Skip to main content
SpringerLink
Log in
Book cover

Chronic Inflammation pp 277–290Cite as

Role of Double-Stranded RNA Pathways in Immunometabolism in Obesity

  • Chapter
  • First Online:

  • 1978 Accesses

Abstract

During the pathogenesis of obesity, a broad array of inflammatory and stress responses are frequently evoked in insulin-targeted metabolic tissues such as liver and adipose tissue, leading to chronic, low grade, local inflammation which plays a central role in the disruption of systemic metabolic homeostasis. This atypical state engages immune response pathways, including recruitment of immune cells into metabolic tissues, activation of IkB kinase (IKK) and c-Jun N-terminal kinase (JNK) pathways, and elevated production of an array of immune mediators, which negatively impact on nutrient metabolism and insulin action. However, the molecular basis for the induction of metabolic inflammation and the vast network of pathological responses remains elusive. Recent evidence indicates that metabolic inflammation results from deregulated double-stranded RNA (dsRNA) processing/signaling in metabolic tissues, which adversely regulates systemic glucose metabolism in obesity. These findings suggest the involvement of altered RNA networks in the immunometabolic regulation of obesity. This review focuses on the regulation of endogenous dsRNA and protein networks and how their functional changes are associated with inflammatory responses, resulting in the metabolic sequelae of obesity.

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

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   219.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   279.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   279.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  • Arkan MC, Hevener AL, Greten FR, Maeda S, Li ZW, Long JM, Wynshaw-Boris A, Poli G, Olefsky J, Karin M (2005) IKK-beta links inflammation to obesity-induced insulin resistance. Nat Med 11:191–198

    Article  CAS  PubMed  Google Scholar 

  • Bachellerie JP, Cavaille J, Huttenhofer A (2002) The expanding snoRNA world. Biochimie 84:775–790

    Article  CAS  PubMed  Google Scholar 

  • Carvalho-Filho MA, Carvalho BM, Oliveira AG, Guadagnini D, Ueno M, Dias MM, Tsukumo DM, Hirabara SM, Reis LF, Curi R et al (2012) Double-stranded RNA-activated protein kinase is a key modulator of insulin sensitivity in physiological conditions and in obesity in mice. Endocrinology 153:5261–5274

    Article  CAS  PubMed  Google Scholar 

  • Chan SY, Zhang YY, Hemann C, Mahoney CE, Zweier JL, Loscalzo J (2009) MicroRNA-210 controls mitochondrial metabolism during hypoxia by repressing the iron-sulfur cluster assembly proteins ISCU1/2. Cell Metab 10:273–284

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen Y, Gelfond JA, McManus LM, Shireman PK (2009) Reproducibility of quantitative RT-PCR array in miRNA expression profiling and comparison with microarray analysis. BMC Genomics 10:407

    Article  PubMed  PubMed Central  Google Scholar 

  • Chendrimada TP, Gregory RI, Kumaraswamy E, Norman J, Cooch N, Nishikura K, Shiekhattar R (2005) TRBP recruits the dicer complex to Ago2 for microRNA processing and gene silencing. Nature 436:740–744

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Daniels SM, Gatignol A (2012) The multiple functions of TRBP, at the hub of cell responses to viruses, stress, and cancer. Microbiol Mol Biol Rev 76:652–666

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Davis JE, Gabler NK, Walker-Daniels J, Spurlock ME (2008) Tlr-4 deficiency selectively protects against obesity induced by diets high in saturated fat. Obesity 16:1248–1255

    Article  CAS  PubMed  Google Scholar 

  • De Benedetti A, Williams GJ, Baglioni C (1985) Inhibition of binding to initiation complexes of nascent reovirus mRNA by double-stranded RNA-dependent protein kinase. J Virol 54:408–413

    PubMed  PubMed Central  Google Scholar 

  • Ding SW (2010) RNA-based antiviral immunity. Nat Rev Immunol 10:632–644

    Article  CAS  PubMed  Google Scholar 

  • Donath MY, Shoelson SE (2011) Type 2 diabetes as an inflammatory disease. Nat Rev Immunol 11:98–107

    Article  CAS  PubMed  Google Scholar 

  • Eley HL, Russell ST, Tisdale MJ (2007) Attenuation of muscle atrophy in a murine model of cachexia by inhibition of the dsRNA-dependent protein kinase. Br J Cancer 96:1216–1222

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Frost RJ, Olson EN (2011) Control of glucose homeostasis and insulin sensitivity by the Let-7 family of microRNAs. Proc Natl Acad Sci U S A 108:21075–21080

