Exercise training reduces intrahepatic lipid content in people with and people without nonalcoholic fatty liver

American Journal of Physiology - Endocrinology and Metabolism

Volumn 314, Issue 2, 2018, Pages E165-E173

  Brouwers, Bram ^a,b   Schrauwen Hinderling, Vera B ^a,b   Jelenik, Tomas ^c   Gemmink, Anne ^a,b   Sparks, Lauren M ^e,f   Havekes, Bas ^a,b   Bruls, Yvonne ^a,b   Dahlmans, Dennis ^a,b   Roden, Michael ^c,d   Hesselink, Matthijs K C ^a,b   Schrauwen, Patrick ^a,b  

^a MAASTRICHT UNIVERSITY   (Netherlands)

^b MAASTRICHT UNIVERSITY MEDICAL CENTER   (Netherlands)

^c LEIBNIZ CENTER FOR DIABETES RESEARCH AT HEINRICH HEINE UNIVERSITY DÜSSELDORF   (Germany)

^d HEINRICH HEINE UNIVERSITY   (Germany)

^e FLORIDA HOSPITAL   (United States)

^f BURNHAM INSTITUTE   (United States)

Author keywords

Hyperinsulinemic euglycemic clamp; Insulin resistance; Magnetic resonance spectroscopy

Indexed keywords

ADENOSINE TRIPHOSPHATE; ESTER DERIVATIVE; LIPID; PHOSPHODIESTER; PHOSPHOMONOESTER; PHOSPHORUS; UNCLASSIFIED DRUG;

ADIPOSE TISSUE; ADULT; AEROBIC EXERCISE; AGED; ARTICLE; BODY COMPOSITION; BODY MASS; CLINICAL ARTICLE; CONTROLLED STUDY; CYCLING; ENERGY METABOLISM; EXERCISE TOLERANCE; HUMAN; HYPERINSULINEMIC-EUGLYCEMIC CLAMP TECHNIQUE; INSULIN SENSITIVITY; KINESIOTHERAPY; LIPID ANALYSIS; LIPID LIVER LEVEL; LIVER METABOLISM; MALE; MUSCLE STRENGTH; NONALCOHOLIC FATTY LIVER; NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY; OXYGEN TENSION; PHOSPHORUS MAGNETIC RESONANCE SPECTROSCOPY; PRIORITY JOURNAL; PROTON NUCLEAR MAGNETIC RESONANCE; RESISTANCE TRAINING; THERAPY EFFECT; TREATMENT DURATION; CHEMISTRY; CONTROLLED CLINICAL TRIAL; DOWN REGULATION; EXERCISE; FEMALE; GLUCOSE CLAMP TECHNIQUE; LIPID METABOLISM; LIVER; METABOLISM; MIDDLE AGED; PATHOLOGY; PHYSIOLOGY;

ADULT; AGED; DOWN-REGULATION; EXERCISE; FEMALE; GLUCOSE CLAMP TECHNIQUE; HUMANS; LIPID METABOLISM; LIPIDS; LIVER; MAGNETIC RESONANCE SPECTROSCOPY; MALE; MIDDLE AGED; NON-ALCOHOLIC FATTY LIVER DISEASE;

EID: 85043589015     PISSN: 01931849     EISSN: 15221555     Source Type: Journal    
DOI: 10.1152/ajpendo.00266.2017     Document Type: Article

References (53)

