Advertisement

Basic Research in Cardiology

, 108:369 | Cite as

Age-dependent effects of high fat-diet on murine left ventricles: role of palmitate

  • Anne-Cathleen Aurich
  • Bernd Niemann
  • Ruping Pan
  • Stefanie Gruenler
  • Hassan Issa
  • Rolf-Edgar Silber
  • Susanne RohrbachEmail author
Original Contribution

Abstract

Obesity-associated heart disease results in myocardial lipid accumulation leading to lipotoxicity. However, recent studies are suggestive of protective effects of high-fat diets (HFD). To determine whether age results in differential changes in diet-induced obesity, we fed young and old (3 and 18 months) male C57Bl/6 mice control diet, low-fat diet (both 10 kcal% fat) or HFD (45 kcal% fat) for 16 weeks, after which we analyzed LV function, mitochondrial changes, and potential modifiers of myocardial structure. HFD or age did not change LV systolic function, although a mildly increased BNP was observed in all old mice. This was associated with increased myocardial collagen, triglyceride, diacylglycerol, and ceramide content as well as higher caspase 3 activation in old mice with highest levels in old HFD mice. Pyruvate-dependent respiration and mitochondrial biogenesis were reduced in all old mice and in young HFD mice. Activation of AMPK, a strong inducer of mitochondrial biogenesis, was reduced in both HFD groups and in old control or LFD mice. Cardiomyocytes from old rats demonstrated significantly reduced AMPK activation, impaired mitochondrial biogenesis, higher ceramide content, and reduced viability after palmitate (C16:0) in vitro, while no major deleterious effects were observed in young cardiomyocytes. Aged but not young cardiomyocytes were unable to respond to higher palmitate with increased fatty acid oxidation. Thus, HFD results in cardiac structural alterations and accumulation of lipid intermediates predominantly in old mice, possibly due to the inability of old cardiomyocytes to adapt to high-fatty acid load.

Keywords

Lipotoxicity Mitochondria Aging Obesity Palmitic acid 

Notes

Acknowledgments

This study was supported by the DFG (RO 2328/2-1) and Deutsche Stiftung für Herzforschung (F/05/05). We appreciate the technical assistance of R. Gall, B. Heinze and D. Schreiber.

Conflict of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

Supplementary material

395_2013_369_MOESM1_ESM.pdf (272 kb)
Supplementary material 1 (PDF 273 kb)

