Ectopic Fat Accumulation in the Liver and Glucose Homeostasis

  • Toshinari TakamuraEmail author
  • Hirofumi Misu
  • Shuichi Kaneko


Liver fat is associated not only with enhanced hepatic glucose production but also with skeletal muscle insulin resistance, supporting a central role of fatty liver in systemic insulin resistance and existence of a network between the liver and skeletal muscle. Palmitate and cholesterol act as toxic lipids to cause hepatic insulin resistance via mitochondria-derived oxidative stress. Obesity-mediated disruption in crosstalk among protein-, glucose- and lipid-metabolism pathways results in hepatic insulin resistance, enhanced gluconeogenesis and liver steatosis by impairing proteasome function. The liver plays as an endocrine organ to produce functional hepatokines and thereby mediates fatty liver-associated skeletal muscle insulin resistance through unique mechanisms. Selenoprotein P is upregulated through FoxOs and hyperglycemia and causes resistance to insulin, angiogenesis and exercise through reductive stress. LECT2 is upregulated in satiety through AMPK inactivation and contributes to the development of muscle insulin resistance and obesity by activating JNK and by impairing myogenesis, respectively.

Therefore, overnutrition evokes remodeling of nutrient homeostasis by toxic lipids and proteasome dysfunction in the liver. The remodeling also results in the overproduction of hepatokines that disrupt inter-organ network leading to pathology of diabetes.