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fu Y, Dominissini D, Rechavi G, He C (2014) Gene expression regulation mediated through reversible m(6)a RNA methylation. Nat Rev Genet 15:293–306

    Article  CAS  PubMed  Google Scholar 

  • Garcia MA, Gil J, Ventoso I, Guerra S, Domingo E, Rivas C, Esteban M (2006) Impact of protein kinase PKR in cell biology: from antiviral to antiproliferative action. Microbiol Mol Biol Rev 70:1032–1060

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gregor MF, Hotamisligil GS (2011) Inflammatory mechanisms in obesity. Annu Rev Immunol 29:415–445

    Article  CAS  PubMed  Google Scholar 

  • Gregory RI, Chendrimada TP, Cooch N, Shiekhattar R (2005) Human RISC couples microRNA biogenesis and posttranscriptional gene silencing. Cell 123:631–640

    Article  CAS  PubMed  Google Scholar 

  • Hirosumi J, Tuncman G, Chang L, Gorgun CZ, Uysal KT, Maeda K, Karin M, Hotamisligil GS (2002) A central role for JNK in obesity and insulin resistance. Nature 420:333–336

    Article  CAS  PubMed  Google Scholar 

  • Holcik M, Sonenberg N (2005) Translational control in stress and apoptosis. Nat Rev Mol Cell Biol 6:318–327

    Article  CAS  PubMed  Google Scholar 

  • Holland WL, Bikman BT, Wang LP, Yuguang G, Sargent KM, Bulchand S, Knotts TA, Shui G, Clegg DJ, Wenk MR et al (2011) Lipid-induced insulin resistance mediated by the proinflammatory receptor TLR4 requires saturated fatty acid-induced ceramide biosynthesis in mice. J Clin Invest 121:1858–1870

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hotamisligil GS (2006) Inflammation and metabolic disorders. Nature 444:860–867

    Article  CAS  PubMed  Google Scholar 

  • Hotamisligil GS (2010) Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell 140:900–917

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Iliopoulos D, Polytarchou C, Hatziapostolou M, Kottakis F, Maroulakou IG, Struhl K, Tsichlis PN (2009) MicroRNAs differentially regulated by Akt isoforms control EMT and stem cell renewal in cancer cells. Sci Signal 2:ra62

    Google Scholar 

  • Jammi NV, Whitby LR, Beal PA (2003) Small molecule inhibitors of the RNA-dependent protein kinase. Biochem Biophys Res Commun 308:50–57

    Article  CAS  PubMed  Google Scholar 

  • Jin C, Henao-Mejia J, Flavell RA (2013) Innate immune receptors: key regulators of metabolic disease progression. Cell Metab 17:873–882

    Article  CAS  PubMed  Google Scholar 

  • Jinek M, Doudna JA (2009) A three-dimensional view of the molecular machinery of RNA interference. Nature 457:405–412

    Article  CAS  PubMed  Google Scholar 

  • Kim JK, Fillmore JJ, Sunshine MJ, Albrecht B, Higashimori T, Kim DW, Liu ZX, Soos TJ, Cline GW, O’Brien WR et al (2004) PKC-theta knockout mice are protected from fat-induced insulin resistance. J Clin Invest 114:823–827

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kok KH, Ng MH, Ching YP, Jin DY (2007) Human TRBP and PACT directly interact with each other and associate with dicer to facilitate the production of small interfering RNA. J Biol Chem 282:17649–17657

    Article  CAS  PubMed  Google Scholar 

  • Konner AC, Bruning JC (2011) Toll-like receptors: linking inflammation to metabolism. Trends Endocrinol Metab TEM 22:16–23

    Article  PubMed  Google Scholar 

  • Kornfeld JW, Baitzel C, Konner AC, Nicholls HT, Vogt MC, Herrmanns K, Scheja L, Haumaitre C, Wolf AM, Knippschild U et al (2013) Obesity-induced overexpression of miR-802 impairs glucose metabolism through silencing of Hnf1b. Nature 494:111–115

    Article  CAS  PubMed  Google Scholar 

  • Lafontaine DL, Tollervey D (1998) Birth of the snoRNPs: the evolution of the modification-guide snoRNAs. Trends Biochem Sci 23:383–388

    Article  CAS  PubMed  Google Scholar 

  • Lee M, Kim B, Kim VN (2014) Emerging roles of RNA modification: m(6)a and U-tail. Cell 158:980–987

    Article  CAS  PubMed  Google Scholar 

  • Lumeng CN, Saltiel AR (2011) Inflammatory links between obesity and metabolic disease. J Clin Invest 121:2111–2117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Meurs E, Chong K, Galabru J, Thomas NS, Kerr IM, Williams BR, Hovanessian AG (1990) Molecular cloning and characterization of the human double-stranded RNA-activated protein kinase induced by interferon. Cell 62:379–390

