Increased hepatic fatty acid polyunsaturation precedes ectopic lipid deposition in the liver in adaptation to high-fat diets in mice

  • Ana Francisca Soares
  • João M. N. Duarte
  • Rolf Gruetter
Research Article



We monitored hepatic lipid content (HLC) and fatty acid (FA) composition in the context of enhanced lipid handling induced by a metabolic high-fat diet (HFD) challenge and fasting.

Materials and methods

Mice received a control diet (10% of kilocalories from fat, N = 14) or an HFD (45% or 60% of kilocalories from fat, N = 10 and N = 16, respectively) for 26 weeks. A subset of five mice receiving an HFD (60% of kilocalories from fat) were switched to the control diet for the final 7 weeks. At nine time points, magnetic resonance spectroscopy was performed in vivo at 14.1 T, interleaved with glucose tolerance tests.


Glucose intolerance promptly developed with the HFD, followed by a progressive increase of fasting insulin level, simultaneously with that of HLC. These metabolic defects were normalized by dietary reversal. HFD feeding immediately increased polyunsaturation of hepatic FA, before lipid accumulation. Fasting-induced changes in hepatic lipids (increased HLC and FA polyunsaturation, decreased FA monounsaturation) in control-diet-fed mice were not completely reproduced in HFD-fed mice, not even after dietary reversal.


A similar adaptation of hepatic lipids to both fasting and an HFD suggests common mechanisms of lipid trafficking from adipose tissue to the liver. Altered hepatic lipid handling with fasting indicates imperfect metabolic recovery from HFD exposure.


Insulin resistance Liver Nuclear Magnetic Resonance Nutrition Obesity Polyunsaturated fat 



This work received financial support from the Swiss National Science Foundation (grant 148250 to JMND), the Centre d’Imagerie BioMédicale of the University of Lausanne, the University of Geneva, the University Hospital of Geneva, the University Hospital of Lausanne, the École Polythenique Fédérale de Lausanne, the Leenaards Foundation, and the Louis-Jeantet Foundation. The authors are grateful to Blanca Lizarbe for her help with animal monitoring. The authors are also grateful to Anne-Catherine Clerc and Analina da Silva for technical support.

Author contributions

AFS designed the study, performed liver magnetic resonance spectroscopy experiments, collected, analyzed, and interpreted data, and drafted the manuscript. JMND designed the study, edited the manuscript, and contributed to the discussion. RG edited the manuscript and contributed to the discussion.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

Ethical standards

All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.