Fatty liver Insulin resistance Hepatokine Selenoprotein P LECT2 


  1. 1.
    Yamada T, Katagiri H (2007) Avenues of communication between the brain and tissues/organs involved in energy homeostasis. Endocr J 54(4):497–505. PubMed Epub 2007/05/19. engCrossRefPubMedGoogle Scholar
  2. 2.
    (OECD) TOfEC-oaD. OBESITY Update. 2014.Google Scholar
  3. 3.
    (IDF) IDF. IDF DIABETES ATLAS (2014) 6: Available from:
  4. 4.
    Matsuzawa N, Takamura T, Kurita S, Misu H, Ota T, Ando H et al (2007) Lipid-induced oxidative stress causes steatohepatitis in mice fed an atherogenic diet. Hepatology 46(5):1392–1403. PubMed engCrossRefPubMedGoogle Scholar
  5. 5.
    Nakamura S, Takamura T, Matsuzawa-Nagata N, Takayama H, Misu H, Noda H et al (2009) Palmitate induces insulin resistance in H4IIEC3 hepatocytes through reactive oxygen species produced by mitochondria. J Biol Chem 284(22):14809–14818. PubMed engCrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Mootha VK, Lindgren CM, Eriksson KF, Subramanian A, Sihag S, Lehar J et al (2003) PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet 34(3):267–273. PubMedCrossRefPubMedGoogle Scholar
  7. 7.
    Takamura T, Misu H, Matsuzawa-Nagata N, Sakurai M, Ota T, Shimizu A et al (2008) Obesity upregulates genes involved in oxidative phosphorylation in livers of diabetic patients. Obesity (Silver Spring) 16(12):2601–2609. PubMed Epub 2008/10/11. engCrossRefGoogle Scholar
  8. 8.
    Michael MD, Kulkarni RN, Postic C, Previs SF, Shulman GI, Magnuson MA et al (2000) Loss of insulin signaling in hepatocytes leads to severe insulin resistance and progressive hepatic dysfunction. Mol Cell 6(1):87–97. PubMedCrossRefPubMedGoogle Scholar
  9. 9.
    Lauro D, Kido Y, Castle AL, Zarnowski MJ, Hayashi H, Ebina Y et al (1998) Impaired glucose tolerance in mice with a targeted impairment of insulin action in muscle and adipose tissue. Nat Genet 20(3):294–298. PubMed Epub 1998/11/07. engCrossRefPubMedGoogle Scholar
  10. 10.
    Sakurai M, Takamura T, Ota T, Ando H, Akahori H, Kaji K et al (2007) Liver steatosis, but not fibrosis, is associated with insulin resistance in nonalcoholic fatty liver disease. J Gastroenterol 42(4):312–317. PubMed engCrossRefPubMedGoogle Scholar
  11. 11.
    Kato K, Takamura T, Takeshita Y, Ryu Y, Misu H, Ota T et al (2014) Ectopic fat accumulation and distant organ-specific insulin resistance in Japanese people with nonalcoholic fatty liver disease. PLoS One 9(3):e92170. PubMed Pubmed Central PMCID: 3961287CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Thamer C, Machann J, Bachmann O, Haap M, Dahl D, Wietek B et al (2003) Intramyocellular lipids: anthropometric determinants and relationships with maximal aerobic capacity and insulin sensitivity. J Clin Endocrinol Metab 88(4):1785–1791. PubMedCrossRefPubMedGoogle Scholar
  13. 13.
    Kim JK, Michael MD, Previs SF, Peroni OD, Mauvais-Jarvis F, Neschen S et al (2000) Redistribution of substrates to adipose tissue promotes obesity in mice with selective insulin resistance in muscle. J Clin Invest 105(12):1791–1797. PubMed Pubmed Central PMCID: 378504CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Flannery C, Dufour S, Rabol R, Shulman GI, Petersen KF (2012) Skeletal muscle insulin resistance promotes increased hepatic de novo lipogenesis, hyperlipidemia, and hepatic steatosis in the elderly. Diabetes 61(11):2711–2717. PubMed Pubmed Central PMCID: 3478531CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Uno K, Katagiri H, Yamada T, Ishigaki Y, Ogihara T, Imai J et al (2006) Neuronal pathway from the liver modulates energy expenditure and systemic insulin sensitivity. Science 312(5780):1656–1659. PubMed engCrossRefPubMedGoogle Scholar
  16. 16.
    Newgard CB (2012) Interplay between lipids and branched-chain amino acids in development of insulin resistance. Cell Metab 15(5):606–614. PubMed Pubmed Central PMCID: 3695706CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Takamura T, Misu H, Ota T, Kaneko S (2012) Fatty liver as a consequence and cause of insulin resistance: lessons from type 2 diabetic liver. Endocr J 59(9):745–763. PubMedCrossRefPubMedGoogle Scholar
  18. 18.
    Brown MS, Goldstein JL (2008) Selective versus total insulin resistance: a pathogenic paradox. Cell Metab 7(2):95–96. PubMedCrossRefPubMedGoogle Scholar
  19. 19.
    Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, Parks EJ (2005) Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest 115(5):1343–1351. PubMed Pubmed Central PMCID: 1087172CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Rutkowski DT, Wu J, Back SH, Callaghan MU, Ferris SP, Iqbal J et al (2008) UPR pathways combine to prevent hepatic steatosis caused by ER stress-mediated suppression of transcriptional master regulators. Dev Cell 15(6):829–840. PubMed Pubmed Central PMCID: 2923556CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Shimano H (2007) SREBP-1c and TFE3, energy transcription factors that regulate hepatic insulin signaling. J Mol Med 85(5):437–444. PubMedCrossRefPubMedGoogle Scholar