1. Ackermans MT, Pereira Arias AM, Bisschop PH, Endert E, Sauerwein HP, Romijn JA. The quantification of gluconeogenesis in healthy men by (2)H2O and [2-(13)C]glycerol yields different results: rates of gluconeogenesis in healthy men measured with (2)H2O are higher than those measured with [2-(13)C]glycerol. J Clin Endocrinol Metab 86: 2220–2226, 2001.
2. Armstrong MJ, Hazlehurst JM, Hull D, Guo K, Borrows S, Yu J, Gough SC, Newsome PN, Tomlinson JW. Abdominal subcutaneous adipose tissue insulin resistance and lipolysis in patients with non-alcoholic steatohepatitis. Diabetes Obes Metab 16: 651–660, 2014. doi:10. 1111/dom.12272.
3. Bacchi E, Negri C, Targher G, Faccioli N, Lanza M, Zoppini G, Zanolin E, Schena F, Bonora E, Moghetti P. Both resistance training and aerobic training reduce hepatic fat content in type 2 diabetic subjects with NAFLD (The RAED2 randomized trial). Hepatology 58: 1287–1295, 2013. doi:10.1002/hep.26393.
4. Bilet L, Brouwers B, van Ewijk PA, Hesselink MK, Kooi ME, Schrauwen P, Schrauwen-Hinderling VB. Acute exercise does not decrease liver fat in men with overweight or NAFLD. Sci Rep 5: 9709, 2015. doi:10.1038/srep09709.
5. Brouwers B, Hesselink MK, Schrauwen P, Schrauwen-Hinderling VB. Effects of exercise training on intrahepatic lipid content in humans. Diabetologia 59: 2068–2079, 2016. doi:10.1007/s00125-016-4037-x.
6. Brouwers B, Schrauwen-Hinderling VB, Jelenik T, Gemmink A, Havekes B, Bruls Y, Dahlmans D, Roden M, Hesselink MKC, Schrauwen P. Metabolic disturbances of non-alcoholic fatty liver resemble the alterations typical for type 2 diabetes. Clin Sci (Lond) 131: 1905–1917, 2017. doi:10.1042/CS20170261.
7. Browning JD, Baker JA, Rogers T, Davis J, Satapati S, Burgess SC. Short-term weight loss and hepatic triglyceride reduction: evidence of a metabolic advantage with dietary carbohydrate restriction. Am J Clin Nutr 93: 1048–1052, 2011. doi:10.3945/ajcn.110.007674.
8. Caldwell S, Argo C. The natural history of non-alcoholic fatty liver disease. Dig Dis 28: 162–168, 2010. doi:10.1159/000282081.
9. Christ-Roberts CY, Pratipanawatr T, Pratipanawatr W, Berria R, Belfort R, Kashyap S, Mandarino LJ. Exercise training increases glycogen synthase activity and GLUT4 expression but not insulin signaling in overweight nondiabetic and type 2 diabetic subjects. Metabolism 53: 1233–1242, 2004. doi:10.1016/j.metabol.2004.03.022.
10. Cuthbertson DJ, Shojaee-Moradie F, Sprung VS, Jones H, Pugh CJ, Richardson P, Kemp GJ, Barrett M, Jackson NC, Thomas EL, Bell JD, Umpleby AM. Dissociation between exercise-induced reduction in liver fat and changes in hepatic and peripheral glucose homoeostasis in obese patients with non-alcoholic fatty liver disease. Clin Sci (Lond) 130: 93–104, 2016. doi:10.1042/CS20150447.
11. DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol Endocrinol Metab 237: E214–E223, 1979.
12. Eckardt K, Görgens SW, Raschke S, Eckel J. Myokines in insulin resistance and type 2 diabetes. Diabetologia 57: 1087–1099, 2014. doi: 10.1007/s00125-014-3224-x.