  1. 1.
    Swinburn BA, Sacks G, Hall KD, McPherson K, Finegood DT, Moodie ML, Gortmaker SL (2011) The global obesity pandemic: shaped by global drivers and local environments. Lancet 378(9793):804–814CrossRefPubMedGoogle Scholar
  2. 2.
    Rydén L, Grant PJ, Anker SD, Berne C, Cosentino F, Danchin N, Deaton C, Escaned J, Hammes H-P, Huikuri H, Marre M, Marx N, Mellbin L, Ostergren J, Patrono C, Seferovic P, Uva MS, Taskinen M-R, Tendera M, Tuomilehto J, Valensi P, Zamorano JL, Achenbach S, Baumgartner H, Bax JJ, Bueno H, Dean V, Erol Ç, Fagard R, Ferrari R, Hasdai D, Hoes AW, Kirchhof P, Knuuti J, Kolh P, Lancellotti P, Linhart A, Nihoyannopoulos P, Piepoli MF, Ponikowski P, Sirnes PA, Tamargo JL, Torbicki A, Wijns W, Windecker S, De Backer G, Ezquerra EA, Avogaro A, Badimon L, Baranova E, Betteridge J, Ceriello A, Funck-Brentano C, Gulba DC, Hoes AW, Kjekshus JK, Lev E, Mueller C, Neyses L, Nilsson PM, Perk J, Reiner Ž, Sattar N, Schächinger V, Scheen A, Schirmer H, Strömberg A, Sudzhaeva S, Viigimaa M, Vlachopoulos C, Xuereb RG (2013) ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J 34(39):3035–3087CrossRefPubMedGoogle Scholar
  3. 3.
    Mosser RE, Maulis MF, Moullé VS, Dunn JC, Carboneau BA, Arasi K, Pappan K, Poitout V, Gannon M (2015) High-fat diet-induced β-cell proliferation occurs prior to insulin resistance in C57Bl/6J male mice. Am J Physiol Endocrinol Metab 308(7):E573–E582CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Gao X, Yan D, Zhao Y, Tao H, Zhou Y (2015) Moderate calorie restriction to achieve normal weight reverses β-cell dysfunction in diet-induced obese mice: involvement of autophagy. Nutr Metab 12:34CrossRefGoogle Scholar
  5. 5.
    van der Heijden RA, Sheedfar F, Morrison MC, Hommelberg PPH, Kor D, Kloosterhuis NJ, Gruben N, Youssef SA, de Bruin A, Hofker MH, Kleemann R, Koonen DPY, Heeringa P (2015) High-fat diet induced obesity primes inflammation in adipose tissue prior to liver in C57BL/6j mice. Aging 7(4):256–267CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Gentile CL, Weir TL, Cox-York KA, Wei Y, Wang D, Reese L, Moran G, Estrada A, Mulligan C, Pagliassotti MJ, Foster MT (2015) The role of visceral and subcutaneous adipose tissue fatty acid composition in liver pathophysiology associated with NAFLD. Adipocyte 4(2):101–112CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Perry RJ, Samuel VT, Petersen KF, Shulman GI (2014) The role of hepatic lipids in hepatic insulin resistance and type 2 diabetes. Nature 510(7503):84–91CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Wiedemann MSF, Wueest S, Item F, Schoenle EJ, Konrad D (2013) Adipose tissue inflammation contributes to short-term high-fat diet-induced hepatic insulin resistance. Am J Physiol Endocrinol Metab 305(3):E388–E395CrossRefPubMedGoogle Scholar
  9. 9.
    Samuel VT, Liu Z-X, Qu X, Elder BD, Bilz S, Befroy D, Romanelli AJ, Shulman GI (2004) Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease. J Biol Chem 279(31):32345–32353CrossRefPubMedGoogle Scholar
  10. 10.
    Boon Mariëtte R, Bakker Leontine EH, Haks Mariëlle C, Quinten E, Schaart G, Van Beek L, Wang Y, Van Schinkel L, Van Harmelen V, Meinders AE, Ottenhoff Tom HM, Van Dijk KW, Guigas B, Jazet Ingrid M, Rensen Patrick CN (2014) Short-term high-fat diet increases macrophage markers in skeletal muscle accompanied by impaired insulin signalling in healthy male subjects. Clin Sci 128(2):143–151CrossRefGoogle Scholar
  11. 11.
    Bakker LEH, van Schinkel LD, Guigas B, Streefland TCM, Jonker JT, van Klinken JB, van der Zon GCM, Lamb HJ, Smit JWA, Pijl H, Meinders AE, Jazet IM (2013) A 5-day high-fat, high-calorie diet impairs insulin sensitivity in healthy, young South Asian men but not in Caucasian men. Diabetes 63(1):248–258CrossRefGoogle Scholar
