Obesity is associated with insulin resistance, diabetes mellitus, hypertension, and dyslipidemia; less well known is its association with non-alcoholic fatty liver disease (NAFLD). The prevalence of NAFLD is 14-21 percent in some populations, is more common in those who are diabetic or over age 45, and can lead to fibrosis and cirrhosis. Recent evidence indicates that NAFLD is a consequence of disordered hepatic energy homeostasis. Several emerging lines of evidence suggest the overall hypothesis that disordered hepatic energy homeostasis and subsequent NAFLD may play a central role in mediating the adverse metabolic effects of obesity and may influence the success of weight loss interventions. Unfortunately, prior clinical studies have been limited. We, therefore, have the following specific hypotheses: 1) NAFLD and disordered hepatic energy homeostasis will be common in SHOW participants; 2) NAFLD will be associated with disordered energy homeostasis, African-American race and male gender; 3) disordered hepatic energy homeostasis will be associated with a proinflammatory state, and adaptive decreases in normal energy requirements; 4) those with disordered hepatic energy homeostasis will have a weaker response to the SHOW intervention compared to those with normal hepatic energy homeostasis; and 5) the SHOW intervention will improve NAFLD and hepatic energy homeostasis in those with little or no defect in hepatic energy homeostasis but worsen it in those with moderate to severe defects. To test these hypotheses we propose a single center ancillary study to the SHOW trial. The study sample for the ancillary study would be the 313 SHOW participants enrolled at Johns Hopkins. We will measure symptoms of hunger and fatigue (0, 6, 12 mo.) and collect additional data including liver enzymes (0, 6, 12 mo.), MRI Spectroscopy (0, 12 mo.), and ketone bodies, insulin levels, and proinflammatory cytokines (0, 12 mo.) The main outcomes will be the prevalence, correlation, and 1-year progression of NAFLD and disordered hepatic energy homeostasis. Our secondary outcomes will be weight change, physical activity, dietary intake, and symptoms of hunger and fatigue in those with and without NAFLD and disordered hepatic energy homeostasis. If our hypotheses are confirmed, this study will establish blood and other clinical markers of NAFLD and disordered hepatic energy homeostasis, which will facilitate population based research; advance our understanding of the pathophysiology of NAFLD; establish disordered hepatic energy homeostasis as a biologic modifier of behavioral approaches to weight loss; and determine whether weight loss improves NAFLD or poses unsuspected risks.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (ZDK1-GRB-1 (M1))
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Harrison, Barbara
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Johns Hopkins University
Internal Medicine/Medicine
Schools of Medicine
United States
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