The prevalence of obesity is increasing at alarming rates in the United States such that bariatric surgery has become an accepted therapeutic option for adults and adolescents with morbid obesity. Bariatric surgery provides significant metabolic benefits, including resolution of type-2 diabetes and marked reduction in hypercholesterolemia, that precede the weight loss produced by these surgeries. The mechanisms responsible for these weight-independent metabolic benefits are poorly understood. Dr. Kohli's long-term research objective is to characterize the mechanisms behind these weight-loss-independent metabolic benefits of bariatric surgical procedures and translate those observations into more scalable non-invasive therapeutic measures. In this proposal Dr. Kohli will focus on the benefits of bariatric surgery to obesity related hypercholesterolemias by using a unique surgical procedure called "Ileal Transposition" in a rat model. This weight loss surgery has been previously shown to produce improved glucose tolerance similar to roux-en-y- gastric bypass without gastric size restriction or malabsorption. Dr. Kohli has generated exciting preliminary data using this surgical model that include a significant reduction in cholesterol levels that is independent of weight loss.
The specific aims of his proposal will examine the mechanistic links between bile acid entero-hepatic circulation and cholesterol absorption, sensing, and endogenous production in this bariatric surgery model. He will also investigate the role of adaptation of the transposed segment of the ileum in reduction of cholesterol. These studies build on Dr. Kohli's prior work as a fellow investigating the mechanisms involved in lipid-induced nutritional stress producing hepatic steatosis. The primary goal of this mentored career development award is to provide a pathway for Dr. Kohli, a trained pediatric gastroenterologist and hepatologist, to achieve scientific independence. By developing an expertise in lipid and bile acid metabolism using small-animal surgical-obesity-intervention models, he will distinguish himself from his mentor, Professor Randy Seeley, and be well-positioned to make significant scientific and medical contributions to the understanding of obesity in children and adolescents.

Public Health Relevance

Bariatric surgery is now an accepted treatment for the morbidly obese adult or adolescent. Certain benefits of these surgeries, such as reduced cholesterol and resolution of diabetes, occur even prior to weight loss. This proposal seeks to identify the key mechanisms involved in these weight-loss-independent improvements in cholesterol levels and then translate those findings to non-invasive more scalable treatment options.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08DK084310-04
Application #
8326213
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Podskalny, Judith M,
Project Start
2009-09-01
Project End
2013-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
4
Fiscal Year
2012
Total Cost
$149,927
Indirect Cost
$11,106
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
Mehta, Minesh; Slaughter, Crystal; Xanthakos, Stavra A et al. (2014) High prevalence of hepatitis B non-immunity in paediatric non-alcoholic fatty liver disease patients. Dig Liver Dis 46:760-1
Ryan, Karen K; Tremaroli, Valentina; Clemmensen, Christoffer et al. (2014) FXR is a molecular target for the effects of vertical sleeve gastrectomy. Nature 509:183-8
Ibrahim, Samar H; Gores, Gregory J; Hirsova, Petra et al. (2014) Mixed lineage kinase 3 deficient mice are protected against the high fat high carbohydrate diet-induced steatohepatitis. Liver Int 34:427-37
Habegger, Kirk M; Al-Massadi, Omar; Heppner, Kristy M et al. (2014) Duodenal nutrient exclusion improves metabolic syndrome and stimulates villus hyperplasia. Gut 63:1238-46
Myronovych, Andriy; Kirby, Michelle; Ryan, Karen K et al. (2014) Vertical sleeve gastrectomy reduces hepatic steatosis while increasing serum bile acids in a weight-loss-independent manner. Obesity (Silver Spring) 22:390-400
Myronovych, Andriy; Salazar-Gonzalez, Rosa-Maria; Ryan, Karen K et al. (2014) The role of small heterodimer partner in nonalcoholic fatty liver disease improvement after sleeve gastrectomy in mice. Obesity (Silver Spring) 22:2301-11
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
Kohli, Rohit; Bradley, David; Setchell, Kenneth D et al. (2013) Weight loss induced by Roux-en-Y gastric bypass but not laparoscopic adjustable gastric banding increases circulating bile acids. J Clin Endocrinol Metab 98:E708-12
Kohli, Rohit; Setchell, Kenneth Dr; Kirby, Michelle et al. (2013) A surgical model in male obese rats uncovers protective effects of bile acids post-bariatric surgery. Endocrinology 154:2341-51

Showing the most recent 10 out of 21 publications