13. Fabbrini E, Magkos F, Mohammed BS, Pietka T, Abumrad NA, Patterson BW, Okunade A, Klein S. Intrahepatic fat, not visceral fat, is linked with metabolic complications of obesity. Proc Natl Acad Sci USA 106: 15430–15435, 2009. doi:10.1073/pnas.0904944106.
14. Finegood DT, Bergman RN, Vranic M. Estimation of endogenous glucose production during hyperinsulinemic-euglycemic glucose clamps. Comparison of unlabeled and labeled exogenous glucose infusates. Diabetes 36: 914–924, 1987. doi:10.2337/diab.36.8.914.
15. Goodpaster BH, Delany JP, Otto AD, Kuller L, Vockley J, South-Paul JE, Thomas SB, Brown J, McTigue K, Hames KC, Lang W, Jakicic JM. Effects of diet and physical activity interventions on weight loss and cardiometabolic risk factors in severely obese adults: a randomized trial. JAMA 304: 1795–1802, 2010. doi:10.1001/jama.2010.1505.
16. Groop LC, Bonadonna RC, DelPrato S, Ratheiser K, Zyck K, Ferrannini E, DeFronzo RA. Glucose and free fatty acid metabolism in non-insulin-dependent diabetes mellitus. Evidence for multiple sites of insulin resistance. J Clin Invest 84: 205–213, 1989. doi:10.1172/JCI114142.
17. Guiu B, Petit JM, Loffroy R, Ben Salem D, Aho S, Masson D, Hillon P, Krause D, Cercueil JP. Quantification of liver fat content: comparison of triple-echo chemical shift gradient-echo imaging and in vivo proton MR spectroscopy. Radiology 250: 95–102, 2009. doi:10.1148/radiol.2493080217.
18. Hallsworth K, Fattakhova G, Hollingsworth KG, Thoma C, Moore S, Taylor R, Day CP, Trenell MI. Resistance exercise reduces liver fat and its mediators in non-alcoholic fatty liver disease independent of weight loss. Gut 60: 1278–1283, 2011. doi:10.1136/gut.2011.242073.
19. Hallsworth K, Thoma C, Hollingsworth KG, Cassidy S, Anstee QM, Day CP, Trenell MI. Modified high-intensity interval training reduces liver fat and improves cardiac function in non-alcoholic fatty liver disease: a randomized controlled trial. Clin Sci (Lond) 129: 1097–1105, 2015. doi:10.1042/CS20150308.
20. Hannukainen JC, Borra R, Linderborg K, Kallio H, Kiss J, Lepomäki V, Kalliokoski KK, Kujala UM, Kaprio J, Heinonen OJ, Komu M, Parkkola R, Ahotupa M, Lehtimäki T, Huupponen R, Iozzo P, Nuutila P. Liver and pancreatic fat content and metabolism in healthy monozygotic twins with discordant physical activity. J Hepatol 54: 545– 552, 2011. doi:10.1016/j.jhep.2010.07.029.
21. Hwang JH, Stein DT, Barzilai N, Cui MH, Tonelli J, Kishore P, Hawkins M. Increased intrahepatic triglyceride is associated with peripheral insulin resistance: in vivo MR imaging and spectroscopy studies. Am J Physiol Endocrinol Metab 293: E1663–E1669, 2007. doi:10.1152/ajpendo.00590.2006.
22. Johnson NA, Sachinwalla T, Walton DW, Smith K, Armstrong A, Thompson MW, George J. Aerobic exercise training reduces hepatic and visceral lipids in obese individuals without weight loss. Hepatology 50: 1105–1112, 2009. doi:10.1002/hep.23129.
23. Keating SE, Hackett DA, George J, Johnson NA. Exercise and nonalcoholic fatty liver disease: a systematic review and meta-analysis. J Hepatol 57: 157–166, 2012. doi:10.1016/j.jhep.2012.02.023.
