This application by a new investigator focuses on the identification of key regulators in skeletal muscle that simultaneously promote the capacity to utilize fat-derived energy and increase the responsiveness to insulin. These two features of healthy metabolism are progressively lost as part of type 2 diabetes pathogenesis. Often, mechanisms that stimulate the use of fat-derived energy in muscle produce resistance to insulin. The overall goal of this proposal is to identify regulatory mediators that increase the capacity of muscle to utilize fat-derived fuel while enhancing sensitivity to insulin. The central hypothesis of this proposal is that PPAR-gamma directly promotes metabolic health in muscle by regulating specific components of lipid metabolism and insulin signaling. Preliminary studies presented herein, using a cell-based model of skeletal muscle, demonstrate that PPAR-gamma directly stimulates the use of fat-derived energy as well as insulin sensitivity. This proposal will employ this model and a newly developed transgenic mouse model in order to dissect the molecular events initiated by PPAR-gamma that lead to the observed improvements in fat utilization and insulin sensitivity.
The specific aims of this proposal are to: (1) identify the cellular and molecular mechanisms by which muscle PPAR-gamma promotes lipid metabolism without impeding insulin signaling;(2) identify the cellular mechanisms by which muscle PPAR-gamma promotes insulin sensitivity by dissecting the components of signaling upstream of observed enhancements;and (3) determine the whole-body metabolic consequences of enhanced muscle PPAR-gamma action using a recently-created transgenic model. The therapeutic value of selective activation of PPAR-gamma in muscle will be modeled using a murine model of insulin resistance.

Public Health Relevance

This application, from a new investigator, focuses on identifying molecular regulators that simultaneously promote the use of fat-derived energy and responsiveness to insulin in skeletal muscle. The knowledge gained from the successful completion of this project will help design new strategies to prevent and treat type 2 diabetes onset and progression.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK081548-04
Application #
8255591
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Laughlin, Maren R
Project Start
2009-07-15
Project End
2013-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
4
Fiscal Year
2012
Total Cost
$257,277
Indirect Cost
$85,759
Name
University of Iowa
Department
Pediatrics
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
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