  12. 12.
    Monetti M, Levin MC, Watt MJ, Sajan MP, Marmor S, Hubbard BK, Stevens RD, Bain JR, Newgard CB, Farese RV Sr, Hevener AL, Farese RV Jr (2007) Dissociation of hepatic steatosis and insulin resistance in mice overexpressing DGAT in the liver. Cell Metab 6(1):69–78CrossRefPubMedGoogle Scholar
  13. 13.
    Minehira K, Young SG, Villanueva CJ, Yetukuri L, Oresic M, Hellerstein MK, Farese RV, Horton JD, Preitner F, Thorens B, Tappy L (2008) Blocking VLDL secretion causes hepatic steatosis but does not affect peripheral lipid stores or insulin sensitivity in mice. J Lipid Res 49(9):2038–2044CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Wilson CG, Tran JL, Erion DM, Vera NB, Febbraio M, Weiss EJ (2016) Hepatocyte-specific disruption of CD36 attenuates fatty liver and improves insulin sensitivity in HFD-fed mice. Endocrinology 157(2):570–585CrossRefPubMedGoogle Scholar
  15. 15.
    Koonen DPY, Jacobs RL, Febbraio M, Young ME, Soltys C-LM, Ong H, Vance DE, Dyck JRB (2007) Increased hepatic CD36 expression contributes to dyslipidemia associated with diet-induced obesity. Diabetes 56(12):2863–2871CrossRefPubMedGoogle Scholar
  16. 16.
    Brøns C, Jensen CB, Storgaard H, Hiscock NJ, White A, Appel JS, Jacobsen S, Nilsson E, Larsen CM, Astrup A, Quistorff B, Vaag A (2009) Impact of short-term high-fat feeding on glucose and insulin metabolism in young healthy men. J Physiol 587(10):2387–2397CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Marks KA, Marvyn PM, Henao JJA, Bradley RM, Stark KD, Duncan RE (2015) Fasting enriches liver triacylglycerol with n-3 polyunsaturated fatty acids: implications for understanding the adipose–liver axis in serum docosahexaenoic acid regulation. Genes Nutr 10(6):39CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Heijboer AC, Donga E, Voshol PJ, Dang Z-C, Havekes LM, Romijn JA, Corssmit EPM (2005) Sixteen hours of fasting differentially affects hepatic and muscle insulin sensitivity in mice. J Lipid Res 46(3):582–588CrossRefPubMedGoogle Scholar
  19. 19.
    Langhi C, Baldán Á (2015) CIDEC/Fsp27 is regulated by PPARα and plays a critical role in fasting- and diet-induced hepatosteatosis. Hepatology 61(4):1227–1238CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Buettner R, Parhofer KG, Woenckhaus M, Wrede CE, Kunz-Schughart LA, Schölmerich J, Bollheimer LC (2006) Defining high-fat-diet rat models: metabolic and molecular effects of different fat types. J Mol Endocrinol 36(3):485–501CrossRefPubMedGoogle Scholar
  21. 21.
    Duivenvoorde LPM, van Schothorst EM, Swarts HM, Kuda O, Steenbergh E, Termeulen S, Kopecky J, Keijer J (2015) A difference in fatty acid composition of isocaloric high-fat diets alters metabolic flexibility in male C57BL/6JOlaHsd mice. PLoS ONE 10(6):e0128515CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Nunes PM, Wright AJ, Veltien A, van Asten JJA, Tack CJ, Jones JG, Heerschap A (2014) Dietary lipids do not contribute to the higher hepatic triglyceride levels of fructose-compared to glucose-fed mice. FASEB J 28(5):1988–1997CrossRefPubMedGoogle Scholar
  23. 23.
    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 Investig 115(5):1343–1351CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Jonkers RAM, Geraedts TR, van Loon LJC, Nicolay K, Prompers JJ (2012) Multitissue assessment of in vivo postprandial intracellular lipid partitioning in rats using localized 1H-[13C] magnetic resonance spectroscopy. Magn Reson Med 68(4):997–1006CrossRefPubMedGoogle Scholar
  25. 25.
    Gruetter R, Tkáč I (2000) Field mapping without reference scan using asymmetric echo-planar techniques. Magn Reson Med 43(2):319–323CrossRefPubMedGoogle Scholar
  26. 26.
