  CAS  PubMed  Google Scholar 

  84. Soutschek, J. et al. Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs. Nature 432, 173–178 (2004).

    Article  PubMed  Google Scholar 

  85. Gao, S. et al. The effect of chemical modification and nanoparticle formulation on stability and biodistribution of siRNA in mice. Mol. Ther. 17, 1225–1233 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Weisman, S., Hirsch-Lerner, D., Barenholz, Y. & Talmon, Y. Nanostructure of cationic lipid-oligonucleotide complexes. Biophys. J. 87, 609–614 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Torchilin, V. P. et al. Poly(ethylene glycol) on the liposome surface: on the mechanism of polymer-coated liposome longevity. Biochim. Biophys. Acta 1195, 11–20 (1994).

    Article  CAS  PubMed  Google Scholar 

  88. Hafez, I. M., Maurer, N. & Cullis, P. R. On the mechanism whereby cationic lipids promote intracellular delivery of polynucleic acids. Gene Ther. 8, 1188–1196 (2001).

    Article  CAS  PubMed  Google Scholar 

  89. Xu, Y. & Szoka, F. C. Jr. Mechanism of DNA release from cationic liposome/DNA complexes used in cell transfection. Biochemistry 35, 5616–5623 (1996).

    Article  CAS  PubMed  Google Scholar 

  90. Zelphati, O. & Szoka, F. C. Jr. Mechanism of oligonucleotide release from cationic liposomes. Proc. Natl Acad. Sci. USA 93, 11493–11498 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Torchilin, V. P. Recent approaches to intracellular delivery of drugs and DNA and organelle targeting. Annu. Rev. Biomed. Eng. 8, 343–375 (2006).

    Article  CAS  PubMed  Google Scholar 

  92. Malek, A. et al. In vivo pharmacokinetics, tissue distribution and underlying mechanisms of various PEI(-PEG)/siRNA complexes. Toxicol. Appl. Pharmacol. 236, 97–108 (2009).

    Article  CAS  PubMed  Google Scholar 

  93. Lanford, R. E. et al. Therapeutic silencing of microRNA-122 in primates with chronic hepatitis C virus infection. Science 327, 198–201 (2010).

    Article  CAS  PubMed  Google Scholar 

  94. Hardy, O. T. et al. Body mass index-independent inflammation in omental adipose tissue associated with insulin resistance in morbid obesity. Surg. Obes. Relat. Dis. 7, 60–67 (2011).

    Article  PubMed  Google Scholar 

  95. Winer, S. et al. Normalization of obesity-associated insulin resistance through immunotherapy. Nat. Med. 15, 921–929 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Feuerer, M. et al. Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat. Med. 15, 930–939 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Liu, J. et al. Genetic deficiency and pharmacological stabilization of mast cells reduce diet-induced obesity and diabetes in mice. Nat. Med. 15, 940–945 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Weisberg, S. P. et al. Obesity is associated with macrophage accumulation in adipose tissue. J. Clin. Invest. 112, 1796–1808 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Wentworth, J. M. et al. Pro-inflammatory CD11c+CD206+ adipose tissue macrophages are associated with insulin resistance in human obesity. Diabetes 59, 1648–1656 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Heilbronn, L. K. & Campbell, L. V. Adipose tissue macrophages, low grade inflammation and insulin resistance in human obesity. Curr. Pharm. Des 14, 1225–1230 (2008).

    Article  CAS  Google Scholar 

  101. Xu, H. et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J. Clin. Invest. 112, 1821–1830 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Halberg, N., Wernstedt-Asterholm, I. & Scherer, P. E. The adipocyte as an endocrine cell. Endocrinol. Metab. Clin. North Am. 37, 753–768 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Scherer, P. E. Adipose tissue: from lipid storage compartment to endocrine organ. Diabetes 55, 1537–1545 (2006).

    Article  CAS  PubMed  Google Scholar 

  104. Wang, P., Mariman, E., Renes, J. & Keijer, J. The secretory function of adipocytes in the physiology of white adipose tissue. J. Cell Physiol. 216, 3–13 (2008).