References

  1. 1.
    Abu-Erreish GM, Neely JR, Whitmer JT, Whitman V, Sanadi DR (1977) Fatty acid oxidation by isolated perfused working hearts of aged rats. Am J Physiol 232:E258–E262PubMedGoogle Scholar
  2. 2.
    Alon T, Friedman JM, Socci ND (2003) Cytokine-induced patterns of gene expression in skeletal muscle tissue. J Biol Chem 278:32324–32334. doi: 10.1074/jbc.M300972200 PubMedCrossRefGoogle Scholar
  3. 3.
    Barger PM, Kelly DP (2000) PPAR signaling in the control of cardiac energy metabolism. Trends Cardiovasc Med 10:238–245 [pii]:S1050-1738(00)00077-3PubMedCrossRefGoogle Scholar
  4. 4.
    Carmona A, Freedland RA (1989) Comparison among the lipogenic potential of various substrates in rat hepatocytes: the differential effects of fructose-containing diets on hepatic lipogenesis. J Nutr 119:1304–1310PubMedGoogle Scholar
  5. 5.
    Chess DJ, Khairallah RJ, O’Shea KM, Xu W, Stanley WC (2009) A high-fat diet increases adiposity but maintains mitochondrial oxidative enzymes without affecting development of heart failure with pressure overload. Am J Physiol Heart Circ Physiol 297:H1585–H1593. doi: 10.1152/ajpheart.00599.2009 PubMedCrossRefGoogle Scholar
  6. 6.
    Chiu HC, Kovacs A, Ford DA, Hsu FF, Garcia R, Herrero P, Saffitz JE, Schaffer JE (2001) A novel mouse model of lipotoxic cardiomyopathy. J Clin Invest 107:813–822. doi: 10.1172/JCI10947 PubMedCrossRefGoogle Scholar
  7. 7.
    Cole MA, Murray AJ, Cochlin LE, Heather LC, McAleese S, Knight NS, Sutton E, Jamil AA, Parassol N, Clarke K (2011) A high fat diet increases mitochondrial fatty acid oxidation and uncoupling to decrease efficiency in rat heart. Basic Res Cardiol 106:447–457. doi: 10.1007/s00395-011-0156-1 PubMedCrossRefGoogle Scholar
  8. 8.
    D’Alessandro ME, Chicco A, Lombardo YB (2008) Dietary fish oil reverses lipotoxicity, altered glucose metabolism, and nPKCepsilon translocation in the heart of dyslipemic insulin-resistant rats. Metabolism 57:911–919 [pii]:S0026-0495(08)00076-0PubMedCrossRefGoogle Scholar
  9. 9.
    Davies SP, Carling D, Hardie DG (1989) Tissue distribution of the AMP-activated protein kinase, and lack of activation by cyclic-AMP-dependent protein kinase, studied using a specific and sensitive peptide assay. Eur J Biochem 186:123–128PubMedCrossRefGoogle Scholar
  10. 10.
    Degens H, de Brouwer KF, Gilde AJ, Lindhout M, Willemsen PH, Janssen BJ, van der Vusse GJ, van Bilsen M (2006) Cardiac fatty acid metabolism is preserved in the compensated hypertrophic rat heart. Basic Res Cardiol 101:17–26. doi: 10.1007/s00395-005-0549-0 PubMedCrossRefGoogle Scholar
  11. 11.
    Dong F, Li Q, Sreejayan N, Nunn JM, Ren J (2007) Metallothionein prevents high-fat diet induced cardiac contractile dysfunction: role of peroxisome proliferator activated receptor gamma coactivator 1alpha and mitochondrial biogenesis. Diabetes 56:2201–2212. doi: 10.2337/db06-1596 PubMedCrossRefGoogle Scholar
  12. 12.
    Dressler KA, Kolesnick RN (1990) Ceramide 1-phosphate, a novel phospholipid in human leukemia (HL-60) cells. Synthesis via ceramide from sphingomyelin. J Biol Chem 265:14917–14921PubMedGoogle Scholar
  13. 13.
    Dutta K, Podolin DA, Davidson MB, Davidoff AJ (2001) Cardiomyocyte dysfunction in sucrose-fed rats is associated with insulin resistance. Diabetes 50:1186–1192PubMedCrossRefGoogle Scholar
  14. 14.