24. Kistler KD, Brunt EM, Clark JM, Diehl AM, Sallis JF, Schwimmer JB, Group NCR; NASH CRN Research Group. Physical activity recommendations, exercise intensity, and histological severity of nonalcoholic fatty liver disease. Am J Gastroenterol 106: 460–468, 2011. doi:10.1038/ajg.2010.488.
25. Korenblat KM, Fabbrini E, Mohammed BS, Klein S. Liver, muscle, and adipose tissue insulin action is directly related to intrahepatic triglyceride content in obese subjects. Gastroenterology 134: 1369–1375, 2008. doi:10.1053/j.gastro.2008.01.075.
26. Kuipers H, Verstappen FT, Keizer HA, Geurten P, van Kranenburg G. Variability of aerobic performance in the laboratory and its physiologic correlates. Int J Sports Med 6: 197–201, 1985. doi:10.1055/s-2008-1025839.
27. Larson-Meyer DE, Heilbronn LK, Redman LM, Newcomer BR, Frisard MI, Anton S, Smith SR, Alfonso A, Ravussin E. Effect of calorie restriction with or without exercise on insulin sensitivity, beta-cell function, fat cell size, and ectopic lipid in overweight subjects. Diabetes Care 29: 1337–1344, 2006. doi:10.2337/dc05-2565.
28. Lazo M, Solga SF, Horska A, Bonekamp S, Diehl AM, Brancati FL, Wagenknecht LE, Pi-Sunyer FX, Kahn SE, Clark JM; Fatty Liver Subgroup of the Look AHEAD Research Group. Effect of a 12-month intensive lifestyle intervention on hepatic steatosis in adults with type 2 diabetes. Diabetes Care 33: 2156–2163, 2010. doi:10.2337/dc10-0856.
29. Lim EL, Hollingsworth KG, Aribisala BS, Chen MJ, Mathers JC, Taylor R. Reversal of type 2 diabetes: normalisation of beta cell function in association with decreased pancreas and liver triacylglycerol. Diabetologia 54: 2506–2514, 2011. doi:10.1007/s00125-011-2204-7.
30. Lindeboom L, Nabuurs CI, Hesselink MK, Wildberger JE, Schrauwen P, Schrauwen-Hinderling VB. Proton magnetic resonance spectroscopy reveals increased hepatic lipid content after a single high-fat meal with no additional modulation by added protein. Am J Clin Nutr 101: 65–71, 2015. doi:10.3945/ajcn.114.094730.
31. Malin SK, Haus JM, Solomon TP, Blaszczak A, Kashyap SR, Kirwan JP. Insulin sensitivity and metabolic flexibility following exercise training among different obese insulin-resistant phenotypes. Am J Physiol Endocrinol Metab 305: E1292–E1298, 2013. doi:10.1152/ajpendo.00441.2013.
32. Meex RC, Schrauwen-Hinderling VB, Moonen-Kornips E, Schaart G, Mensink M, Phielix E, van de Weijer T, Sels JP, Schrauwen P, Hesselink MK. Restoration of muscle mitochondrial function and metabolic flexibility in type 2 diabetes by exercise training is paralleled by increased myocellular fat storage and improved insulin sensitivity. Diabetes 59: 572–579, 2010. doi:10.2337/db09-1322.
