Semin Liver Dis 2012; 32(01): 065-079
DOI: 10.1055/s-0032-1306427
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Exercise and the Liver: Implications for Therapy in Fatty Liver Disorders

Nathan A. Johnson
1   Discipline of Exercise and Sport Science, University of Sydney, Australia
2   Boden Institute of Obesity, Nutrition, Exercise & Eating Disorders, University of Sydney, Australia
,
Shelley E. Keating
1   Discipline of Exercise and Sport Science, University of Sydney, Australia
,
Jacob George
3   Storr Liver Unit, Westmead Millennium Institute and Westmead Hospital, University of Sydney, Australia.
› Author Affiliations
Further Information

Publication History

Publication Date:
13 March 2012 (online)

Abstract

The increasing recognition that fatty liver plays a direct role in the pathogenesis of cardiovascular and metabolic disease has resulted in significant research enquiry into the efficacy of lifestyle therapy in modulating liver fat. Recently, this has extended to the specific investigation of a possible independent benefit of physical activity/exercise in nonalcoholic fatty liver disease (NAFLD). In this article we review the effect of acute and regular exercise (training) on metabolism, including liver glucose and lipid metabolism, and the available human trials that have compared the benefit of regular exercise versus a nonexercise control on liver fat. The limited human research suggests that exercise can reduce liver fat and that this benefit may be mediated, in part, by a reduction in hepatic lipogenesis. The relative importance of extrahepatic adaptations and acute versus regular exercise in explaining this benefit are discussed. From a clinical perspective, the revelation of a benefit of exercise per se offers a novel approach for liver fat reduction, and highlights the importance of incorporating fitness assessment and prescription in the management of patients with fatty liver disorders. Implementation of exercise therapy in a clinical setting is arguably the biggest challenge because evidence shows that mere provision of information about the benefits of exercise and/or exercise prescription to the patient does not translate to positive outcomes. Rather, the focus should be on implementing strategies to promote behavior change including regular contact and assessment with a health care professional, self-monitoring, and personalization of goals that focus on changing physical activity behavior.

 
  • References

  • 1 Browning JD, Szczepaniak LS, Dobbins R , et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 2004; 40 (6) 1387-1395
  • 2 Szczepaniak LS, Nurenberg P, Leonard D , et al. Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population. Am J Physiol Endocrinol Metab 2005; 288 (2) E462-E468
  • 3 Bellentani S, Saccoccio G, Masutti F , et al. Prevalence of and risk factors for hepatic steatosis in Northern Italy. Ann Intern Med 2000; 132 (2) 112-117
  • 4 Targher G, Bertolini L, Poli F , et al. Nonalcoholic fatty liver disease and risk of future cardiovascular events among type 2 diabetic patients. Diabetes 2005; 54 (12) 3541-3546
  • 5 Yki-Järvinen H. Fat in the liver and insulin resistance. Ann Med 2005; 37 (5) 347-356
  • 6 Hoppeler H, Howald H, Conley K , et al. Endurance training in humans: aerobic capacity and structure of skeletal muscle. J Appl Physiol 1985; 59 (2) 320-327
  • 7 Holloszy JO. Biochemical adaptations in muscle. Effects of exercise on mitochondrial oxygen uptake and respiratory enzyme activity in skeletal muscle. J Biol Chem 1967; 242 (9) 2278-2282
  • 8 Bergström J, Hermansen L, Hultman E, Saltin B. Diet, muscle glycogen and physical performance. Acta Physiol Scand 1967; 71 (2) 140-150
  • 9 Wahren J, Felig P, Hendler R, Ahlborg G. Glucose and amino acid metabolism during recovery after exercise. J Appl Physiol 1973; 34 (6) 838-845
  • 10 Thorell A, Hirshman MF, Nygren J , et al. Exercise and insulin cause GLUT-4 translocation in human skeletal muscle. Am J Physiol 1999; 277 (4 Pt 1) E733-E741
  • 11 Winder WW. Energy-sensing and signaling by AMP-activated protein kinase in skeletal muscle. J Appl Physiol 2001; 91 (3) 1017-1028
  • 12 Ahlborg G, Felig P, Hagenfeldt L, Hendler R, Wahren J. Substrate turnover during prolonged exercise in man. Splanchnic and leg metabolism of glucose, free fatty acids, and amino acids. J Clin Invest 1974; 53 (4) 1080-1090