    Article  CAS  PubMed  Google Scholar 

  105. Kamei, N. et al. Overexpression of monocyte chemoattractant protein-1 in adipose tissues causes macrophage recruitment and insulin resistance. J. Biol. Chem. 281, 26602–26614 (2006).

    Article  CAS  PubMed  Google Scholar 

  106. Kanda, H. et al. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J. Clin. Invest. 116, 1494–1505 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Kirk, E. A., Sagawa, Z. K., McDonald, T. O., O'Brien, K. D. & Heinecke, J. W. Monocyte chemoattractant protein deficiency fails to restrain macrophage infiltration into adipose tissue [corrected]. Diabetes 57, 1254–1261 (2008).

    Article  CAS  PubMed  Google Scholar 

  108. Inouye, K. E. et al. Absence of CC chemokine ligand 2 does not limit obesity-associated infiltration of macrophages into adipose tissue. Diabetes 56, 2242–2250 (2007).

    Article  CAS  PubMed  Google Scholar 

  109. Yuan, M. et al. Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta. Science 293, 1673–1677 (2001).

    Article  CAS  PubMed  Google Scholar 

  110. Goldfine, A. B. et al. Use of salsalate to target inflammation in the treatment of insulin resistance and type 2 diabetes. Clin. Transl. Sci. 1, 36–43 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Hundal, R. S. et al. Mechanism by which high-dose aspirin improves glucose metabolism in type 2 diabetes. J. Clin. Invest. 109, 1321–1326 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Larsen, C. M. et al. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N. Engl. J. Med. 356, 1517–1526 (2007).

    Article  CAS  PubMed  Google Scholar 

  113. Dinarello, C. A. The role of the interleukin-1-receptor antagonist in blocking inflammation mediated by interleukin-1. N. Engl. J. Med. 343, 732–734 (2000).

    Article  CAS  PubMed  Google Scholar 

  114. Barbuio, R., Milanski, M., Bertolo, M. B., Saad, M. J. & Velloso, L. A. Infliximab reverses steatosis and improves insulin signal transduction in liver of rats fed a high-fat diet. J. Endocrinol. 194, 539–550 (2007).

    Article  CAS  PubMed  Google Scholar 

  115. Hotamisligil, G. S., Arner, P., Caro, J. F., Atkinson, R. L. & Spiegelman, B. M. Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance. J. Clin. Invest. 95, 2409–2415 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Hotamisligil, G. S., Shargill, N. S. & Spiegelman, B. M. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 259, 87–91 (1993).

    Article  CAS  PubMed  Google Scholar 

  117. Ofei, F., Hurel, S., Newkirk, J., Sopwith, M. & Taylor, R. Effects of an engineered human anti-TNF-alpha antibody (CDP571) on insulin sensitivity and glycemic control in patients with NIDDM. Diabetes 45, 881–885 (1996).

    Article  PubMed  Google Scholar 

  118. Bernstein, L. E., Berry, J., Kim, S., Canavan, B. & Grinspoon, S. K. Effects of etanercept in patients with the metabolic syndrome. Arch. Intern. Med. 166, 902–908 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Dominguez, H. et al. Metabolic and vascular effects of tumor necrosis factor-alpha blockade with etanercept in obese patients with type 2 diabetes. J. Vasc. Res. 42, 517–525 (2005).

    Article  CAS  PubMed  Google Scholar 

  120. Stanley, T. L. et al. TNF-α antagonism with etanercept decreases glucose and increases the proportion of high molecular weight adiponectin in obese subjects with features of the metabolic syndrome. J. Clin. Endocrinol. Metab. 96, E146–E150 (2011).

    Article  CAS  PubMed  Google Scholar 

  121. Choi, B. et al. Tumor necrosis factor α small interfering RNA decreases herpes simplex virus-induced inflammation in a mouse model. J. Dermatol. Sci. 52, 87–97 (2008).