  22. 22.
    Ozcan U, Cao Q, Yilmaz E, Lee AH, Iwakoshi NN, Ozdelen E et al (2004) Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 306(5695):457–461. PubMedCrossRefPubMedGoogle Scholar
  23. 23.
    Ozcan U, Yilmaz E, Ozcan L, Furuhashi M, Vaillancourt E, Smith RO et al (2006) Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science 313(5790):1137–1140. PubMedCrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Walter P, Ron D (2011) The unfolded protein response: from stress pathway to homeostatic regulation. Science 334(6059):1081–1086. PubMedCrossRefPubMedGoogle Scholar
  25. 25.
    Yalcin A, Hotamisligil GS (2013) Impact of ER protein homeostasis on metabolism. Diabetes 62(3):691–693. PubMed Pubmed Central PMCID: 3581203CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Voges D, Zwickl P, Baumeister W (1999) The 26S proteasome: a molecular machine designed for controlled proteolysis. Annu Rev Biochem 68:1015–1068. PubMedCrossRefPubMedGoogle Scholar
  27. 27.
    Otoda T, Takamura T, Misu H, Ota T, Murata S, Hayashi H et al (2013) Proteasome dysfunction mediates obesity-induced endoplasmic reticulum stress and insulin resistance in the liver. Diabetes 62(3):811–824. PubMed Pubmed Central PMCID: 3581221CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Yang L, Li P, Fu S, Calay ES, Hotamisligil GS (2010) Defective hepatic autophagy in obesity promotes ER stress and causes insulin resistance. Cell Metab 11(6):467–478. PubMed Pubmed Central PMCID: 2881480CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Hirano Y, Yoshida M, Shimizu M, Sato R (2001) Direct demonstration of rapid degradation of nuclear sterol regulatory element-binding proteins by the ubiquitin-proteasome pathway. J Biol Chem 276(39):36431–36437. PubMedCrossRefPubMedGoogle Scholar
  30. 30.
    Zhou Y, Lee J, Reno CM, Sun C, Park SW, Chung J et al (2011) Regulation of glucose homeostasis through a XBP-1-FoxO1 interaction. Nat Med 17(3):356–365. PubMed Pubmed Central PMCID: 3897616CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Queisser MA, Yao D, Geisler S, Hammes HP, Lochnit G, Schleicher ED et al (2010) Hyperglycemia impairs proteasome function by methylglyoxal. Diabetes 59(3):670–678. PubMed Pubmed Central PMCID: 2828656CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Portero-Otin M, Pamplona R, Ruiz MC, Cabiscol E, Prat J, Bellmunt MJ (1999) Diabetes induces an impairment in the proteolytic activity against oxidized proteins and a heterogeneous effect in nonenzymatic protein modifications in the cytosol of rat liver and kidney. Diabetes 48(11):2215–2220. PubMedCrossRefPubMedGoogle Scholar
  33. 33.
    Wang X, Hu Z, Hu J, Du J, Mitch WE (2006) Insulin resistance accelerates muscle protein degradation: Activation of the ubiquitin-proteasome pathway by defects in muscle cell signaling. Endocrinology 147(9):4160–4168. PubMedCrossRefPubMedGoogle Scholar
  34. 34.
    Ozcan L, Ergin AS, Lu A, Chung J, Sarkar S, Nie D et al (2009) Endoplasmic reticulum stress plays a central role in development of leptin resistance. Cell Metab 9(1):35–51. PubMedCrossRefPubMedGoogle Scholar
  35. 35.
    Takamura T, Misu H, Yamashita T, Kaneko S (2008) SAGE application in the study of diabetes. Curr Pharm Biotechnol 9(5):392–399. PubMed Epub 2008/10/16. engCrossRefPubMedGoogle Scholar
  36. 36.
    Misu H, Takamura T, Matsuzawa N, Shimizu A, Ota T, Sakurai M et al (2007) Genes involved in oxidative phosphorylation are coordinately upregulated with fasting hyperglycaemia in livers of patients with type 2 diabetes. Diabetologia 50(2):268–277. PubMedCrossRefPubMedGoogle Scholar
  37. 37.
    Ota T, Takamura T, Kurita S, Matsuzawa N, Kita Y, Uno M et al (2007) Insulin resistance accelerates a dietary rat model of nonalcoholic steatohepatitis. Gastroenterology 132(1):282–293. PubMed engCrossRefPubMedGoogle Scholar
  38. 38.
    Matsuzawa-Nagata N, Takamura T, Ando H, Nakamura S, Kurita S, Misu H et al (2008) Increased oxidative stress precedes the onset of high-fat diet-induced insulin resistance and obesity. Metabolism 57(8):1071–1077. PubMed engCrossRefPubMedGoogle Scholar
  39. 39.
    Ando H, Takamura T, Matsuzawa-Nagata N, Shima KR, Nakamura S, Kumazaki M et al (2009) The hepatic circadian clock is preserved in a lipid-induced mouse model of non-alcoholic steatohepatitis. Biochem Biophys Res Commun 380(3):684–688. PubMed Epub 2009/03/17. engCrossRefPubMedGoogle Scholar
