News & Research

    University of Michigan, Ann Arbor, Michigan

Gastric Fuel Sensing and Energy Metabolism

General Research Subject: Obesity

Focus: Obesity, Obesity\Animal Models, Signal Transduction (Non-Insulin Action), Signal Transduction (Non-Insulin Action)\Hormones, Signal Transduction (Non-Insulin Action)\Transgenic Models

Type of Grant: Basic Science

Project Start Date: January 1, 2013

Project End Date: December 31, 2015

Research Description

Obesity, a significant health burden on American society, is tightly associated with type 2 diabetes. Increase in caloric intake is the driving force for caloric surplus leading to obesity. While the brain is critical in the control of caloric intake, other organs such as the stomach and adipose tissues are involved in this regulation. Gastric bypass surgery is the most effective treatment option for obesity and diabetes. Pharmacological intervention of the stomach (pharmacological gastric bypass) to replace the surgery is attempting and requires the identification of therapeutic targets in the stomach. Our preliminary studies have identified a molecule named mammalian target of rapamycin in a specific type of cells in the stomach named gastric endocrine cells. This molecule plays a critical role in the coordination of nutrient availability and ingestive behavior.

In this proposal, we will use cell biological and mouse transgenic techniques to examine how this molecule detects the nutrition supply and coordinates the food intake to match the overall energy needs. Completion of this proposal will advance our understanding on how energy supply affects intracellular processes in gastric endocrine cells, and will provide new information on the interaction between these cells and nutrients. Defining the mechanisms on this interaction would shift therapeutic focus on obesity to gastric targets.

Research Profile

What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and curing diabetes?

Obesity, a significant health burden on American society, is tightly associated with type 2 diabetes. Increase in caloric intake is the driving force for caloric surplus leading to obesity. While the brain is critical in the control of caloric intake, other organs such as the stomach and adipose tissues are involved in this regulation. The goal of this project is to elucidate the mechanism by which the stomach integrates energy levels at the organism level to coordinate energy intake and expenditure. We hypothesize that mTOR signaling pathway in the gastric mucosa plays a critical role in the coordination of nutrient availability and ingestive behavior via the production of ghrelin.

We propose to use cell biological and transgenic techniques to achieve the following goals: 1) To examine the function of mTOR signaling in fuel sensing and ghrelin production in gastric ghrelin cells. 2) To determine the mechanisms by which gastric mTOR signaling regulates food intake and energy metabolism in mice. Completion of this proposal will advance our understanding on how energy supply affects intracellular processes in the production of ghrelin, and will provide new information on the interaction between gastric endocrine cells and nutrients. Defining the mTOR signaling pathways to inhibit the production of ghrelin would shift therapeutic focus on obesity and type 2 diabetes to gastric targets.

If a person with diabetes were to ask you how your project will help them in the future, how would you respond?

Gastric bypass surgery is the most effective treatment option for obesity and diabetes. Pharmacological intervention of the stomach (pharmacological gastric bypass) to replace the surgery is attempting and requires the identification of therapeutic targets in the stomach. We believe that dysfunction of the stomach in the coordination of nutrient availability and energy intake is critical for the development of obesity and diabetes. Completion of this project will provide a rationale for the correction of this gastric dysfunction and the intervention of obesity and type 2 diabetes.

Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your efforts?

As a gastrointestinal physiologist, I have focused my research on the gastric hormones which are critical for the control of energy metabolism. We have recently identified the gastric mTOR signaling pathway as an important mechanism by which the stomach coordinates the energy supply with the energy intake. This mechanism is critical for the maintenance of the energy balance and largely contributes to the glucose homeostasis. We therefore believe that defining the mechanism by which gastric mTOR signaling regulates energy metabolism and glucose homeostasis will provide an alternative therapy for obesity and type 2 diabetes. This award will provide a great opportunity for me to characterize the role of gastric mTOR signaling in the development of obesity and diabetes.

In what direction do you see the future of diabetes research going?

Understanding how gastric bypass improves the impaired glucose metabolism in type 2 diabetes is one of the most important directions in diabetes research. Another important direction is to elucidate the mechanisms by which insulin resistance develops in obesity.