    Fang CX, Dong F, Thomas DP, Ma H, He L, Ren J (2008) Hypertrophic cardiomyopathy in high-fat diet-induced obesity: role of suppression of forkhead transcription factor and atrophy gene transcription. Am J Physiol Heart Circ Physiol 295:H1206–H1215. doi: 10.1152/ajpheart.00319.2008 PubMedCrossRefGoogle Scholar
  15. 15.
    Fang X, Fetros J, Dadson KE, Xu A, Sweeney G (2009) Leptin prevents the metabolic effects of adiponectin in L6 myotubes. Diabetologia 52:2190–2200. doi: 10.1007/s00125-009-1462-0 PubMedCrossRefGoogle Scholar
  16. 16.
    Fang X, Palanivel R, Cresser J, Schram K, Ganguly R, Thong FS, Tuinei J, Xu A, Abel ED, Sweeney G (2010) An APPL1-AMPK signaling axis mediates beneficial metabolic effects of adiponectin in the heart. Am J Physiol Endocrinol Metab 299:E721–E729. doi: 10.1152/ajpendo.00086.2010 PubMedCrossRefGoogle Scholar
  17. 17.
    Finck BN, Han X, Courtois M, Aimond F, Nerbonne JM, Kovacs A, Gross RW, Kelly DP (2003) A critical role for PPARalpha-mediated lipotoxicity in the pathogenesis of diabetic cardiomyopathy: modulation by dietary fat content. Proc Natl Acad Sci USA 100:1226–1231. doi: 10.1073/pnas.0336724100 PubMedCrossRefGoogle Scholar
  18. 18.
    Flachs P, Horakova O, Brauner P, Rossmeisl M, Pecina P, Franssen-van Hal N, Ruzickova J, Sponarova J, Drahota Z, Vlcek C, Keijer J, Houstek J, Kopecky J (2005) Polyunsaturated fatty acids of marine origin upregulate mitochondrial biogenesis and induce beta-oxidation in white fat. Diabetologia 48:2365–2375. doi: 10.1007/s00125-005-1944-7 PubMedCrossRefGoogle Scholar
  19. 19.
    Flachs P, Mohamed-Ali V, Horakova O, Rossmeisl M, Hosseinzadeh-Attar MJ, Hensler M, Ruzickova J, Kopecky J (2006) Polyunsaturated fatty acids of marine origin induce adiponectin in mice fed a high-fat diet. Diabetologia 49:394–397. doi: 10.1007/s00125-005-0053-y PubMedCrossRefGoogle Scholar
  20. 20.
    Galvao TF, Brown BH, Hecker PA, O’Connell KA, O’Shea KM, Sabbah HN, Rastogi S, Daneault C, Des Rosiers C, Stanley WC (2012) High intake of saturated fat, but not polyunsaturated fat, improves survival in heart failure despite persistent mitochondrial defects. Cardiovasc Res 93:24–32. doi: 10.1093/cvr/cvr258 PubMedCrossRefGoogle Scholar
  21. 21.
    Ge F, Hu C, Hyodo E, Arai K, Zhou S, Lobdell H IV, Walewski JL, Homma S, Berk PD (2012) Cardiomyocyte triglyceride accumulation and reduced ventricular function in mice with obesity reflect increased long chain fatty acid uptake and de novo fatty acid synthesis. J Obes 2012:205648. doi: 10.1155/2012/205648 PubMedCrossRefGoogle Scholar
  22. 22.
    Gonsolin D, Couturier K, Garait B, Rondel S, Novel-Chate V, Peltier S, Faure P, Gachon P, Boirie Y, Keriel C, Favier R, Pepe S, Demaison L, Leverve X (2007) High dietary sucrose triggers hyperinsulinemia, increases myocardial beta-oxidation, reduces glycolytic flux and delays post-ischemic contractile recovery. Mol Cell Biochem 295:217–228. doi: 10.1007/s11010-006-9291-7 PubMedCrossRefGoogle Scholar
  23. 23.
    Gonzalez AA, Kumar R, Mulligan JD, Davis AJ, Saupe KW (2004) Effects of aging on cardiac and skeletal muscle AMPK activity: basal activity, allosteric activation, and response to in vivo hypoxemia in mice. Am J Physiol Regul Integr Comp Physiol 287:R1270–R1275. doi: 10.1152/ajpregu.00409.2004 PubMedCrossRefGoogle Scholar
  24. 24.
    Hansford RG (1978) Lipid oxidation by heart mitochondria from young adult and senescent rats. Biochem J 170:285–295PubMedGoogle Scholar
  25. 25.
