This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Obesity is associated with insulin resistance, diabetes mellitus, hypertension, and dyslippidemia; less well known its association with nonalcoholic fatty liver disease (NAFLD). The prevalence of NAFLD is 14-21% 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 homeostatis. 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 Look AHEAD participants; 2)NAFLD will be associated with disordered energy homeostasis, African-American race and male gender; 3) normal energy requirements; 4)those with disordered hepatic energy homeostasis will have a weaker response to the Look AHEAD intervention compared to those with normal 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 Look AHEAD trial. The study sample for the ancillary study would be the 313 Look AHEAD 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, correlates, 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 humger 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.
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