33. Ng M, Fleming T, Robinson M, Thomson B, Graetz N, Margono C, Mullany EC, Biryukov S, Abbafati C, Abera SF, Abraham JP, Abu-Rmeileh NM, Achoki T, AlBuhairan FS, Alemu ZA, Alfonso R, Ali MK, Ali R, Guzman NA, Ammar W, Anwari P, Banerjee A, Barquera S, Basu S, Bennett DA, Bhutta Z, Blore J, Cabral N, Nonato IC, Chang JC, Chowdhury R, Courville KJ, Criqui MH, Cundiff DK, Dabhadkar KC, Dandona L, Davis A, Dayama A, Dharmaratne SD, Ding EL, Durrani AM, Esteghamati A, Farzadfar F, Fay DF, Feigin VL, Flaxman A, Forouzanfar MH, Goto A, Green MA, Gupta R, Hafezi-Nejad N, Hankey GJ, Harewood HC, Havmoeller R, Hay S, Hernandez L, Husseini A, Idrisov BT, Ikeda N, Islami F, Jahangir E, Jassal SK, Jee SH, Jeffreys M, Jonas JB, Kabagambe EK, Khalifa SE, Kengne AP, Khader YS, Khang YH, Kim D, Kimokoti RW, Kinge JM, Kokubo Y, Kosen S, Kwan G, Lai T, Leinsalu M, Li Y, Liang X, Liu S, Logroscino G, Lotufo PA, Lu Y, Ma J, Mainoo NK, Mensah GA, Merriman TR, Mokdad AH, Moschandreas J, Naghavi M, Naheed A, Nand D, Narayan KM, Nelson EL, Neuhouser ML, Nisar MI, Ohkubo T, Oti SO, Pedroza A, Prabhakaran D, Roy N, Sampson U, Seo H, Sepanlou SG, Shibuya K, Shiri R, Shiue I, Singh GM, Singh JA, Skirbekk V, Stapelberg NJ, Sturua L, Sykes BL, Tobias M, Tran BX, Trasande L, Toyoshima H, van de Vijver S, Vasankari TJ, Veerman JL, Velasquez-Melendez G, Vlassov VV, Vollset SE, Vos T, Wang C, Wang X, Weiderpass E, Werdecker A, Wright JL, Yang YC, Yatsuya H, Yoon J, Yoon SJ, Zhao Y, Zhou M, Zhu S, Lopez AD, Murray CJ, Gakidou E. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 384: 766–781, 2014. doi:10.1016/S0140-6736(14)60460-8.
34. Oh S, So R, Shida T, Matsuo T, Kim B, Akiyama K, Isobe T, Okamoto Y, Tanaka K, Shoda J. High-intensity aerobic exercise improves both hepatic fat content and stiffness in sedentary obese men with nonalcoholic fatty liver disease. Sci Rep 7: 43029, 2017. doi:10.1038/srep43029.
35. Pedersen BK, Febbraio MA. Muscles, exercise and obesity: skeletal muscle as a secretory organ. Nat Rev Endocrinol 8: 457–465, 2012. doi:10.1038/nrendo.2012.49.
36. Peronnet F, Massicotte D. Table of nonprotein respiratory quotient: an update. Can J Sport Sci 16: 23–29, 1991.
37. Petersen KF, Dufour S, Befroy D, Lehrke M, Hendler RE, Shulman GI. Reversal of nonalcoholic hepatic steatosis, hepatic insulin resistance, and hyperglycemia by moderate weight reduction in patients with type 2 diabetes. Diabetes 54: 603–608, 2005. doi:10.2337/diabetes.54.3.603.
38. Reynolds JM, Gordon TJ, Robergs RA. Prediction of one repetition maximum strength from multiple repetition maximum testing and anthropometry. J Strength Cond Res 20: 584–592, 2006. doi:10.1519/R-15304.1.
39. Schmid AI, Szendroedi J, Chmelik M, Krssák M, Moser E, Roden M. Liver ATP synthesis is lower and relates to insulin sensitivity in patients with type 2 diabetes. Diabetes Care 34: 448–453, 2011. doi:10.2337/dc10-1076.
40. Schrauwen-Hinderling VB, Kooi ME, Hesselink MK, Jeneson JA, Backes WH, van Echteld CJ, van Engelshoven JM, Mensink M, Schrauwen P. Impaired in vivo mitochondrial function but similar intramyocellular lipid content in patients with type 2 diabetes mellitus and BMI-matched control subjects. Diabetologia 50: 113–120, 2007. doi:10. 1007/s00125-006-0475-1.
41. Sevastianova K, Hakkarainen A, Kotronen A, Cornér A, Arkkila P, Arola J, Westerbacka J, Bergholm R, Lundbom J, Lundbom N, Yki-Järvinen H. Nonalcoholic fatty liver disease: detection of elevated nicotinamide adenine dinucleotide phosphate with in vivo 3.0-T 31P MR spectroscopy with proton decoupling. Radiology 256: 466–473, 2010. doi:10.1148/radiol.10091351.