    Jager S, Handschin C, St-Pierre J, Spiegelman BM (2007) AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha. Proc Natl Acad Sci USA 104:12017–12022. doi: 10.1073/pnas.0705070104 PubMedCrossRefGoogle Scholar
  26. 26.
    Kahn BB, Alquier T, Carling D, Hardie DG (2005) AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism. Cell Metab 1:15–25. doi: 10.1016/j.cmet.2004.12.003 PubMedCrossRefGoogle Scholar
  27. 27.
    Kim JE, Song SE, Kim YW, Kim JY, Park SC, Park YK, Baek SH, Lee IK, Park SY (2010) Adiponectin inhibits palmitate-induced apoptosis through suppression of reactive oxygen species in endothelial cells: involvement of cAMP/protein kinase A and AMP-activated protein kinase. J Endocrinol 207:35–44. doi: 10.1677/JOE-10-0093 PubMedCrossRefGoogle Scholar
  28. 28.
    Li L, Muhlfeld C, Niemann B, Pan R, Li R, Hilfiker-Kleiner D, Chen Y, Rohrbach S (2011) Mitochondrial biogenesis and PGC-1alpha deacetylation by chronic treadmill exercise: differential response in cardiac and skeletal muscle. Basic Res Cardiol 106:1221–1234. doi: 10.1007/s00395-011-0213-9 PubMedCrossRefGoogle Scholar
  29. 29.
    Li L, Pan R, Li R, Niemann B, Aurich AC, Chen Y, Rohrbach S (2011) Mitochondrial biogenesis and peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) deacetylation by physical activity: intact adipocytokine signaling is required. Diabetes 60:157–167. doi: 10.2337/db10-0331 PubMedCrossRefGoogle Scholar
  30. 30.
    Loskovich MV, Grivennikova VG, Cecchini G, Vinogradov AD (2005) Inhibitory effect of palmitate on the mitochondrial NADH: ubiquinone oxidoreductase (complex I) as related to the active-de-active enzyme transition. Biochem J 387:677–683. doi: 10.1042/BJ20041703 PubMedCrossRefGoogle Scholar
  31. 31.
    McMillin JB, Taffet GE, Taegtmeyer H, Hudson EK, Tate CA (1993) Mitochondrial metabolism and substrate competition in the aging fischer rat heart. Cardiovasc Res 27:2222–2228. doi: 10.1093/cvr/27.12.2222 PubMedCrossRefGoogle Scholar
  32. 32.
    Miller TA, LeBrasseur NK, Cote GM, Trucillo MP, Pimentel DR, Ido Y, Ruderman NB, Sawyer DB (2005) Oleate prevents palmitate-induced cytotoxic stress in cardiac myocytes. Biochem Biophys Res Commun 336:309–315. doi: 10.1016/j.bbrc.2005.08.088 PubMedCrossRefGoogle Scholar
  33. 33.
    Minokoshi Y, Kim YB, Peroni OD, Fryer LG, Muller C, Carling D, Kahn BB (2002) Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase. Nature 415:339–343. doi: 10.1038/415339a PubMedCrossRefGoogle Scholar
  34. 34.
    Nascimento AF, Luvizotto RA, Leopoldo AS, Lima-Leopoldo AP, Seiva FR, Justulin LA Jr, Silva MD, Okoshi K, Wang XD, Cicogna AC (2011) Long-term high-fat diet-induced obesity decreases the cardiac leptin receptor without apparent lipotoxicity. Life Sci 88:1031–1038. doi: 10.1016/j.lfs.2011.03.015 PubMedCrossRefGoogle Scholar
  35. 35.
    Niemann B, Chen Y, Issa H, Silber RE, Rohrbach S (2010) Caloric restriction delays cardiac ageing in rats: role of mitochondria. Cardiovasc Res 88:267–276. doi: 10.1093/cvr/cvq273 PubMedCrossRefGoogle Scholar
  36. 36.
    Niemann B, Chen Y, Teschner M, Li L, Silber RE, Rohrbach S (2011) Obesity induces signs of premature cardiac aging in younger patients: the role of mitochondria. J Am Coll Cardiol 57:577–585. doi: 10.1016/j.jacc.2010.09.040 PubMedCrossRefGoogle Scholar
  37. 37.