  • 13 Kjaer M, Engfred K, Fernandes A, Secher NH, Galbo H. Regulation of hepatic glucose production during exercise in humans: role of sympathoadrenergic activity. Am J Physiol 1993; 265 (2 Pt 1) E275-E283
  • 14 Wasserman DH, Spalding JA, Lacy DB, Colburn CA, Goldstein RE, Cherrington AD. Glucagon is a primary controller of hepatic glycogenolysis and gluconeogenesis during muscular work. Am J Physiol 1989; 257 (1 Pt 1) E108-E117
  • 15 Bergström J, Hultman E. A study of the glycogen metabolism during exercise in man. Scand J Clin Lab Invest 1967; 19 (3) 218-228
  • 16 Hultman E, Nilsson LH, Liver glycogen in man. Effect of different diets and muscular exercise. In: Pernow B, Saltin B. , eds. Muscle Metabolism During Exercise. New York: Plenum Press; 1971: 143-151
  • 17 Romijn JA, Coyle EF, Sidossis LS , et al. Regulation of endogenous fat and carbohydrate metabolism in relation to exercise intensity and duration. Am J Physiol 1993; 265 (3 Pt 1) E380-E391
  • 18 Jensen MD. Gender differences in regional fatty acid metabolism before and after meal ingestion. J Clin Invest 1995; 96 (5) 2297-2303
  • 19 Meek SE, Nair KS, Jensen MD. Insulin regulation of regional free fatty acid metabolism. Diabetes 1999; 48 (1) 10-14
  • 20 Havel RJ, Kane JP, Balasse EO, Segel N, Basso LV. Splanchnic metabolism of free fatty acids and production of triglycerides of very low density lipoproteins in normotriglyceridemic and hypertriglyceridemic humans. J Clin Invest 1970; 49 (11) 2017-2035
  • 21 Wolfe BM, Havel JR, Marliss EB, Kane JP, Seymour J, Ahuja SP. Effects of a 3-day fast and of ethanol on splanchnic metabolism of FFA, amino acids, and carbohydrates in healthy young men. J Clin Invest 1976; 57 (2) 329-340
  • 22 Klein S, Peters EJ, Holland OB, Wolfe RR. Effect of short- and long-term beta-adrenergic blockade on lipolysis during fasting in humans. Am J Physiol 1989; 257 (1 Pt 1) E65-E73
  • 23 Stallknecht B, Lorentsen J, Enevoldsen LH , et al. Role of the sympathoadrenergic system in adipose tissue metabolism during exercise in humans. J Physiol 2001; 536 (Pt 1) 283-294
  • 24 Wolfe RR, Klein S, Carraro F, Weber JM. Role of triglyceride-fatty acid cycle in controlling fat metabolism in humans during and after exercise. Am J Physiol 1990; 258 (2 Pt 1) E382-E389
  • 25 Rowell LB, Blackmon JR, Bruce RA. Indocyanine green clearance and estimated hepatic blood flow during mild to maximal exercise in upright man. J Clin Invest 1964; 43: 1677-1690
  • 26 Burguera B, Proctor D, Dietz N, Guo ZK, Joyner M, Jensen MD. Leg free fatty acid kinetics during exercise in men and women. Am J Physiol Endocrinol Metab 2000; 278 (1) E113-E117
  • 27 Watt MJ, Heigenhauser GJF, Spriet LL. Intramuscular triacylglycerol utilization in human skeletal muscle during exercise: is there a controversy?. J Appl Physiol 2002; 93 (4) 1185-1195
  • 28 Coppack SW, Fisher RM, Gibbons GF , et al. Postprandial substrate deposition in human forearm and adipose tissues in vivo. Clin Sci (Lond) 1990; 79 (4) 339-348
  • 29 Kiens B, Essen-Gustavsson B, Christensen NJ, Saltin B. Skeletal muscle substrate utilization during submaximal exercise in man: effect of endurance training. J Physiol 1993; 469: 459-478
  • 30 Børsheim E, Knardahl S, Høstmark AT. Short-term effects of exercise on plasma very low density lipoproteins (VLDL) and fatty acids. Med Sci Sports Exerc 1999; 31 (4) 522-530
  • 31 Helge JW, Watt PW, Richter EA, Rennie MJ, Kiens B. Fat utilization during exercise: adaptation to a fat-rich diet increases utilization of plasma fatty acids and very low density lipoprotein-triacylglycerol in humans. J Physiol 2001; 537 (Pt 3) 1009-1020
  • 32 Sondergaard E, Rahbek I, Sørensen LP , et al. Effects of exercise on VLDL-triglyceride oxidation and turnover. Am J Physiol Endocrinol Metab 2011; 300 (5) E939-E944
  • 33 Boesch C, Egger A, Kreis R , et al. Increase of intrahepatocellular lipids (IHCL) during exercise in healthy volunteers. Proc Intl Soc Magn Reson Med 2009; 17: 2146
  • 34 Johnson NA, van Overbeek D, Chapman PG, Thompson MW, Sachinwalla T, George J. Effect of prolonged exercise and pre-exercise dietary manipulation on hepatic triglycerides in trained men. Eur J Appl Physiol 2011; DOI: 10.1007/s00421-011-2158-y.
