Bariatric surgery is currently the only effective treatment for severe obesity, and the only effective cure for type II diabetes. Research on the mechanism of action of the different bariatric surgical procedures in humans and model systems including pigs, dogs, rats, and mice supports the hypothesis that the beneficial effects result from more than the restrictive or malabsorptive effects of the procedures on food intake. Indeed, data argue that neuroendocrine changes in gut-brain signaling resulting from the Roux-en-Y and gastric sleeve procedures alter satiety, hunger, food preferences, and glucose homeostasis prior to the achievement of significant weight loss. Understanding the cellular and molecular basis of these changes induced by bariatric surgery might lead to the development of pharmaceutical interventions, or improved surgical procedures for the treatment of obesity and diabetes. While several animal models can be used for research on the physiology of bariatric surgery, the mouse provides the best model for studies of cellular and molecular mechanisms because transgenesis can be used to alter individual genes, and to label specific cell types. We show results here demonstrating successful creation of murine bariatric surgery models at Vanderbilt, and the use of the models to identify the first gene that plays an essential role in th efficacy of RYGB for long term maintenance of significant weight loss. The unique hypothesis to be tested is that the efficacy of bariatric surgery results not solely from a collection of changesto Gl signaling, but rather that essential changes in both Gl signaling AND in the plasticity and responsiveness of CNS homeostatic and hedonic circuits act synergistically to restore glucose homeostasis, and create a new weight set point. In this interdisciplinary team grant application, we bring together leading experts in human and murine bariatric surgery, murine pathology, Gl anatomy and function, obesity and diabetes, and quantitative human genetics to jointly study surgical preparations from humans and mice in order to identify the genes and cell types mediating the efficacy of bariatric surgery.

Public Health Relevance

Bariatric surgery is the only effective treatment for severe obesity and type 1 diabetes, but is costly, invasive, and not understood mechanistically. This program will combine bariatric surgery in transgenic mice with physiological and genetic studies in humans to determine the molecular/cellular basis for the efficacy of this procedure with the goal of improving surgical methods and facilitating discovery of new therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Resource-Related Research Projects (R24)
Project #
1R24DK096527-01A1
Application #
8583364
Study Section
Special Emphasis Panel (ZDK1-GRB-J (M2))
Program Officer
Teff, Karen L
Project Start
2013-09-16
Project End
2015-08-31
Budget Start
2013-09-16
Budget End
2014-08-31
Support Year
1
Fiscal Year
2013
Total Cost
$612,030
Indirect Cost
$212,030
Name
Vanderbilt University Medical Center
Department
Physiology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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Reddy, India A; Stanwood, Gregg D; Galli, Aurelio (2014) Moving beyond energy homeostasis: new roles for glucagon-like peptide-1 in food and drug reward. Neurochem Int 73:49-55
Panaro, Brandon L; Tough, Iain R; Engelstoft, Maja S et al. (2014) The melanocortin-4 receptor is expressed in enteroendocrine L cells and regulates the release of peptide YY and glucagon-like peptide 1 in vivo. Cell Metab 20:1018-29