    Soares AF, Lei H, Gruetter R (2015) Characterization of hepatic fatty acids in mice with reduced liver fat by ultra-short echo time 1H-MRS at 14.1 T in vivo. NMR Biomed 28(8):1009–1020CrossRefPubMedGoogle Scholar
  27. 27.
    Tkáč I, Starčuk Z, Choi IY, Gruetter R (1999) In vivo 1H NMR spectroscopy of rat brain at 1 ms echo time. Magn Reson Med 41(4):649–656CrossRefPubMedGoogle Scholar
  28. 28.
    Ji Y, Sun S, Xia S, Yang L, Li X, Qi L (2012) Short term high fat diet challenge promotes alternative macrophage polarization in adipose tissue via natural killer T cells and interleukin-4. J Biol Chem 287(29):24378–24386CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Lee YS, Li P, Huh JY, Hwang IJ, Lu M, Kim JI, Ham M, Talukdar S, Chen A, Lu WJ, Bandyopadhyay GK, Schwendener R, Olefsky J, Kim JB (2011) Inflammation is necessary for long-term but not short-term high-fat diet-induced insulin resistance. Diabetes 60(10):2474–2483CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Williams LM, Campbell FM, Drew JE, Koch C, Hoggard N, Rees WD, Kamolrat T, Ngo HT, Steffensen I-L, Gray SR, Tups A (2014) The development of diet-induced obesity and glucose intolerance in C57Bl/6 mice on a high-fat diet consists of distinct phases. PLoS ONE 9(8):e106159CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Kowalski GM, Hamley S, Selathurai A, Kloehn J, De Souza DP, O’Callaghan S, Nijagal B, Tull DL, McConville MJ, Bruce CR (2016) Reversing diet-induced metabolic dysregulation by diet switching leads to altered hepatic de novo lipogenesis and glycerolipid synthesis. Sci Rep 6:27541CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Duncan MJ, Smith JT, Narbaiza J, Mueez F, Bustle LB, Qureshi S, Fieseler C, Legan SJ (2016) Restricting feeding to the active phase in middle-aged mice attenuates adverse metabolic effects of a high-fat diet. Physiol Behav 167:1–9CrossRefPubMedGoogle Scholar
  33. 33.
    Delgado TC, Barosa C, Nunes PM, Cerdán S, Geraldes CFGC, Jones JG (2012) Resolving the sources of plasma glucose excursions following a glucose tolerance test in the rat with deuterated water and [U-13C]glucose. PLoS ONE 7(3):e34042CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Stumvoll M, Mitrakou A, Pimenta W, Jenssen T, Yki-Järvinen H, Van Haeften T, Renn W, Gerich J (2000) Use of the oral glucose tolerance test to assess insulin release and insulin sensitivity. Diabetes Care 23(3):295–301CrossRefPubMedGoogle Scholar
  35. 35.
    Häring H-U (2016) Novel phenotypes of prediabetes? Diabetologia 59:1806–1818CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Seppälä-Lindroos A, Vehkavaara S, Häkkinen A-M, Goto T, Westerbacka J, Sovijärvi A, Halavaara J, Yki-Järvinen H (2002) Fat accumulation in the liver is associated with defects in insulin suppression of glucose production and serum free fatty acids independent of obesity in normal men. J Clin Endocrinol Metab 87(7):3023–3028CrossRefPubMedGoogle Scholar
  37. 37.
    Soares AF, Paz-Montoya J, Lei H, Moniatte M, Gruetter R (2017) Sexual dimorphism in hepatic lipids is associated with the evolution of metabolic status in mice. NMR Biomed. doi: 10.1002/nbm.3761 Google Scholar
  38. 38.
    Steneberg P, Sykaras AG, Backlund F, Straseviciene J, Söderström I, Edlund H (2015) Hyperinsulinemia enhances hepatic expression of the fatty acid transporter Cd36 and provokes hepatosteatosis and hepatic insulin resistance. J Biol Chem 290(31):19034–19043CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Liu T-W, Heden TD, Morris EM, Fritsche KL, Vieira-Potter VJ, Thyfault JP (2015) High-fat diet alters serum fatty acid profiles in obesity prone rats: implications for in vitro studies. Lipids 50(10):997–1008CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Raclot T (2003) Selective mobilization of fatty acids from adipose tissue triacylglycerols. Prog Lipid Res 42(4):257–288CrossRefPubMedGoogle Scholar