    Article  CAS  PubMed  Google Scholar 

  • Meyer KD, Jaffrey SR (2014) The dynamic epitranscriptome: N6-methyladenosine and gene expression control. Nat Rev Mol Cell Biol 15:313–326

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Michel CI, Holley CL, Scruggs BS, Sidhu R, Brookheart RT, Listenberger LL, Behlke MA, Ory DS, Schaffer JE (2011) Small nucleolar RNAs U32a, U33, and U35a are critical mediators of metabolic stress. Cell Metab 14:33–44

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nakamura T, Furuhashi M, Li P, Cao H, Tuncman G, Sonenberg N, Gorgun CZ, Hotamisligil GS (2010) Double-stranded RNA-dependent protein kinase links pathogen sensing with stress and metabolic homeostasis. Cell 140:338–348

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nakamura T, Arduini A, Baccaro B, Furuhashi M, Hotamisligil GS (2014) Small-molecule inhibitors of PKR improve glucose homeostasis in obese diabetic mice. Diabetes 63:526–534

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nakamura T, Kunz RC, Zhang C, Kimura T, Yuan CL, Baccaro B, Namiki Y, Gygi SP, Hotamisligil GS (2015) A critical role for PKR complexes with TRBP in immunometabolic regulation and eIF2alpha phosphorylation in obesity. Cell rep 11:295–307

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nallagatla SR, Toroney R, Bevilacqua PC (2011) Regulation of innate immunity through RNA structure and the protein kinase PKR. Curr Opin Struct Biol 21:119–127

    Article  CAS  PubMed  Google Scholar 

  • Ogden CL, Carroll MD, Kit BK, Flegal KM (2014) Prevalence of childhood and adult obesity in the United States, 2011–2012. Jama 311:806–814

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Olefsky JM, Glass CK (2010) Macrophages, inflammation, and insulin resistance. Annu Rev Physiol 72:219–246

    Article  CAS  PubMed  Google Scholar 

  • Ozcan U, Ozcan L, Yilmaz E, Duvel K, Sahin M, Manning BD, Hotamisligil GS (2008) Loss of the tuberous sclerosis complex tumor suppressors triggers the unfolded protein response to regulate insulin signaling and apoptosis. Mol Cell 29:541–551

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Paroo Z, Ye X, Chen S, Liu Q (2009) Phosphorylation of the human microRNA-generating complex mediates MAPK/Erk signaling. Cell 139:112–122

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pedersen BK, Febbraio MA (2010) Diabetes: treatment of diabetes mellitus: new tricks by an old player. Nat Rev Endocrinol 6:482–483

    Article  PubMed  Google Scholar 

  • Perry RJ, Samuel VT, Petersen KF, Shulman GI (2014) The role of hepatic lipids in hepatic insulin resistance and type 2 diabetes. Nature 510:84–91

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Piatek MJ, Werner A (2014) Endogenous siRNAs: regulators of internal affairs. Biochem Soc Trans 42:1174–1179

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Reaven GM, Lithell H, Landsberg L (1996) Hypertension and associated metabolic abnormalities – the role of insulin resistance and the sympathoadrenal system. N Engl J Med 334:374–381

    Article  CAS  PubMed  Google Scholar 

  • Ron D, Walter P (2007) Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 8:519–529

    Article  CAS  PubMed  Google Scholar 

  • Sabio G, Davis RJ (2010) CJun NH2-terminal kinase 1 (JNK1): roles in metabolic regulation of insulin resistance. Trends Biochem Sci 35:490–496

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Saltiel AR (2000) Series introduction: the molecular and physiological basis of insulin resistance: emerging implications for metabolic and cardiovascular diseases. J Clin Invest 106:163–164

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Samuel CE (1993) The eIF-2 alpha protein kinases, regulators of translation in eukaryotes from yeasts to humans. J Biol Chem 268:7603–7606

    CAS  PubMed  Google Scholar 

  • Scruggs BS, Michel CI, Ory DS, Schaffer JE (2012) SmD3 regulates intronic noncoding RNA biogenesis. Mol Cell Biol 32:4092–4103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Semenkovich CF (2006) Insulin resistance and atherosclerosis. J Clin Invest 116:1813–1822

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS (2006) TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest 116:3015–3025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shulman GI (2014) Ectopic fat in insulin resistance, dyslipidemia, and cardiometabolic disease. N Engl J Med 371:1131–1141

    Article  PubMed  Google Scholar 

  • Siomi H, Siomi MC (2009) On the road to reading the RNA-interference code. Nature 457:396–404