    Nunes S, Soares E, Fernandes J, Viana S, Carvalho E, Pereira FC, Reis F (2013) Early cardiac changes in a rat model of prediabetes: brain natriuretic peptide overexpression seems to be the best marker. Cardiovasc Diabetol 12:44 [pii]:1475-2840-12-44PubMedCrossRefGoogle Scholar
  38. 38.
    Okere IC, Chandler MP, McElfresh TA, Rennison JH, Sharov V, Sabbah HN, Tserng KY, Hoit BD, Ernsberger P, Young ME, Stanley WC (2006) Differential effects of saturated and unsaturated fatty acid diets on cardiomyocyte apoptosis, adipose distribution, and serum leptin. Am J Physiol Heart Circ Physiol 291:H38–H44. doi: 10.1152/ajpheart.01295.2005 PubMedCrossRefGoogle Scholar
  39. 39.
    Park TS, Hu Y, Noh HL, Drosatos K, Okajima K, Buchanan J, Tuinei J, Homma S, Jiang XC, Abel ED, Goldberg IJ (2008) Ceramide is a cardiotoxin in lipotoxic cardiomyopathy. J Lipid Res 49:2101–2112. doi: 10.1194/jlr.M800147-JLR200 [pii]PubMedCrossRefGoogle Scholar
  40. 40.
    Preiss J, Loomis CR, Bishop WR, Stein R, Niedel JE, Bell RM (1986) Quantitative measurement of sn-1,2-diacylglycerols present in platelets, hepatocytes, and ras- and sis-transformed normal rat kidney cells. J Biol Chem 261:8597–8600PubMedGoogle Scholar
  41. 41.
    Randle PJ, Garland PB, Hales CN, Newsholme EA (1963) The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet 1:785–789PubMedCrossRefGoogle Scholar
  42. 42.
    Rennison JH, McElfresh TA, Okere IC, Patel HV, Foster AB, Patel KK, Stoll MS, Minkler PE, Fujioka H, Hoit BD, Young ME, Hoppel CL, Chandler MP (2008) Enhanced acyl-CoA dehydrogenase activity is associated with improved mitochondrial and contractile function in heart failure. Cardiovasc Res 79:331–340. doi: 10.1093/cvr/cvn066 PubMedCrossRefGoogle Scholar
  43. 43.
    Rennison JH, McElfresh TA, Okere IC, Vazquez EJ, Patel HV, Foster AB, Patel KK, Chen Q, Hoit BD, Tserng KY, Hassan MO, Hoppel CL, Chandler MP (2007) High-fat diet postinfarction enhances mitochondrial function and does not exacerbate left ventricular dysfunction. Am J Physiol Heart Circ Physiol 292:H1498–H1506. doi: 10.1152/ajpheart.01021.2006 PubMedCrossRefGoogle Scholar
  44. 44.
    Rohrbach S, Niemann B, Abushouk AM, Holtz J (2006) Caloric restriction and mitochondrial function in the ageing myocardium. Exp Gerontol 41:525–531. doi: 10.1016/j.exger.2006.02.001 PubMedCrossRefGoogle Scholar
  45. 45.
    Sparks LM, Xie H, Koza RA, Mynatt R, Hulver MW, Bray GA, Smith SR (2005) A high-fat diet coordinately downregulates genes required for mitochondrial oxidative phosphorylation in skeletal muscle. Diabetes 54:1926–1933. doi: 10.2337/diabetes.54.7.1926 PubMedCrossRefGoogle Scholar
  46. 46.
    Stanley WC, Dabkowski ER, Ribeiro RF Jr, O’Connell KA (2012) Dietary fat and heart failure: moving from lipotoxicity to lipoprotection. Circ Res 110:764–776. doi: 10.1161/CIRCRESAHA.111.253104 PubMedCrossRefGoogle Scholar
  47. 47.
    Steinberg GR, Rush JW, Dyck DJ (2003) AMPK expression and phosphorylation are increased in rodent muscle after chronic leptin treatment. Am J Physiol Endocrinol Metab 284:E648–E654. doi: 10.1152/ajpendo.00318.2002 PubMedGoogle Scholar
  48. 48.
    Stride N, Larsen S, Treebak JT, Hansen CN, Hey-Mogensen M, Speerschneider T, Jensen TE, Jeppesen J, Wojtaszewski JF, Richter EA, Kober L, Dela F (2012) 5′-AMP activated protein kinase is involved in the regulation of myocardial beta-oxidative capacity in mice. Front Physiol 3:33. doi: 10.3389/fphys.2012.00033 PubMedCrossRefGoogle Scholar
  49. 49.