  41. 41.
    Viljanen APM, Iozzo P, Borra R, Kankaanpää M, Karmi A, Lautamäki R, Järvisalo M, Parkkola R, Rönnemaa T, Guiducci L, Lehtimäki T, Raitakari OT, Mari A, Nuutila P (2009) Effect of weight loss on liver free fatty acid uptake and hepatic insulin resistance. J Clin Endocrinol Metab 94(1):50–55CrossRefPubMedGoogle Scholar
  42. 42.
    Wang Y, Botolin D, Xu J, Christian B, Mitchell E, Jayaprakasam B, Nair M, Peters JM, Busik J, Olson LK, Jump DB (2006) Regulation of hepatic fatty acid elongase and desaturase expression in diabetes and obesity. J Lipid Res 47(9):2028–2041CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Weiss K, Mihály J, Liebisch G, Marosvölgyi T, Garcia AL, Schmitz G, Decsi T, Rühl R (2013) Effect of high versus low doses of fat and vitamin A dietary supplementation on fatty acid composition of phospholipids in mice. Genes Nutr 9(1):368CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Ntambi JM (1992) Dietary regulation of stearoyl-CoA desaturase 1 gene expression in mouse liver. J Biol Chem 267(15):10925–10930PubMedGoogle Scholar
  45. 45.
    Duarte JAG, Carvalho F, Pearson M, Horton JD, Browning JD, Jones JG, Burgess SC (2014) A HFD suppresses de novo lipogenesis and desaturation, but not elongation and triglyceride synthesis in mice. J Lipid Res 55(12):2541–2553CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Oosterveer MH, van Dijk TH, Tietge UJF, Boer T, Havinga R, Stellaard F, Groen AK, Kuipers F, Reijngoud D-J (2009) High fat feeding induces hepatic fatty acid elongation in mice. PLoS ONE 4(6):e6066CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Jaeger D, Schoiswohl G, Hofer P, Schreiber R, Schweiger M, Eichmann TO, Pollak NM, Poecher N, Grabner GF, Zierler KA, Eder S, Kolb D, Radner FPW, Preiss-Landl K, Lass A, Zechner R, Kershaw EE, Haemmerle G (2015) Fasting-induced G0/G1 switch gene 2 and FGF21 expression in the liver are under regulation of adipose tissue derived fatty acids. J Hepatol 63(2):437–445CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Bidar AW, Ploj K, Lelliott C, Nelander K, Winzell MS, Böttcher G, Oscarsson J, Storlien L, Hockings PD (2012) In vivo imaging of lipid storage and regression in diet-induced obesity during nutrition manipulation. Am J Physiol Endocrinol Metab 303(11):E1287–E1295CrossRefPubMedGoogle Scholar
  49. 49.
    Foster MT, Softic S, Caldwell J, Kohli R, deKloet AD, Seeley RJ (2013) Subcutaneous adipose tissue transplantation in diet-induced obese mice attenuates metabolic dysregulation while removal exacerbates it. Physiol Rep 1(2):e00015CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Luu YK, Lublinsky S, Ozcivici E, Capilla E, Pessin JE, Rubin CT, Judex S (2009) In vivo quantification of subcutaneous and visceral adiposity by micro-computed tomography in a small animal model. Med Eng Phys 31(1):34–41CrossRefPubMedGoogle Scholar
  51. 51.
    Valsesia A, Saris WH, Astrup A, Hager J, Masoodi M (2016) Distinct lipid profiles predict improved glycemic control in obese, nondiabetic patients after a low-caloric diet intervention: the diet, obesity and genes randomized trial. Am J Clin Nutr 104(3):566–575CrossRefPubMedGoogle Scholar

Copyright information

© ESMRMB 2017

Authors and Affiliations

  1. 1.Laboratory for Functional and Metabolic ImagingSwiss Federal Institute of TechnologyLausanneSwitzerland
  2. 2.Department of RadiologyUniversity of GenevaGenevaSwitzerland
  3. 3.Department of Radiology, Faculty of Biology and MedicineUniversity of LausanneLausanneSwitzerland

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