    Article  CAS  PubMed  Google Scholar 

  • Strodthoff D, Ma Z, Wirstrom T, Strawbridge RJ, Ketelhuth DF, Engel D, Clarke R, Falkmer S, Hamsten A, Hansson GK et al (2015) Toll-like receptor 3 influences glucose homeostasis and beta-cell insulin secretion. Diabetes 64(10):3425–3438

    Article  CAS  PubMed  Google Scholar 

  • Takeuchi O, Akira S (2009) Innate immunity to virus infection. Immunol Rev 227:75–86

    Article  CAS  PubMed  Google Scholar 

  • Tzatsos A, Kandror KV (2006) Nutrients suppress phosphatidylinositol 3-kinase/Akt signaling via raptor-dependent mTOR-mediated insulin receptor substrate 1 phosphorylation. Mol Cell Biol 26:63–76

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vandanmagsar B, Youm YH, Ravussin A, Galgani JE, Stadler K, Mynatt RL, Ravussin E, Stephens JM, Dixit VD (2011) The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat Med 17:179–188

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wen H, Gris D, Lei Y, Jha S, Zhang L, Huang MT, Brickey WJ, Ting JP (2011) Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling. Nat Immunol 12:408–415

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Whipple JM, Youssef OA, Aruscavage PJ, Nix DA, Hong C, Johnson WE, Bass BL (2015) Genome-wide profiling of the C. elegans dsRNAome. RNA 21:786–800

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • White E, Schlackow M, Kamieniarz-Gdula K, Proudfoot NJ, Gullerova M (2014) Human nuclear dicer restricts the deleterious accumulation of endogenous double-stranded RNA. Nat Struct Mol Biol 21:552–559

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Williams BR (2001) Signal integration via PKR. Sci STKE 2001:RE2

    CAS  PubMed  Google Scholar 

  • Wilson RC, Doudna JA (2013) Molecular mechanisms of RNA interference. Annu Rev Biophys 42:217–239

    Article  CAS  PubMed  Google Scholar 

  • World Health Organization (2015) Obesity and overweight. http://www.who.int/mediacentre/factsheets/fs311/en

  • Wu LH, Huang CC, Adhikarakunnathu S, San Mateo LR, Duffy KE, Rafferty P, Bugelski P, Raymond H, Deutsch H, Picha K et al (2012) Loss of toll-like receptor 3 function improves glucose tolerance and reduces liver steatosis in obese mice. Metab Clin Exp 61:1633–1645

    Article  CAS  PubMed  Google Scholar 

  • Youssef OA, Safran SA, Nakamura T, Nix DA, Hotamisligil GS, Bass BL (2015) Potential role for snoRNAs in PKR activation during metabolic stress. Proc Natl Acad Sci U S A 112:5023–5028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhu H, Shyh-Chang N, Segre AV, Shinoda G, Shah SP, Einhorn WS, Takeuchi A, Engreitz JM, Hagan JP, Kharas MG et al (2011) The Lin28/let-7 axis regulates glucose metabolism. Cell 147:81–94

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zipeto MA, Jiang Q, Melese E, Jamieson CH (2015) RNA rewriting, recoding, and rewiring in human disease. Trends Mol Med 21(9):549–559

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgment

I am grateful to the members of my laboratory, particularly Celvie L. Yuan and Elise Bernhard for helpful discussions and comments. I thank Vivian Hwa and Jason Fan for thoughtful comments. I acknowledge support from the American Heart Association, Digestive Disease Research Core Center in Cincinnati (DK078392), the Diabetes Action Research and Education Foundation, and PRESTO from the Japan Science and Technology Agency.

Author information

Authors and Affiliations

  1. Divisions of Endocrinology and Developmental Biology, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    Takahisa Nakamura

  2. PRESTO, Japan Science and Technology Agency, Kawaguchi, 332-0012, Japan

    Takahisa Nakamura

Authors
  1. Takahisa Nakamura
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Takahisa Nakamura .

Editor information

Editors and Affiliations

  1. Interdisciplinary Program for Biomedical Sciences Institute for Academic Initiatives, Osaka University, Suita, Japan

    Masayuki Miyasaka

  2. Department of Immunobiology and Pharmacological Genetics Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan

    Kiyoshi Takatsu

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer Japan

About this chapter

Cite this chapter

Nakamura, T. (2016). Role of Double-Stranded RNA Pathways in Immunometabolism in Obesity. In: Miyasaka, M., Takatsu, K. (eds) Chronic Inflammation. Springer, Tokyo. https://doi.org/10.1007/978-4-431-56068-5_21

Download citation

Publish with us

Policies and ethics

Search

Navigation