Translational Approach to Examine the Importance of Aerobic Fitness on Nonalcoholic Fatty Liver Disease [abstract]

Comparative Medicine - OneHealth and Comparative Medicine Poster Session.Low cardiorespiratory fitness, independent of physical activity levels, is the best predictor of early mortality and is linked to type 2 diabetes and CVD. In the absence of exercise training, it is believed that genetic inheritance accounts for up to 70% of the variation in intrinsic aerobic fitness. Recent cross-sectional reports in humans also have linked low aerobic fitness with nonalcoholic fatty liver disease (NAFLD). NAFLD, fatty liver not due to alcohol consumption, encompasses a gamut of liver maladaptations and is a primary cause of chronic liver disease and liver-related morbidity and mortality. NAFLD occurs in ~30% of US adults, 75-100% of obese and extremely obese individuals, and is considered the hepatic component of the metabolic syndrome. Despite the recent observations in humans between low fitness and NAFLD, there is a paucity of mechanistic information detailing this link. In order to address this important clinical problem, we have developed an interdisciplinary team across multiple institutions and fields of study and have taken a translational approach, employing both novel whole animal model studies and isolated primary hepatocyte cell culture experiments, to gain mechanistic insight into the human observational studies. We have utilized a novel rat model in which rats are artificially selected over several generations for high and low intrinsic endurance capacity, resulting in high capacity runners (HCR) with high aerobic fitness and low capacity runners (LCR) with significantly lower aerobic fitness (Science, 307:418-20, 2005). These rats display contrasting phenotypes without the influence of exercise training, making them an excellent model to mechanistically assess the role of aerobic fitness on NAFLD. Utilizing this model, we have provided the first mechanistic evidence that the LCR rats have reduced hepatic mitochondrial content and oxidative capacity, increased hepatic de novo lipogenic profiles, and develop hepatic steatosis with progression to greater fibrosis and apoptosis compared to the HCR rats. The LCR rats also are unable to maintain systemic insulin sensitivity following exposure to high-fat feeding. However, since it is impossible to completely eliminate the influence of peripheral factors on liver metabolism, we have subsequently isolated primary hepatocytes from HCR and LCR rats. We have observed a similar phenotype in the primary hepatocytes from LCR animals, with significant reductions in fatty acid oxidation and the inability to maintain insulin signaling in response to lipid exposure compared with HCR hepatocytes. These findings have important clinical implications, as low aerobic fitness due to physical inactivity and/or genetic inheritability may lead to increased susceptibility to NAFLD, and suggest that the clinical measurement of aerobic fitness may serve as a valuable prognostic tool. We are currently conducting a human clinical trial to assess the efficacy of exercise in improving aerobic fitness and reducing NAFLD, and because exercise is the proven method to increase aerobic fitness, it should remain the cornerstone therapy for fatty liver disease

Interdisciplinary Approach to Examine the Effects of Lifestyle Modifications on Nonalcoholic Fatty Liver Disease