  40. 40.
    Misu H, Takamura T, Takayama H, Hayashi H, Matsuzawa-Nagata N, Kurita S et al (2010) A liver-derived secretory protein, selenoprotein P, causes insulin resistance. Cell Metab 12(5):483–495. PubMed Epub 2010/11/03. engCrossRefPubMedGoogle Scholar
  41. 41.
    Speckmann B, Walter PL, Alili L, Reinehr R, Sies H, Klotz LO et al (2008) Selenoprotein P expression is controlled through interaction of the coactivator PGC-1alpha with FoxO1a and hepatocyte nuclear factor 4alpha transcription factors. Hepatology 48(6):1998–2006. PubMedCrossRefPubMedGoogle Scholar
  42. 42.
    Takayama H, Misu H, Iwama H, Chikamoto K, Saito Y, Murao K et al (2014) Metformin suppresses expression of the selenoprotein P gene via an AMP-activated kinase (AMPK)/FoxO3a pathway in H4IIEC3 hepatocytes. J Biol Chem 289(1):335–345. PubMed Pubmed Central PMCID: 3879556CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Ishikura K, Misu H, Kumazaki M, Takayama H, Matsuzawa-Nagata N, Tajima N et al (2014) Selenoprotein P as a diabetes-associated hepatokine that impairs angiogenesis by inducing VEGF resistance in vascular endothelial cells. Diabetologia 57(9):1968–1976. PubMedCrossRefPubMedGoogle Scholar
  44. 44.
    Stranges S, Marshall JR, Natarajan R, Donahue RP, Trevisan M, Combs GF et al (2007) Effects of long-term selenium supplementation on the incidence of type 2 diabetes: a randomized trial. Ann Intern Med 147(4):217–223. PubMed Epub 2007/07/11. engCrossRefPubMedGoogle Scholar
  45. 45.
    Iwakami S, Misu H, Takeda T, Sugimori M, Matsugo S, Kaneko S et al (2011) Concentration-dependent dual effects of hydrogen peroxide on insulin signal transduction in H4IIEC hepatocytes. PLoS One 6(11):e27401, PubMed Pubmed Central PMCID: 3216925. Epub 2011/11/22. engCrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Loh K, Deng H, Fukushima A, Cai X, Boivin B, Galic S et al (2009) Reactive oxygen species enhance insulin sensitivity. Cell Metab 10(4):260–272. PubMed Epub 2009/10/08. engCrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Ristow M, Zarse K, Oberbach A, Kloting N, Birringer M, Kiehntopf M et al (2009) Antioxidants prevent health-promoting effects of physical exercise in humans. Proc Natl Acad Sci U S A 106(21):8665–8670, PubMed Pubmed Central PMCID: 2680430. Epub 2009/05/13. engCrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Misu H, Ishikura K, Kurita S, Takeshita Y, Ota T, Saito Y et al (2012) Inverse correlation between serum levels of selenoprotein P and adiponectin in patients with type 2 diabetes. PLoS One 7(4):e34952. PubMed Pubmed Central PMCID: 3319626. Epub 2012/04/13. engCrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Iwabu M, Yamauchi T, Okada-Iwabu M, Sato K, Nakagawa T, Funata M et al (2010) Adiponectin and AdipoR1 regulate PGC-1alpha and mitochondria by Ca(2+) and AMPK/SIRT1. Nature 464(7293):1313–1319. PubMedCrossRefPubMedGoogle Scholar
  50. 50.
    Lan F, Misu H, Chikamoto K, Takayama H, Kikuchi A, Mohri K et al (2014) LECT2 functions as a hepatokine that links obesity to skeletal muscle insulin resistance. Diabetes 63(5):1649–1664. PubMedCrossRefPubMedGoogle Scholar
  51. 51.
    Yamagoe S, Yamakawa Y, Matsuo Y, Minowada J, Mizuno S, Suzuki K (1996) Purification and primary amino acid sequence of a novel neutrophil chemotactic factor LECT2. Immunol Lett 52(1):9–13. PubMedCrossRefPubMedGoogle Scholar
  52. 52.
    Yamagoe S, Mizuno S, Suzuki K (1998) Molecular cloning of human and bovine LECT2 having a neutrophil chemotactic activity and its specific expression in the liver. Biochim Biophys Acta 1396(1):105–113. PubMedCrossRefPubMedGoogle Scholar
  53. 53.
    Lu XJ, Chen J, Yu CH, Shi YH, He YQ, Zhang RC et al (2013) LECT2 protects mice against bacterial sepsis by activating macrophages via the CD209a receptor. J Exp Med 210(1):5–13. PubMed Pubmed Central PMCID: 3549712CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Chen CK, Yang CY, Hua KT, Ho MC, Johansson G, Jeng YM et al (2014) Leukocyte cell-derived chemotaxin 2 antagonizes MET receptor activation to suppress hepatocellular carcinoma vascular invasion by protein tyrosine phosphatase 1B recruitment. Hepatology 59(3):974–985. PubMedCrossRefPubMedGoogle Scholar

Copyright information

© Springer Japan 2016

Authors and Affiliations

  • Toshinari Takamura
    • 1
    Email author
  • Hirofumi Misu
    • 1
  • Shuichi Kaneko
    • 2
  1. 1.Department of Comprehensive MetabologyKanazawa University Graduate School of Medical SciencesKanazawaJapan
  2. 2.Department of Disease Control and HomeostasisKanazawa University Graduate School of Medical SciencesKanazawaJapan

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