  • 35 van Loon LJ, Koopman R, Stegen JH, Wagenmakers AJ, Keizer HA, Saris WH. Intramyocellular lipids form an important substrate source during moderate intensity exercise in endurance-trained males in a fasted state. J Physiol 2003; 553 (Pt 2) 611-625
  • 36 Kuo CC, Fattor JA, Henderson GC, Brooks GA. Lipid oxidation in fit young adults during postexercise recovery. J Appl Physiol 2005; 99 (1) 349-356
  • 37 Kiens B, Richter EA. Utilization of skeletal muscle triacylglycerol during postexercise recovery in humans. Am J Physiol 1998; 275 (2 Pt 1) E332-E337
  • 38 Warren A, Howden EJ, Williams AD, Fell JW, Johnson NA. Postexercise fat oxidation: effect of exercise duration, intensity, and modality. Int J Sport Nutr Exerc Metab 2009; 19 (6) 607-623
  • 39 Richter EA, Garetto LP, Goodman MN, Ruderman NB. Muscle glucose metabolism following exercise in the rat: increased sensitivity to insulin. J Clin Invest 1982; 69 (4) 785-793
  • 40 Bogardus C, Ravussin E, Robbins DC, Wolfe RR, Horton ES, Sims EAH. Effects of physical training and diet therapy on carbohydrate metabolism in patients with glucose intolerance and non-insulin-dependent diabetes mellitus. Diabetes 1984; 33 (4) 311-318
  • 41 Zachwieja JJ, Costill DL, Pascoe DD, Robergs RA, Fink WJ. Influence of muscle glycogen depletion on the rate of resynthesis. Med Sci Sports Exerc 1991; 23 (1) 44-48
  • 42 Devlin JT, Horton ES. Effects of prior high-intensity exercise on glucose metabolism in normal and insulin-resistant men. Diabetes 1985; 34 (10) 973-979
  • 43 Devlin JT, Hirshman M, Horton ED, Horton ES. Enhanced peripheral and splanchnic insulin sensitivity in NIDDM men after single bout of exercise. Diabetes 1987; 36 (4) 434-439
  • 44 Richter EA, Derave W, Wojtaszewski JF. Glucose, exercise and insulin: emerging concepts. J Physiol 2001; 535 (Pt 2) 313-322
  • 45 Maehlum S, Hermansen L. Muscle glycogen concentration during recovery after prolonged severe exercise in fasting subjects. Scand J Clin Lab Invest 1978; 38 (6) 557-560
  • 46 Gollnick PD, Armstrong RB, Saltin B, Saubert IV CW, Sembrowich WL, Shepherd RE. Effect of training on enzyme activity and fiber composition of human skeletal muscle. J Appl Physiol 1973; 34 (1) 107-111
  • 47 Holloszy JO, Coyle EF. Adaptations of skeletal muscle to endurance exercise and their metabolic consequences. J Appl Physiol 1984; 56 (4) 831-838
  • 48 Henriksson J, Reitman JS. Time course of changes in human skeletal muscle succinate dehydrogenase and cytochrome oxidase activities and maximal oxygen uptake with physical activity and inactivity. Acta Physiol Scand 1977; 99 (1) 91-97
  • 49 Turcotte LP, Richter EA, Kiens B. Increased plasma FFA uptake and oxidation during prolonged exercise in trained vs untrained humans. Am J Physiol 1992; 262 (6 Pt 1) E791-E799
  • 50 Kiens B, Kristiansen S, Jensen P, Richter EA, Turcotte LP. Membrane associated fatty acid binding protein (FABPpm) in human skeletal muscle is increased by endurance training. Biochem Biophys Res Commun 1997; 231 (2) 463-465
  • 51 Spina RJ, Chi MM, Hopkins MG, Nemeth PM, Lowry OH, Holloszy JO. Mitochondrial enzymes increase in muscle in response to 7-10 days of cycle exercise. J Appl Physiol 1996; 80 (6) 2250-2254
  • 52 Hoppeler H, Lüthi P, Claassen H, Weibel ER, Howald H. The ultrastructure of the normal human skeletal muscle. A morphometric analysis on untrained men, women and well-trained orienteers. Pflugers Arch 1973; 344 (3) 217-232