    Article  CAS  PubMed  Google Scholar 

  122. Nau, G. J. et al. A chemoattractant cytokine associated with granulomas in tuberculosis and silicosis. Proc. Natl Acad. Sci. USA 94, 6414–6419 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Giachelli, C. M., Lombardi, D., Johnson, R. J., Murry, C. E. & Almeida, M. Evidence for a role of osteopontin in macrophage infiltration in response to pathological stimuli in vivo. Am. J. Pathol. 152, 353–358 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Ashkar, S. et al. Eta-1 (osteopontin): an early component of type-1 (cell-mediated) immunity. Science 287, 860–864 (2000).

    Article  CAS  PubMed  Google Scholar 

  125. Bruemmer, D. et al. Angiotensin II-accelerated atherosclerosis and aneurysm formation is attenuated in osteopontin-deficient mice. J. Clin. Invest. 112, 1318–1331 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Nomiyama, T. et al. Osteopontin mediates obesity-induced adipose tissue macrophage infiltration and insulin resistance in mice. J. Clin. Invest. 117, 2877–2888 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Kaneider, N. C., Leger, A. J. & Kuliopulos, A. Therapeutic targeting of molecules involved in leukocyte-endothelial cell interactions. FEBS J. 273, 4416–4424 (2006).

    Article  CAS  PubMed  Google Scholar 

  128. Feral, C. C. et al. Blocking the α4 integrin-paxillin interaction selectively impairs mononuclear leukocyte recruitment to an inflammatory site. J. Clin. Invest. 116, 715–723 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Ghosh, S. et al. Natalizumab for active Crohn's disease. N. Engl. J. Med. 348, 24–32 (2003).

    Article  CAS  PubMed  Google Scholar 

  130. Miller, D. H. et al. A controlled trial of natalizumab for relapsing multiple sclerosis. N. Engl. J. Med. 348, 15–23 (2003).

    Article  CAS  PubMed  Google Scholar 

  131. Sheridan, C. Third Tysabri adverse case hits drug class. Nat. Rev. Drug Discov. 24, 357–358 (2005).

    Article  CAS  Google Scholar 

  132. Sheridan, C. Tysabri raises alarm bells on drug class. Nat. Biotechnol. 23, 397–398 (2005).

    Article  CAS  PubMed  Google Scholar 

  133. Herre, J., Gordon, S. & Brown, G. D. Dectin-1 and its role in the recognition of beta-glucans by macrophages. Mol. Immunol. 40, 869–876 (2004).

    Article  CAS  PubMed  Google Scholar 

  134. Aouadi, M. et al. Orally delivered siRNA targeting macrophage Map4k4 suppresses systemic inflammation. Nature 458, 1180–1184 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Tesz, G. J. et al. Glucan particles for selective delivery of siRNA to phagocytic cells in mice. Biochem. J. doi: 10.1042/BJ20110352.

  136. Khoury, M. et al. Efficient new cationic liposome formulation for systemic delivery of small interfering RNA silencing tumor necrosis factor alpha in experimental arthritis. Arthritis Rheum. 54, 1867–1877 (2006).

    Article  CAS  PubMed  Google Scholar 

  137. Zheng, X., Vladau, C., Shunner, A. & Min, W. P. siRNA specific delivery system for targeting dendritic cells. Methods Mol. Biol. 623, 173–188 (2010).

    Article  CAS  PubMed  Google Scholar 

  138. Zheng, X. et al. A novel in vivo siRNA delivery system specifically targeting dendritic cells and silencing CD40 genes for immunomodulation. Blood 113, 2646–2654 (2009).

    Article  CAS  PubMed  Google Scholar 

  139. Lee, S., Yang, S. C., Kao, C. Y., Pierce, R. H. & Murthy, N. Solid polymeric microparticles enhance the delivery of siRNA to macrophages in vivo. Nucleic Acids Res. 37, e145 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Alshamsan, A. et al. STAT3 silencing in dendritic cells by siRNA polyplexes encapsulated in PLGA nanoparticles for the modulation of anticancer immune response. Mol. Pharm. doi: 10.1021/mp100067u.

