Daily exercise vs. caloric restriction for prevention of nonalcoholic fatty liver disease in the OLETF rat model.

The maintenance of normal body weight either through dietary modification or being habitually more physically active is associated with reduced incidence of nonalcoholic fatty liver disease (NAFLD). However, the means by which weight gain is prevented and potential mechanisms activated remain largely unstudied. Here, we sought to determine the effects of obesity prevention by daily exercise vs. caloric restriction on NAFLD in the hyperphagic, Otsuka Long-Evans Tokushima Fatty (OLETF) rat. At 4 wk of age, male OLETF rats (n = 7-8/group) were randomized to groups of ad libitum fed, sedentary (OLETF-SED), voluntary wheel running exercise (OLETF-EX), or caloric restriction (OLETF-CR; 70% of SED) until 40 wk of age. Nonhyperphagic, control strain Long-Evans Tokushima Otsuka (LETO) rats were kept in sedentary cage conditions for the duration of the study (LETO-SED). Both daily exercise and caloric restriction prevented obesity and the development of type 2 diabetes observed in the OLETF-SED rats, with glucose tolerance during a glucose tolerance test improved to a greater extent in the OLETF-EX animals (30-50% lower glucose and insulin areas under the curve, P < 0.05). Both daily exercise and caloric restriction also prevented excess hepatic triglyceride and diacylglycerol accumulation (P < 0.001), hepatocyte ballooning and nuclear displacement, and the increased perivenular fibrosis and collagen deposition that occurred in the obese OLETF-SED animals. However, despite similar hepatic phenotypes, OLETF-EX rats also exhibited increased hepatic mitochondrial fatty acid oxidation, enhanced oxidative enzyme function and protein content, and further suppression of hepatic de novo lipogenesis proteins compared with OLETF-CR. Prevention of obesity by either daily exercise or caloric restriction attenuates NAFLD development in OLETF rats. However, daily exercise may offer additional health benefits on glucose homeostasis and hepatic mitochondrial function compared with restricted diet alone.

[1]  R. Rector,et al.  Mitochondrial dysfunction precedes insulin resistance and hepatic steatosis and contributes to the natural history of non-alcoholic fatty liver disease in an obese rodent model. , 2010, Journal of hepatology.

[2]  R. Rector,et al.  Changes in skeletal muscle mitochondria in response to the development of type 2 diabetes or prevention by daily wheel running in hyperphagic OLETF rats. , 2010, American journal of physiology. Endocrinology and metabolism.

[3]  E. Jackvony,et al.  Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis , 2010, Hepatology.

[4]  S. Klein,et al.  Diet and Exercise Interventions Reduce Intrahepatic Fat Content and Improve Insulin Sensitivity in Obese Older Adults , 2009, Obesity.

[5]  D. Sabatini,et al.  An Emerging Role of mTOR in Lipid Biosynthesis , 2009, Current Biology.

[6]  V. Nobili,et al.  Childhood NAFLD: a ticking time-bomb? , 2009, Gut.

[7]  J. George,et al.  Aerobic exercise training reduces hepatic and visceral lipids in obese individuals without weight loss , 2009, Hepatology.

[8]  F. Booth,et al.  Changes in visceral adipose tissue mitochondrial content with type 2 diabetes and daily voluntary wheel running in OLETF rats , 2009, The Journal of physiology.

[9]  A. Bauman,et al.  Independent effects of physical activity in patients with nonalcoholic fatty liver disease , 2009, Hepatology.

[10]  Nathan R. Qi,et al.  Rats selectively bred for low aerobic capacity have reduced hepatic mitochondrial oxidative capacity and susceptibility to hepatic steatosis and injury , 2009, The Journal of physiology.

[11]  Claudio R. Santos,et al.  SREBP Activity Is Regulated by mTORC1 and Contributes to Akt-Dependent Cell Growth , 2008, Cell metabolism.

[12]  J. Sowers,et al.  Angiotensin II-induced non-alcoholic fatty liver disease is mediated by oxidative stress in transgenic TG(mRen2)27(Ren2) rats. , 2008, Journal of hepatology.

[13]  F. Booth,et al.  Cessation of daily exercise dramatically alters precursors of hepatic steatosis in Otsuka Long‐Evans Tokushima Fatty (OLETF) rats , 2008, The Journal of physiology.

[14]  R. O’Doherty,et al.  A moderate increase in carnitine palmitoyltransferase 1a activity is sufficient to substantially reduce hepatic triglyceride levels. , 2008, American journal of physiology. Endocrinology and metabolism.

[15]  P. Painter,et al.  Health‐related fitness and physical activity in patients with nonalcoholic fatty liver disease , 2008, Hepatology.

[16]  F. Booth,et al.  Exercise-induced attenuation of obesity, hyperinsulinemia, and skeletal muscle lipid peroxidation in the OLETF rat. , 2008, Journal of applied physiology.

[17]  F. Booth,et al.  Daily exercise increases hepatic fatty acid oxidation and prevents steatosis in Otsuka Long-Evans Tokushima Fatty rats. , 2008, American journal of physiology. Gastrointestinal and liver physiology.

