Skeletal muscle is a major player in glucose homeostasis as muscle accounts for 80-90% of whole body glucose clearance. In obese individuals, excessive storage of triglyceride (TG) in white adipose tissue results in ectopic storage of TG in peripheral organs such as liver and skeletal muscle. Excessive intramuscular triglyceride (IMTG) has been correlated with impaired insulin-stimulated glucose uptake and therefore, serves as a surrogate marker for insulin resistance and type 2 diabetes. An emerging view is increased accumulation of TG in skeletal muscle correlates with increased levels of lipid metabolites that inhibit insulin signal transduction and are thus considered """"""""lipotoxic."""""""" It is now thought that the ability to store TG in tissues, thereby lowering levels of diacylglycerol (DAG) and other lipid metabolites, is critical to maintaining insulin sensitivity. The identification of Fat-Inducing Transcript proteins (FIT1 and FIT2), which are important for lipid droplet biogenesis, gives me the unique opportunity to directly test this hypothesis.
In Specific Aim 1, we will examine the effects of FIT1 or FIT2 transgene expression in type II (fast/glycolytic) skeletal muscle on glucose and lipid metabolism. We will measure various physiological parameters using indirect calorimetry, glucose tolerance and insulin tolerance tests as well as an examination of pathways important for regulating lipid and glucose metabolism using molecular biological methods.
In Specific Aim 2, we will examine the effects of whole body FIT1 deficiency, muscle FIT2 deficiency and FIT1/FIT2 combined deficiency on glucose and lipid metabolism. We will then measure the same parameters stated in Specific Aim 1. The findings from this work will help us understand the role of FIT1 and FIT2 in muscle lipid and glucose metabolism and in obesity-associated diseases.
|Miranda, Diego A; Koves, Timothy R; Gross, David A et al. (2011) Re-patterning of skeletal muscle energy metabolism by fat storage-inducing transmembrane protein 2. J Biol Chem 286:42188-99|