    Szczepaniak LS, Victor RG, Orci L, Unger RH (2007) Forgotten but not gone: the rediscovery of fatty heart, the most common unrecognized disease in America. Circ Res 101:759–767. doi: 10.1161/CIRCRESAHA.107.160457 PubMedCrossRefGoogle Scholar
  50. 50.
    Turdi S, Fan X, Li J, Zhao J, Huff AF, Du M, Ren J (2010) AMP-activated protein kinase deficiency exacerbates aging-induced myocardial contractile dysfunction. Aging Cell 9:592–606. doi: 10.1111/j.1474-9726.2010.00586.x PubMedCrossRefGoogle Scholar
  51. 51.
    Turdi S, Kandadi MR, Zhao J, Huff AF, Du M, Ren J (2011) Deficiency in AMP-activated protein kinase exaggerates high fat diet-induced cardiac hypertrophy and contractile dysfunction. J Mol Cell Cardiol 50:712–722. doi: 10.1111/j.1474-9726.2010.00586.x PubMedCrossRefGoogle Scholar
  52. 52.
    Turner N, Bruce CR, Beale SM, Hoehn KL, So T, Rolph MS, Cooney GJ (2007) Excess lipid availability increases mitochondrial fatty acid oxidative capacity in muscle: evidence against a role for reduced fatty acid oxidation in lipid-induced insulin resistance in rodents. Diabetes 56:2085–2092. doi: 10.2337/db07-0093 PubMedCrossRefGoogle Scholar
  53. 53.
    Unger RH (2005) Hyperleptinemia: protecting the heart from lipid overload. Hypertension 45:1031–1034. doi: 10.1161/01.HYP.0000165683.09053.02 PubMedCrossRefGoogle Scholar
  54. 54.
    Unger RH (2002) Lipotoxic diseases. Annu Rev Med 53:319–336. doi: 10.1146/annurev.med.53.082901.104057 PubMedCrossRefGoogle Scholar
  55. 55.
    Wilson CR, Tran MK, Salazar KL, Young ME, Taegtmeyer H (2007) Western diet, but not high fat diet, causes derangements of fatty acid metabolism and contractile dysfunction in the heart of Wistar rats. Biochem J 406:457–467. doi: 10.1042/BJ20070392 PubMedCrossRefGoogle Scholar
  56. 56.
    Yamauchi T, Kamon J, Minokoshi Y, Ito Y, Waki H, Uchida S, Yamashita S, Noda M, Kita S, Ueki K, Eto K, Akanuma Y, Froguel P, Foufelle F, Ferre P, Carling D, Kimura S, Nagai R, Kahn BB, Kadowaki T (2002) Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med 8:1288–1295. doi: 10.1038/nm788 PubMedCrossRefGoogle Scholar
  57. 57.
    Yang C, Aye CC, Li X, Diaz Ramos A, Zorzano A, Mora S (2012) Mitochondrial dysfunction in insulin resistance: differential contributions of chronic insulin and saturated fatty acid exposure in muscle cells. Biosci Rep 32:465–478. doi: 10.1042/BSR20120034 PubMedCrossRefGoogle Scholar
  58. 58.
    Zhang L, Ussher JR, Oka T, Cadete VJ, Wagg C, Lopaschuk GD (2011) Cardiac diacylglycerol accumulation in high fat-fed mice is associated with impaired insulin-stimulated glucose oxidation. Cardiovasc Res 89:148–156. doi: 10.1093/cvr/cvq266 PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Anne-Cathleen Aurich
    • 1
  • Bernd Niemann
    • 2
    • 4
  • Ruping Pan
    • 1
    • 5
  • Stefanie Gruenler
    • 1
  • Hassan Issa
    • 3
  • Rolf-Edgar Silber
    • 2
  • Susanne Rohrbach
    • 1
    • 5
    Email author
  1. 1.Institute of PathophysiologyMartin Luther University Halle-WittenbergHalleGermany
  2. 2.Department of Cardiothoracic SurgeryMartin Luther University Halle-WittenbergHalleGermany
  3. 3.Department of Pediatric CardiologyMartin Luther University Halle-WittenbergHalleGermany
  4. 4.Department of Cardiac and Vascular SurgeryJustus Liebig University GiessenGiessenGermany
  5. 5.Institute of PhysiologyJustus Liebig University GiessenGiessenGermany

Personalised recommendations