42. Shah K, Stufflebam A, Hilton TN, Sinacore DR, Klein S, Villareal DT. Diet and exercise interventions reduce intrahepatic fat content and improve insulin sensitivity in obese older adults. Obesity (Silver Spring) 17: 2162–2168, 2009. doi:10.1038/oby.2009.126.
43. Shojaee-Moradie F, Baynes KC, Pentecost C, Bell JD, Thomas EL, Jackson NC, Stolinski M, Whyte M, Lovell D, Bowes SB, Gibney J, Jones RH, Umpleby AM. Exercise training reduces fatty acid availability and improves the insulin sensitivity of glucose metabolism. Diabetologia 50: 404–413, 2007. doi:10.1007/s00125-006-0498-7.
44. Steele R. Influences of glucose loading and of injected insulin on hepatic glucose output. Ann N Y Acad Sci 82: 420–430, 1959. doi:10.1111/j.1749-6632.1959.tb44923.x.
45. Sullivan S, Kirk EP, Mittendorfer B, Patterson BW, Klein S. Randomized trial of exercise effect on intrahepatic triglyceride content and lipid kinetics in nonalcoholic fatty liver disease. Hepatology 55: 1738– 1745, 2012. doi:10.1002/hep.25548.
46. Szczepaniak LS, Nurenberg P, Leonard D, Browning JD, Reingold JS, Grundy S, Hobbs HH, Dobbins RL. Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population. Am J Physiol Endocrinol Metab 288: E462–E468, 2005. doi:10.1152/ajpendo.00064.2004.
47. Szendroedi J, Chmelik M, Schmid AI, Nowotny P, Brehm A, Krssak M, Moser E, Roden M. Abnormal hepatic energy homeostasis in type 2 diabetes. Hepatology 50: 1079–1086, 2009. doi:10.1002/hep.23093.
48. Tilg H, Moschen AR, Roden M. NAFLD and diabetes mellitus. Nat Rev Gastroenterol Hepatol 14: 32–42, 2017. doi:10.1038/nrgastro.2016.147.
49. Utzschneider KM, Kahn SE. Review: The role of insulin resistance in nonalcoholic fatty liver disease. J Clin Endocrinol Metab 91: 4753–4761, 2006. doi:10.1210/jc.2006-0587.
50. van der Heijden GJ, Wang ZJ, Chu ZD, Sauer PJ, Haymond MW, Rodriguez LM, Sunehag AL. A 12-week aerobic exercise program reduces hepatic fat accumulation and insulin resistance in obese, Hispanic adolescents. Obesity (Silver Spring) 18: 384–390, 2010. doi:10.1038/oby.2009.274.
51. van de Weijer T, Phielix E, Bilet L, Williams EG, Ropelle ER, Bierwagen A, Livingstone R, Nowotny P, Sparks LM, Paglialunga S, Szendroedi J, Havekes B, Moullan N, Pirinen E, Hwang JH, Schrauwen-Hinderling VB, Hesselink MK, Auwerx J, Roden M, Schrauwen P. Evidence for a direct effect of the NAD+ precursor acipimox on muscle mitochondrial function in humans. Diabetes 64: 1193–1201, 2015. doi:10.2337/db14-0667.
52. World Health Organization and International Diabetes Federation. Definition and Diagnosis of Diabetes Mellitus and Intermediate Hyperglycaemia: Report of a WHO/IDF Consultation. Geneva, Switzerland: World Health Organization, 2006.
53. Yokoyama H, Mori K, Emoto M, Araki T, Teramura M, Mochizuki K, Tashiro T, Motozuka K, Inoue Y, Nishizawa Y. Non-oxidative glucose disposal is reduced in type 2 diabetes, but can be restored by aerobic exercise. Diabetes Obes Metab 10: 400–407, 2008. doi:10.1111/j.1463-1326.2007.00716.x.