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.
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.
|Baack, Michelle L; Wang, Chunlin; Hu, Shanming et al. (2014) Hyperglycemia induces embryopathy, even in the absence of systemic maternal diabetes: an in vivo test of the fuel mediated teratogenesis hypothesis. Reprod Toxicol 46:129-36|
|Lamping, K G; Nuno, D W; Coppey, L J et al. (2013) Modification of high saturated fat diet with n-3 polyunsaturated fat improves glucose intolerance and vascular dysfunction. Diabetes Obes Metab 15:144-52|
|Hu, Shanming; Yao, Jianrong; Howe, Alexander A et al. (2012) Peroxisome proliferator-activated receptor ýý decouples fatty acid uptake from lipid inhibition of insulin signaling in skeletal muscle. Mol Endocrinol 26:977-88|
|Baack, M L; Norris, A W; Yao, J et al. (2012) Long-chain polyunsaturated fatty acid levels in US donor human milk: meeting the needs of premature infants? J Perinatol 32:598-603|
|Norris, Andrew W; Sigmund, Curt D (2012) A second chance for a PPAR? targeted therapy? Circ Res 110:8-11|
|Norris, Andrew W; Wang, Chunlin; Yao, Jianrong et al. (2011) Effect of insulin and dexamethasone on fetal assimilation of maternal glucose. Endocrinology 152:255-62|
|Yao, Jianrong; Wang, Chunlin; Walsh, Susan A et al. (2010) Localized fetomaternal hyperglycemia: spatial and kinetic definition by positron emission tomography. PLoS One 5:e12027|