[18]  S. DiCarlo,et al.  A chronic increase in physical activity inhibits fed-state mTOR/S6K1 signaling and reduces IRS-1 serine phosphorylation in rat skeletal muscle. , 2008, Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme.

[19]  C. Mounier,et al.  Role of the PI3-kinase/mTor pathway in the regulation of the stearoyl CoA desaturase (SCD1) gene expression by insulin in liver , 2007, Journal of Cell Communication and Signaling.

[20]  C. Day,et al.  Benefits of lifestyle modification in NAFLD , 2007, Gut.

[21]  R. Cortright,et al.  Peroxisomal-mitochondrial oxidation in a rodent model of obesity-associated insulin resistance. , 2007, American journal of physiology. Endocrinology and metabolism.

[22]  D. Muoio,et al.  Skeletal muscle adaptation to fatty acid depends on coordinated actions of the PPARs and PGC1 alpha: implications for metabolic disease. , 2007, Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme.

[23]  F. Colina,et al.  Uric acid and anti‐TNF antibody improve mitochondrial dysfunction in ob/ob mice , 2006, Hepatology.

[24]  T. Moran,et al.  Hyperphagia and obesity of OLETF rats lacking CCK1 receptors: developmental aspects. , 2006, Developmental psychobiology.

[25]  R. Ross,et al.  Association of cardiorespiratory fitness, body mass index, and waist circumference to nonalcoholic fatty liver disease. , 2006, Gastroenterology.

[26]  Ping Li,et al.  Peroxisome Proliferator-activated Receptor-γ Co-activator 1α-mediated Metabolic Remodeling of Skeletal Myocytes Mimics Exercise Training and Reverses Lipid-induced Mitochondrial Inefficiency* , 2005, Journal of Biological Chemistry.

[27]  O. Cummings,et al.  Design and validation of a histological scoring system for nonalcoholic fatty liver disease , 2005, Hepatology.

[28]  J. Jessurun,et al.  Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. , 2005, The Journal of clinical investigation.

[29]  J. Cline,et al.  Mice heterozygous for a defect in mitochondrial trifunctional protein develop hepatic steatosis and insulin resistance. , 2005, Gastroenterology.

[30]  K. Petersen,et al.  Reversal of nonalcoholic hepatic steatosis, hepatic insulin resistance, and hyperglycemia by moderate weight reduction in patients with type 2 diabetes. , 2005, Diabetes.

[31]  Jonathan C. Cohen,et al.  Prevalence of hepatic steatosis in an urban population in the United States: Impact of ethnicity , 2004, Hepatology.

[32]  J. Horton,et al.  Molecular mediators of hepatic steatosis and liver injury. , 2004, The Journal of clinical investigation.

[33]  J. Arenas,et al.  Defective hepatic mitochondrial respiratory chain in patients with nonalcoholic steatohepatitis , 2003, Hepatology.

[34]  J. Clore,et al.  Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. , 2001, Gastroenterology.

[35]  G. Brandi,et al.  Prevalence of and Risk Factors for Hepatic Steatosis in Northern Italy , 2000, Annals of Internal Medicine.

[36]  J. Parks,et al.  Mitochondrial abnormalities in non-alcoholic steatohepatitis. , 1999, Journal of hepatology.

[37]  K. Tanikawa,et al.  Therapeutic effects of restricted diet and exercise in obese patients with fatty liver. , 1997, Journal of hepatology.

[38]  M M Tai,et al.  A Mathematical Model for the Determination of Total Area Under Glucose Tolerance and Other Metabolic Curves , 1994, Diabetes Care.

[39]  K. Kawano,et al.  Spontaneous Long-Term Hyperglycemic Rat With Diabetic Complications: Otsuka Long-Evans Tokushima Fatty (OLETF) Strain , 1992, Diabetes.

[40]  R. Turner,et al.  Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man , 1985, Diabetologia.

[41]  T. Suga,et al.  Changes in peroxisomal fatty acid oxidation in the diabetic rat liver. , 1981, Journal of biochemistry.

[42]  J. Stern,et al.  Spontaneous activity and adipose cellularity in the genetically obese Zucker rat (fafa). , 1977, Metabolism: clinical and experimental.

[43]  D. Pette,et al.  Metabolic differentiation of distinct muscle types at the level of enzymatic organization. , 1969, European journal of biochemistry.

[44]  J. Folch,et al.  A simple method for the isolation and purification of total lipides from animal tissues. , 1957, The Journal of biological chemistry.

[45]  M. Lazo,et al.  Is exercise an effective treatment for NASH? Knowns and unknowns. , 2009, Annals of hepatology.

[46]  G. Farrell,et al.  LIVER FAILURE AND LIVER DISEASE Nonalcoholic Fatty Liver Disease: From Steatosis to Cirrhosis , 2006 .

[47]  I. Singh,et al.  Increased peroxisomal fatty acid beta-oxidation and enhanced expression of peroxisome proliferator-activated receptor-alpha in diabetic rat liver. , 1999, Molecular and cellular biochemistry.

[48]  P. Srere,et al.  [1] Citrate synthase. [EC 4.1.3.7. Citrate oxaloacetate-lyase (CoA-acetylating)] , 1969 .