  • 53 Romijn JA, Coyle EF, Sidossis LS , et al. Regulation of endogenous fat and carbohydrate metabolism in relation to exercise intensity and duration. Am J Physiol 1993; 265 (3 Pt 1) E380-E391
  • 54 Williams PT, Krauss RM, Wood PD, Lindgren FT, Giotas C, Vranizan KM. Lipoprotein subfractions of runners and sedentary men. Metabolism 1986; 35 (1) 45-52
  • 55 Kelley GA, Kelley KS, Franklin B. Aerobic exercise and lipids and lipoproteins in patients with cardiovascular disease: a meta-analysis of randomized controlled trials. J Cardiopulm Rehabil 2006; 26 (3) 131-139 , quiz 140–141, discussion 142–144
  • 56 Kelley GA, Kelley KS, Vu Tran Z. Aerobic exercise, lipids and lipoproteins in overweight and obese adults: a meta-analysis of randomized controlled trials. Int J Obes (Lond) 2005; 29 (8) 881-893
  • 57 Thompson PD, Cullinane EM, Sady SP, Flynn MM, Chenevert CB, Herbert PN. High density lipoprotein metabolism in endurance athletes and sedentary men. Circulation 1991; 84 (1) 140-152
  • 58 Halverstadt A, Phares DA, Wilund KR, Goldberg AP, Hagberg JM. Endurance exercise training raises high-density lipoprotein cholesterol and lowers small low-density lipoprotein and very low-density lipoprotein independent of body fat phenotypes in older men and women. Metabolism 2007; 56 (4) 444-450
  • 59 Kraus WE, Houmard JA, Duscha BD , et al. Effects of the amount and intensity of exercise on plasma lipoproteins. N Engl J Med 2002; 347 (19) 1483-1492
  • 60 Thompson PD, Crouse SF, Goodpaster B, Kelley D, Moyna N, Pescatello L. The acute versus the chronic response to exercise. Med Sci Sports Exerc 2001; 33 (6, Suppl) S438-S445 , discussion S452–S453
  • 61 Cullinane E, Siconolfi S, Saritelli A, Thompson PD. Acute decrease in serum triglycerides with exercise: is there a threshold for an exercise effect?. Metabolism 1982; 31 (8) 844-847
  • 62 Magkos F, Patterson BW, Mohammed BS, Mittendorfer B. A single 1-h bout of evening exercise increases basal FFA flux without affecting VLDL-triglyceride and VLDL-apolipoprotein B-100 kinetics in untrained lean men. Am J Physiol Endocrinol Metab 2007; 292 (6) E1568-E1574
  • 63 Pedersen BK. The anti-inflammatory effect of exercise: its role in diabetes and cardiovascular disease control. In: Essays in Biochemistry. Vol. 42: The Biochemical Basis of the Health Effects of Exercise. London: Portland Press; 2006: 105-117
  • 64 Samuel VT, Petersen KF, Shulman GI. Lipid-induced insulin resistance: unravelling the mechanism. Lancet 2010; 375 (9733) 2267-2277
  • 65 Palmer M, Schaffner F. Effect of weight reduction on hepatic abnormalities in overweight patients. Gastroenterology 1990; 99 (5) 1408-1413
  • 66 Ueno T, Sugawara H, Sujaku K , et al. Therapeutic effects of restricted diet and exercise in obese patients with fatty liver. J Hepatol 1997; 27 (1) 103-107
  • 67 Hickman IJ, Clouston AD, Macdonald GA , et al. Effect of weight reduction on liver histology and biochemistry in patients with chronic hepatitis C. [see comment] Gut 2002; 51 (1) 89-94
  • 68 Huang MA, Greenson JK, Chao C , et al. One-year intense nutritional counseling results in histological improvement in patients with non-alcoholic steatohepatitis: a pilot study. Am J Gastroenterol 2005; 100 (5) 1072-1081
  • 69 Sreenivasa Baba C, Alexander G, Kalyani B , et al. Effect of exercise and dietary modification on serum aminotransferase levels in patients with nonalcoholic steatohepatitis. [see comment] J Gastroenterol Hepatol 2006; 21 (1 Pt 1) 191-198
  • 70 Osland EJ, Powell EE, Banks M, Jonsson JR, Hickman IJ. Obesity management in liver clinics: translation of research into clinical practice. [see comment] J Gastroenterol Hepatol 2007; 22 (4) 504-509