  141. Shukla, A. K., Verma, M. & Singh, K. N. Superoxide induced deprotection of 1,3-dithiolanes: a convenient method of dedithioacetalization. Indian J. Chem. 43B, 1748–1752 (2004).

    CAS  Google Scholar 

  142. Lih-Brody, L. et al. Increased oxidative stress and decreased antioxidant defenses in mucosa of inflammatory bowel disease. Dig. Dis. Sci. 41, 2078–2086 (1996).

    Article  CAS  PubMed  Google Scholar 

  143. Brunner, T., Cohen, S. & Monsonego, A. Silencing of proinflammatory genes targeted to peritoneal-residing macrophages using siRNA encapsulated in biodegradable microspheres. Biomaterials 31, 2627–2636 (2010).

    Article  CAS  PubMed  Google Scholar 

  144. Kumar, P. et al. T cell-specific siRNA delivery suppresses HIV-1 infection in humanized mice. Cell 134, 577–586 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Song, E. et al. Antibody mediated in vivo delivery of small interfering RNAs via cell-surface receptors. Nat. Biotechnol. 23, 709–717 (2005).

    Article  CAS  PubMed  Google Scholar 

  146. Peer, D., Zhu, P., Carman, C. V., Lieberman, J. & Shimaoka, M. Selective gene silencing in activated leukocytes by targeting siRNAs to the integrin lymphocyte function-associated antigen-1. Proc. Natl Acad. Sci. USA 104, 4095–4100 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Kim, S. S. et al. Targeted delivery of siRNA to macrophages for anti-inflammatory treatment. Mol. Ther. 18, 993–1001 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Subramanya, S. et al. Targeted delivery of small interfering RNA to human dendritic cells to suppress dengue virus infection and associated proinflammatory cytokine production. J. Virol. 84, 2490–2501 (2010).

    Article  CAS  PubMed  Google Scholar 

  149. Nishimura, S. et al. CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat. Med. 15, 914–920 (2009).

    Article  CAS  PubMed  Google Scholar 

  150. Wellen, K. E. & Hotamisligil, G. S. Inflammation, stress, and diabetes. J. Clin. Invest. 115, 1111–1119 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Asano, M., Toda, M., Sakaguchi, N. & Sakaguchi, S. Autoimmune disease as a consequence of developmental abnormality of a T cell subpopulation. J. Exp. Med. 184, 387–396 (1996).

    Article  CAS  PubMed  Google Scholar 

  152. Ilan, Y. et al. Induction of regulatory T cells decreases adipose inflammation and alleviates insulin resistance in ob/ob mice. Proc. Natl Acad. Sci. USA 107, 9765–9770 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  153. Peipp, M. et al. A recombinant CD7-specific single-chain immunotoxin is a potent inducer of apoptosis in acute leukemic T cells. Cancer Res. 62, 2848–2855 (2002).

    CAS  PubMed  Google Scholar 

  154. Bremer, E. et al. Target cell-restricted apoptosis induction of acute leukemic T cells by a recombinant tumor necrosis factor-related apoptosis-inducing ligand fusion protein with specificity for human CD7. Cancer Res. 65, 3380–3388 (2005).

    Article  CAS  PubMed  Google Scholar 

  155. Frankel, A. E. et al. Therapy of patients with T-cell lymphomas and leukemias using an anti-CD7 monoclonal antibody-ricin A chain immunotoxin. Leuk. Lymphoma 26, 287–298 (1997).

    Article  CAS  PubMed  Google Scholar 

  156. Lazarovits, A. I. et al. Human mouse chimeric CD7 monoclonal antibody (SDZCHH380) for the prophylaxis of kidney transplant rejection. Transplant Proc. 25, 820–822 (1993).

