Obesity is often associated with insulin resistance and abnormal production of inflammatory cytokines. Central obesity represents a major risk for the development of type 2 diabetes mellitus (T2DM) and cardiovascular complications. Adipose tissue and especially omentum (adipocytes and resident macrophages) release several cytokines. Bariatric surgery and specifically Roux-en-Y gastric bypass (RYGB) is the only modality that results in sustained weight loss. Our studies and those of others demonstrate that RYGB is effective in reversing T2DM in a high proportion of patients. The mechanisms remain unknown. We have evidence showing that weight loss after surgery is not the sole mechanism behind the metabolic improvements. The improvements occur very early (within 10 days) postop and precede any significant weight loss; they are related to visceral fat distribution and are racially biased, with African Americans showing blunted and more delayed responses than Caucasians. The central hypotheses of this application is that improvements in insulin sensitivity after bariatric surgery are racially biased and begin early in the postoperative period (10-30 days) and are mediated by changes in the secretion of energy-related peptides, while the long-term effects (greater than 1 month) are mediated by down-regulation of inflammatory factors. Additionally, we hypothesize that the removal of the omentum in combination with bariatric surgery enhances the reversal of the insulin resistance and will diminish the racial differences in response to bariatric surgery. We propose a randomized study in Caucasian and African American morbidly obese patients to evaluate changes in glucose and fatty acid metabolism. Patients will be randomized to two groups, one with RYGB alone and the second with RYGB with omentectomy.
Three specific aims are proposed.
In specific aim 1, we will determine the mechanism for the metabolic improvements after RYGB. Specifically, we will examine alterations in the secretion and action of energy related peptides and inflammatory responses.
Specific aim 2 explores the mechanism for the blunted/delayed metabolic improvement after RYGB in African American patients. We will examine the genetic basis for differences in the two races using microarray analysis of muscle and visceral and peripheral adipose tissues. We will explore the role of resident macrophages in mediating associated inflammatory responses.
Specific aim 3 will determine if combining omentectomy with RYGB accelerates and sustains improvements especially in the African American population. The studies include determination of regional fat stores, adipocyte size, tissue macrophage content and macrophage gene expression, diurnal and food-induced secretion of adipokines (leptin, resistin and adiponectin) and of energy regulating-peptides such as ghrelin and PYY. Parameters will be correlated with time dependent changes in inflammatory markers (e.g. CRP, IL-6, TNF-O2R, etc.) and with tissue insulin responsiveness using hyperinsulinemic euglycemic clamps.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
3R01DK070860-04S1
Application #
7637533
Study Section
Clinical and Integrative Gastrointestinal Pathobiology Study Section (CIGP)
Program Officer
Miles, Carolyn
Project Start
2005-04-01
Project End
2010-03-31
Budget Start
2008-04-01
Budget End
2009-03-31
Support Year
4
Fiscal Year
2008
Total Cost
$387,147
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Surgery
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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Wattacheril, Julia; Rose, Kristie L; Hill, Salisha et al. (2017) Non-alcoholic fatty liver disease phosphoproteomics: A functional piece of the precision puzzle. Hepatol Res 47:1469-1483
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Albaugh, Vance L; Flynn, Charles Robb; Cai, Steven et al. (2015) Early Increases in Bile Acids Post Roux-en-Y Gastric Bypass Are Driven by Insulin-Sensitizing, Secondary Bile Acids. J Clin Endocrinol Metab 100:E1225-33
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Tamboli, Robyn A; Breitman, Igal; Marks-Shulman, Pam A et al. (2014) Early weight regain after gastric bypass does not affect insulin sensitivity but is associated with elevated ghrelin. Obesity (Silver Spring) 22:1617-22
Savage, Shane W; Zald, David H; Cowan, Ronald L et al. (2014) Regulation of novelty seeking by midbrain dopamine D2/D3 signaling and ghrelin is altered in obesity. Obesity (Silver Spring) 22:1452-7

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