  • 71 Perseghin G, Lattuada G, De Cobelli F , et al. Habitual physical activity is associated with intrahepatic fat content in humans. Diabetes Care 2007; 30 (3) 683-688
  • 72 Hsieh SD, Yoshinaga H, Muto T, Sakurai Y. Regular physical activity and coronary risk factors in Japanese men. Circulation 1998; 97 (7) 661-665
  • 73 Tiikkainen M, Tamminen M, Häkkinen A-M , et al. Liver-fat accumulation and insulin resistance in obese women with previous gestational diabetes. Obes Res 2002; 10 (9) 859-867
  • 74 Zelber-Sagi S, Nitzan-Kaluski D, Goldsmith R , et al. Role of leisure-time physical activity in nonalcoholic fatty liver disease: a population-based study. Hepatology 2008; 48 (6) 1791-1798
  • 75 Lawlor DA, Sattar N, Smith GD, Ebrahim S. The associations of physical activity and adiposity with alanine aminotransferase and gamma-glutamyltransferase. Am J Epidemiol 2005; 161 (11) 1081-1088
  • 76 Church TS, Kuk JL, Ross R, Priest EL, Biltoft E, Blair SN. Association of cardiorespiratory fitness, body mass index, and waist circumference to nonalcoholic fatty liver disease. Gastroenterology 2006; 130 (7) 2023-2030
  • 77 Nguyen-Duy T-B, Nichaman MZ, Church TS, Blair SN, Ross R. Visceral fat and liver fat are independent predictors of metabolic risk factors in men. Am J Physiol Endocrinol Metab 2003; 284 (6) E1065-E1071
  • 78 McMillan KP, Kuk JL, Church TS, Blair SN, Ross R. Independent associations between liver fat, visceral adipose tissue, and metabolic risk factors in men. Appl Physiol Nutr Metab 2007; 32 (2) 265-272
  • 79 Suzuki A, Lindor K, St Saver J , et al. Effect of changes on body weight and lifestyle in nonalcoholic fatty liver disease. [see comment] J Hepatol 2005; 43 (6) 1060-1066
  • 80 Tamura Y, Tanaka Y, Sato F , et al. Effects of diet and exercise on muscle and liver intracellular lipid contents and insulin sensitivity in type 2 diabetic patients. J Clin Endocrinol Metab 2005; 90 (6) 3191-3196
  • 81 Schäfer S, Kantartzis K, Machann J , et al. Lifestyle intervention in individuals with normal versus impaired glucose tolerance. Eur J Clin Invest 2007; 37 (7) 535-543
  • 82 Kantartzis K, Thamer C, Peter A , et al. High cardiorespiratory fitness is an independent predictor of the reduction in liver fat during a lifestyle intervention in non-alcoholic fatty liver disease. Gut 2009; 58 (9) 1281-1288
  • 83 Shaw K, Gennat H, O'Rourke P, Del Mar C. Exercise for overweight or obesity. Cochrane Database Syst Rev 2007; (4) CD14003817
  • 84 Hansen D, Dendale P, Berger J, van Loon LJC, Meeusen R. The effects of exercise training on fat-mass loss in obese patients during energy intake restriction. Sports Med 2007; 37 (1) 31-46
  • 85 Franz MJ, VanWormer JJ, Crain AL , et al. Weight-loss outcomes: a systematic review and meta-analysis of weight-loss clinical trials with a minimum 1-year follow-up. J Am Diet Assoc 2007; 107 (10) 1755-1767
  • 86 St George A, Bauman A, Johnston A, Farrell G, Chey T, George J. Independent effects of physical activity in patients with nonalcoholic fatty liver disease. Hepatology 2009; 50 (1) 68-76
  • 87 Garber CE, Blissmer B, Deschenes MR , et al; American College of Sports Medicine. American College of Sports Medicine position stand. Quantity and quality of exercise for developing and maintaining cardiorespiratory, musculoskeletal, and neuromotor fitness in apparently healthy adults: guidance for prescribing exercise. Med Sci Sports Exerc 2011; 43 (7) 1334-1359
