Extremely obese adolescents have a markedly higher prevalence of hepatic steatosis (fatty liver) and nonalcoholic steatohepatitis (NASH), a chronic and potentially progressive liver disease associated with increased morbidity and mortality. The effect of bariatric surgery in extremely obese adolescents on outcome of NASH is unknown, and biological predictors of outcome after weight loss induced by bariatric surgery have not been defined. This proposal will address these gaps in knowledge by 1) determining the outcome of hepatic steatosis and NASH after weight loss induced by bariatric surgery in extremely obese adolescents and 2) defining the critical biological determinants of changes in steatosis, inflammation and fibrosis. These goals will be accomplished by conducting a longitudinal observational study in a cohort of extremely obese adolescents with NASH undergoing bariatric surgery. Anthropometries, specific serum laboratory parameters and hepatic histology will be surveyed pre and post-surgical weight loss. Biological predictors of the histologic response of the liver to weight loss will be determined by measuring changes in hypothesized risk factors for hepatic steatosis and NASH, including central adiposity, insulin resistance, circulating free fatty acids and selected adipocytokines. To investigate molecular determinants of hepatic response, hepatic tissue expression of genes regulating lipogenesis, inflammation, apoptosis and fibrosis will be measured. A five year mentored program is proposed that will incorporate both didactic and research training and will be guided by well-established investigators in pediatric liver disease and in the genetics of obesity. The candidate's overarching career goal is to become an independent and innovative clinical research scientist focused on reducing the disease burden related to pediatric and adolescent obesity. To achieve this goal, she will pursue advanced training in 1) principles of human genomic research, 2) molecular aspects of obesity pathophysiology and 3) conduct of clinical trials in order to enable translation of novel research findings back to the bedside. Training in the ethical conduct of human research will be included. The proposed research will yield important insight into biological determinants of the response of hepatic steatosis and NASH after surgically-induced weight loss, while concurrently providing the candidate with the needed training to establish independence as a clinical research scientist. The research proposed is additionally significant because it will identify potential therapeutic targets that may reduce hepatic steatosis and inflammation, and block progression to advanced fibrosis. Further, risk factors for persistence of liver disease after bariatric surgery will be identified. The long-term impact of this study will be to enable development of more personalized and predictive diagnostic and therapeutic strategies for prevention and treatment of NASH.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23DK080888-05
Application #
8296703
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Podskalny, Judith M,
Project Start
2008-07-01
Project End
2013-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
5
Fiscal Year
2012
Total Cost
$176,234
Indirect Cost
$13,054
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
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Xanthakos, Stavra A; Podberesky, Daniel J; Serai, Suraj D et al. (2014) Use of magnetic resonance elastography to assess hepatic fibrosis in children with chronic liver disease. J Pediatr 164:186-8
DeVore, Stephanie; Kohli, Rohit; Lake, Kathleen et al. (2013) A multidisciplinary clinical program is effective in stabilizing BMI and reducing transaminase levels in pediatric patients with NAFLD. J Pediatr Gastroenterol Nutr 57:119-23
Modi, Avani C; Zeller, Meg H; Xanthakos, Stavra A et al. (2013) Adherence to vitamin supplementation following adolescent bariatric surgery. Obesity (Silver Spring) 21:E190-5
Sawhney, Payal; Modi, Avani C; Jenkins, Todd M et al. (2013) Predictors and outcomes of adolescent bariatric support group attendance. Surg Obes Relat Dis 9:773-9
Jeffreys, Renee M; Hrovat, Kathleen; Woo, Jessica G et al. (2012) Dietary assessment of adolescents undergoing laparoscopic Roux-en-Y gastric bypass surgery: macro- and micronutrient, fiber, and supplement intake. Surg Obes Relat Dis 8:331-6
Inge, Thomas; Xanthakos, Stavra (2010) Obesity at the extremes: the eyes only see what the mind is prepared to comprehend. J Pediatr 157:3-4
Kohli, Rohit; Boyd, Todd; Lake, Kathleen et al. (2010) Rapid progression of NASH in childhood. J Pediatr Gastroenterol Nutr 50:453-6
Inge, Thomas H; Jenkins, Todd M; Zeller, Meg et al. (2010) Baseline BMI is a strong predictor of nadir BMI after adolescent gastric bypass. J Pediatr 156:103-108.e1
Inge, Thomas H; Xanthakos, Stavra (2010) Sleeve gastrectomy for childhood morbid obesity: why not? Obes Surg 20:118-20

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