Comparative Medicine - OneHealth and Comparative Medicine Poster SessionA critical complication of the obesity epidemic experienced in Westernized societies is nonalcoholic fatty liver disease (NAFLD). NAFLD, fatty liver not due to alcohol consumption, is the most common chronic liver disease and associated with increasing morbidity, mortality, and demand for liver transplantation. NAFLD is a progressive disease with a histological spectrum ranging from hepatic steatosis to nonalcoholic steatohepatitis, advanced fibrosis, and cirrhosis. Approximately one third of all US adults (90 million) have fatty livers, with prevalence rates as high as 75-100% in the obese and morbidly obese. With growing health problems associated with NAFLD, major questions facing research scientists and health care providers are what are the mechanisms responsible for NAFLD development and what is the best treatment strategy. Since drug interventions appear to be only marginally successful, the cornerstone therapy for NAFLD remains lifestyle modifications of exercise and weight loss. However, while recent cross-sectional observations suggest that being more physically active is inversely associated with NAFLD, studies which attempt to identify molecular mechanisms underlying the effects of lifestyle modifications on NAFLD are lacking. To address these clinical questions, we have taken an interdisciplinary approach with collaborations from experts in multiple departments and facilities at the University of Missouri, including Nutrition and Exercise Physiology, Hepatology, Veterinary Biomedical Sciences, and VA investigators. In addition, we have utilized a unique animal model, the hyperphagic Otsuka Long-Evans Tokushima Fatty (OLETF) rat that develops obesity, insulin resistance and overt type 2 diabetes, a model which we liken to overeating, sedentary, obese humans. Through a series of experiments, we found that the natural progression pattern of fatty liver disease in the sedentary OLETF rat closely resembles the human condition (progression from simple hepatic steatosis to hepatocyte ballooning, fibrosis, and inflammation). We also have compelling evidence that hepatic mitochondrial dysfunction is present at an early age and mitochondrial content, function, and mitochondrial health are disrupted with disease progression, suggesting a potential primary event in NAFLD in this animal model. However and perhaps even more important, when OLETF rats are given access to voluntary running wheels and allowed to exercise daily, the initiation and progression of NAFLD is completely prevented. These benefits occur through modification in both peripheral and hepatic factors, including maintenance of glycemic control and enhancement of hepatic mitochondrial content and function. We are currently in the process of translating these very exciting findings in a randomized, human clinical trial examining the impact of different lifestyle modifications in the treatment of NAFLD. Findings from our research group have important public health application, particularly for the 60-80% of Americans who overeat, who are overweight, and who are physically inactive

The antioxidative effects of exercise training-and diet-induced weight loss

The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file.Title from title screen of research.pdf file (viewed on October 16, 2007)Vita.Thesis (Ph. D.) University of Missouri-Columbia 2007.[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT REQUEST OF AUTHOR.] Obesity and insulin resistance (IR) increase the risk for coronary heart disease (CHD); however, much of this risk is not attributable to traditional risk factors. Elevated oxidative stress associated with obesity may represent a link between IR and CHD. PURPOSE: The purpose of the current investigation was to determine whether weight loss beneficially alters biomarkers of oxidative stress and whether these alterations are associated with improvements in measures of insulin resistance. METHODS: Twentyfive sedentary and overweight to obese [body mass index (BMI) = 33.0 [plus-minus sign] 0.8 kg/m[superscript 2] ] individuals (8 males, and 17 females, age = 40 [plus-minus sign] 2 y), with characteristics of the metabolic syndrome, participated in a 4-7 months weight loss program that consisted of both energy restriction ([approximate sign]600 kcal/d) and supervised aerobic exercise (5 d/wk, 45 min/d at 60% VO[subscript 2]max; [approximate sign]375 kcal/d). Fasting blood samples were collected at baseline and post weight loss for the determination of insulin and glucose. IR and insulin sensitivity were assessed by the calculation of the homeostasis model assessment (HOMA) and quantitative insulin sensitivity check index (QUICKI), respectively. Oxidative stress was assessed by oxidized LDL (oxLDL), myeloperoxidase (MPO), and low- and highdensity lipoprotein (LDL and HDL) lipid hydroperoxide levels in serum. Antioxidative status was determined by apolipoprotein A1 (apoA1) concentrations and paraoxonase-1 (PON1) activity and protein concentrations. RESULTS: Aerobic training- and dietinduced weight loss (9.3 [plus-minus sign] 0.3%; mean [plus-minus sign] SE) significantly (p [less-than sign] 0.05) increased insulin sensitivity and reduced insulin resistance, oxLDL, and LDL lipid hydroperoxides, but did not alter HDL lipid hydroperoxides or MPO levels. The lifestyle intervention impacted systemic antioxidative status by increasing apoA1 concentrations and reducing serum PON1 protein and activity levels. Changes in oxidative stress were not associated with alterations in HOMA or QUICKI. CONCLUSION: Diet- and exercise-induced weight loss ([approximate sign]10%) beneficially alters biomarkers of oxidative status and increases measures of insulin sensitivity. Lifestyle modifications represent a means by which to reduce disease risk associated with obesity.Includes bibliographical reference