  • 88 Donnelly JE, Blair SN, Jakicic JM, Manore MM, Rankin JW, Smith BK ; American College of Sports Medicine. American College of Sports Medicine Position Stand. Appropriate physical activity intervention strategies for weight loss and prevention of weight regain for adults. Med Sci Sports Exerc 2009; 41 (2) 459-471
  • 89 Goodpaster BH, Delany JP, Otto AD , et al. Effects of diet and physical activity interventions on weight loss and cardiometabolic risk factors in severely obese adults: a randomized trial. JAMA 2010; 304 (16) 1795-1802
  • 90 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) 2009; 17 (12) 2162-2168
  • 91 Larson-Meyer DE, Newcomer BR, Heilbronn LK , et al; Pennington CALERIE Team. Effect of 6-month calorie restriction and exercise on serum and liver lipids and markers of liver function. Obesity (Silver Spring) 2008; 16 (6) 1355-1362
  • 92 Devries MC, Samjoo IA, Hamadeh MJ, Tarnopolsky MA. Effect of endurance exercise on hepatic lipid content, enzymes, and adiposity in men and women. Obesity (Silver Spring) 2008; 16 (10) 2281-2288
  • 93 Shojaee-Moradie F, Baynes KC, Pentecost C , et al. Exercise training reduces fatty acid availability and improves the insulin sensitivity of glucose metabolism. Diabetologia 2007; 50 (2) 404-413
  • 94 Johnson NA, Sachinwalla T, Walton DW , et al. Aerobic exercise training reduces hepatic and visceral lipids in obese individuals without weight loss. Hepatology 2009; 50 (4) 1105-1112
  • 95 Bonekamp S, Barone BB, Clark J, Stewart KJ. The effect of an exercise training intervention on hepatic steatosis. Hepatology 2008; 48: 806A
  • 96 Sullivan S, Kirk EP, Patterson B, Klein S. Effect of endurance exercise on non-alcoholic fatty liver disease. Gastroenterology 2011; 140: S700-S700
  • 97 Hallsworth K, Fattakhova G, Hollingsworth KG , et al. Resistance exercise reduces liver fat and its mediators in non-alcoholic fatty liver disease independent of weight loss. Gut 2011; 60 (9) 1278-1283
  • 98 Finucane FM, Sharp SJ, Purslow LR , et al. The effects of aerobic exercise on metabolic risk, insulin sensitivity and intrahepatic lipid in healthy older people from the Hertfordshire Cohort Study: a randomised controlled trial. Diabetologia 2010; 53 (4) 624-631
  • 99 Chen SM, Liu CY, Li SR, Huang HT, Tsai CY, Jou HJ. Effects of therapeutic lifestyle program on ultrasound-diagnosed nonalcoholic fatty liver disease. J Chin Med Assoc 2008; 71 (11) 551-558
  • 100 Levinger I, Goodman C, Peake J , et al. Inflammation, hepatic enzymes and resistance training in individuals with metabolic risk factors. Diabet Med 2009; 26 (3) 220-227
  • 101 Thompson D, Markovitch D, Betts JA, Mazzatti D, Turner J, Tyrrell RM. Time course of changes in inflammatory markers during a 6-mo exercise intervention in sedentary middle-aged men: a randomized-controlled trial. J Appl Physiol 2010; 108 (4) 769-779
  • 102 van der Heijden GJ, Wang ZJ, Chu ZD , et al. A 12-week aerobic exercise program reduces hepatic fat accumulation and insulin resistance in obese, Hispanic adolescents. Obesity (Silver Spring) 2010; 18 (2) 384-390
  • 103 Musso G, Gambino R, Cassader M, Pagano G. A meta-analysis of randomized trials for the treatment of nonalcoholic fatty liver disease. Hepatology 2010; 52 (1) 79-104
  • 104 Parker HM, Johnson NA, Burdon CA, Cohn JS, O'Connor HT, George J. Omega-3 supplementation and non-alcoholic fatty liver disease: A systematic review and meta-analysis. J Hepatol 2011; DOI: 10.1152/japplphysiol.00997.2004.
  • 105 Knowler WC, Barrett-Connor E, Fowler SE , et al; Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. [see comment] N Engl J Med 2002; 346 (6) 393-403
  • 106 Laaksonen DE, Lindström J, Lakka TA , et al; Finnish diabetes prevention study. Physical activity in the prevention of type 2 diabetes: the Finnish diabetes prevention study. Diabetes 2005; 54 (1) 158-165
  • 107 Kosaka K, Noda M, Kuzuya T. Prevention of type 2 diabetes by lifestyle intervention: a Japanese trial in IGT males. Diabetes Res Clin Pract 2005; 67 (2) 152-162
  • 108 Pan XR, Li GW, Hu YH , et al. Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance. The Da Qing IGT and Diabetes Study. [see comment] Diabetes Care 1997; 20 (4) 537-544
  • 109 Ramachandran A, Snehalatha C, Mary S, Mukesh B, Bhaskar AD, Vijay V ; Indian Diabetes Prevention Programme (IDPP). The Indian Diabetes Prevention Programme shows that lifestyle modification and metformin prevent type 2 diabetes in Asian Indian subjects with impaired glucose tolerance (IDPP-1). Diabetologia 2006; 49 (2) 289-297
  • 110 Tuomilehto J, Lindström J, Eriksson JG , et al; Finnish Diabetes Prevention Study Group. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001; 344 (18) 1343-1350
  • 111 Ismail I, Keating SE, Baker MK, Johnson NA. A systematic review and meta-analysis of the effect of aerobic vs resistance exercise training on visceral fat. Obes Rev 2011; ••• DOI: 10.1111/j.1467-789X.2011.00931.x.
  • 112 Wei M, Kampert JB, Barlow CE , et al. Relationship between low cardiorespiratory fitness and mortality in normal-weight, overweight, and obese men. JAMA 1999; 282 (16) 1547-1553
  • 113 Sesso HD, Paffenbarger Jr RS, Lee IM. Physical activity and coronary heart disease in men: The Harvard Alumni Health Study. Circulation 2000; 102 (9) 975-980
  • 114 Rector RS, Thyfault JP, Morris RT , et al. Daily exercise increases hepatic fatty acid oxidation and prevents steatosis in Otsuka Long-Evans Tokushima Fatty rats. Am J Physiol Gastrointest Liver Physiol 2008; 294 (3) G619-G626
  • 115 Rector RS, Thyfault JP, Laye MJ , et al. Cessation of daily exercise dramatically alters precursors of hepatic steatosis in Otsuka Long-Evans Tokushima Fatty (OLETF) rats. J Physiol 2008; 586 (Pt 17) 4241-4249
  • 116 Shimomura I, Bashmakov Y, Horton JD. Increased levels of nuclear SREBP-1c associated with fatty livers in two mouse models of diabetes mellitus. J Biol Chem 1999; 274 (42) 30028-30032
  • 117 Thyfault JP, Rector RS, Uptergrove GM , et al. Rats selectively bred for low aerobic capacity have reduced hepatic mitochondrial oxidative capacity and susceptibility to hepatic steatosis and injury. [see comment] J Physiol 2009; 587 (Pt 8) 1805-1816
  • 118 Hoene M, Lehmann R, Hennige AM , et al. Acute regulation of metabolic genes and insulin receptor substrates in the liver of mice by one single bout of treadmill exercise. J Physiol 2009; 587 (Pt 1) 241-252
  • 119 Fiebig RG, Hollander JM, Ji LL. Exercise down-regulates hepatic fatty acid synthase in streptozotocin-treated rats. J Nutr 2001; 131 (9) 2252-2259
  • 120 Griffiths MA, Baker DH, Yu XX, Novakofski J, Oscai L, Ji LL. Effects of acute exercise on hepatic lipogenic enzymes in fasted and refed rats. J Appl Physiol 1995; 79 (3) 879-885
  • 121 Rabøl R, Petersen KF, Dufour S, Flannery C, Shulman GI. Reversal of muscle insulin resistance with exercise reduces postprandial hepatic de novo lipogenesis in insulin resistant individuals. Proc Natl Acad Sci U S A 2011; 108 (33) 13705-13709
  • 122 Richter EA, Ruderman NB. AMPK and the biochemistry of exercise: implications for human health and disease. Biochem J 2009; 418 (2) 261-275
  • 123 Magkos F. Putative factors that may modulate the effect of exercise on liver fat: insights from animal studies. J Nutr Metab 2012; 2012: 827417
  • 124 Solomon TPJ, Haus JM, Marchetti CM, Stanley WC, Kirwan JP. Effects of exercise training and diet on lipid kinetics during free fatty acid-induced insulin resistance in older obese humans with impaired glucose tolerance. Am J Physiol Endocrinol Metab 2009; 297 (2) E552-E559
  • 125 Kotronen A, Juurinen L, Tiikkainen M, Vehkavaara S, Yki-Järvinen H. Increased liver fat, impaired insulin clearance, and hepatic and adipose tissue insulin resistance in type 2 diabetes. Gastroenterology 2008; 135 (1) 122-130
  • 126 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 2008; 134 (5) 1369-1375
  • 127 Wahren J, Sato Y, Ostman J, Hagenfeldt L, Felig P. Turnover and splanchnic metabolism of free fatty acids and ketones in insulin-dependent diabetics at rest and in response to exercise. J Clin Invest 1984; 73 (5) 1367-1376
  • 128 Hannukainen JC, Nuutila P, Borra R , et al. Increased physical activity decreases hepatic free fatty acid uptake: a study in human monozygotic twins. J Physiol 2007; 578 (Pt 1) 347-358
  • 129 Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, Parks EJ. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest 2005; 115 (5) 1343-1351
  • 130 Petersen KF, Dufour S, Savage DB , et al. The role of skeletal muscle insulin resistance in the pathogenesis of the metabolic syndrome. Proc Natl Acad Sci U S A 2007; 104 (31) 12587-12594
  • 131 Charbonneau A, Melancon A, Lavoie C, Lavoie JM. Alterations in hepatic glucagon receptor density and in Gsalpha and Gialpha2 protein content with diet-induced hepatic steatosis: effects of acute exercise. Am J Physiol Endocrinol Metab 2005; 289 (1) E8-E14
  • 132 Charbonneau A, Unson CG, Lavoie J-M. High-fat diet-induced hepatic steatosis reduces glucagon receptor content in rat hepatocytes: potential interaction with acute exercise. J Physiol 2007; 579 (Pt 1) 255-267
  • 133 Albright AFM, Franz M, Hornsby G , et al. American College of Sports Medicine position stand. Exercise and type 2 diabetes. Med Sci Sports Exerc 2000; 32 (7) 1345-1360
  • 134 Thoma C, Day CP, Trenell MI. Lifestyle interventions for the treatment of non-alcoholic fatty liver disease in adults: A systematic review. J Hepatol 2012; 56 (1) 255-266
  • 135 Frith J, Day CP, Robinson L, Elliott C, Jones DEJ, Newton JL. Potential strategies to improve uptake of exercise interventions in non-alcoholic fatty liver disease. J Hepatol 2010; 52 (1) 112-116
  • 136 Trost SG, Owen N, Bauman AE, Sallis JF, Brown W. Correlates of adults' participation in physical activity: review and update. Med Sci Sports Exerc 2002; 34 (12) 1996-2001
  • 137 Moscatiello S, Di Luzio R, Bugianesi E , et al. Cognitive-behavioral treatment of nonalcoholic Fatty liver disease: a propensity score-adjusted observational study. Obesity (Silver Spring) 2011; 19 (4) 763-770