    CAS  PubMed  Google Scholar 

  157. Peer, D., Park, E. J., Morishita, Y., Carman, C. V. & Shimaoka, M. Systemic leukocyte-directed siRNA delivery revealing cyclin D1 as an anti-inflammatory target. Science 319, 627–630 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Kim, S. S. et al. RNAi-mediated CCR5 silencing by LFA-1-targeted nanoparticles prevents HIV infection in BLT mice. Mol. Ther. 18, 370–376 (2010).

    Article  CAS  PubMed  Google Scholar 

  159. Kortylewski, M. et al. In vivo delivery of siRNA to immune cells by conjugation to a TLR9 agonist enhances antitumor immune responses. Nat. Biotechnol. 27, 925–932 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Herrmann, A. et al. Targeting Stat3 in the myeloid compartment drastically improves the in vivo antitumor functions of adoptively transferred T cells. Cancer Res. 70, 7455–7464 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Kortylewski, M. et al. Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity. Nat. Med. 11, 1314–1321 (2005).

    Article  CAS  PubMed  Google Scholar 

  162. Davis, M. E. et al. Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles. Nature 464, 1067–1070 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Brahmamdam, P. et al. Targeted delivery of siRNA to cell death proteins in sepsis. Shock 32, 131–139 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Newgard, C. B., Brady, M. J., O'Doherty, R. M. & Saltiel, A. R. Organizing glucose disposal: emerging roles of the glycogen targeting subunits of protein phosphatase-1. Diabetes 49, 1967–1977 (2000).

    Article  CAS  PubMed  Google Scholar 

  165. Gross, D. N., van den Heuvel, A. P. & Birnbaum, M. J. The role of FoxO in the regulation of metabolism. Oncogene 27, 2320–2336 (2008).

    Article  CAS  PubMed  Google Scholar 

  166. Yamashita, H. et al. A glucose-responsive transcription factor that regulates carbohydrate metabolism in the liver. Proc. Natl Acad. Sci. USA 98, 9116–9121 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Uyeda, K. & Repa, J. J. Carbohydrate response element binding protein, ChREBP, a transcription factor coupling hepatic glucose utilization and lipid synthesis. Cell Metab. 4, 107–110 (2006).

    Article  CAS  PubMed  Google Scholar 

  168. Cheloufi, S., Dos Santos, C. O., Chong, M. M. & Hannon, G. J. A dicer-independent miRNA biogenesis pathway that requires Ago catalysis. Nature 465, 584–589 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Cifuentes, D. et al. A novel miRNA processing pathway independent of Dicer requires Argonaute2 catalytic activity. Science 328, 1694–1698 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Nowotny, M. & Yang, W. Structural and functional modules in RNA interference. Curr. Opin. Struct. Biol. 19, 286–293 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Naqvi, A. R., Islam, M. N., Choudhury, N. R. & Haq, Q. M. The fascinating world of RNA interference. Int. J. Biol. Sci. 5, 97–117 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank the members of their laboratory group for excellent discussions on the issues addressed in this Review. The studies from the authors' laboratory covered in this Review were supported by grants to M. P. Czech from the NIH (DK30898 and DK085753), a Juvenile Diabetes Research Foundation Award (17-2009-546) and by Core Facilities in the University of Massachusetts Diabetes and Endocrinology Research Center also funded by the NIH (DK325220).

Author information

Authors and Affiliations

Authors

Contributions

All authors researched the data for the article, provided a substantial contribution to discussions of the content, contributed equally to writing the article and reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Michael P. Czech.

Ethics declarations

Competing interests

M. P. Czech declares an association with the following company: RXi Pharmaceuticals (stockholder/director, patent holder). M. Aouadi declares an association with the following company: RXi Pharmaceuticals (patent holder), G. J. Tesz declares no competing interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Czech, M., Aouadi, M. & Tesz, G. RNAi-based therapeutic strategies for metabolic disease. Nat Rev Endocrinol 7, 473–484 (2011). https://doi.org/10.1038/nrendo.2011.57

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrendo.2011.57

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing