Effects of PPAR Ligands on Ectopic Fat Accumulation and Inflammation

• Ectopic fat accumulation after 3 months of therapy [ Time Frame: 3 months ] [ Designated as safety issue: No ]
  

• Adipose tissue inflammation [ Time Frame: 3 months ] [ Designated as safety issue: No ]
  

The correlation between obesity, inflammation and ectopic fat accumulation is well recognized; however, the mechanism(s) responsible for obesity induced insulin resistance is not well understood. We will focus on lipotoxicity and inflammation as the link between obesity and insulin resistance. The factors leading to inflammation and ectopic lipid accumulation in obesity and the best intervention to reverse this pathophysiology are not clear. In this study, we will examine inflammation in adipose tissue and muscle lipid mechanism in response to Peroxisome Proliferator Activated Receptors (PPAR) and ligands have synergistic anti-inflammatory effects in adipose tissue and activation of PPAR and decrease muscle lipid oxidation and redistribution of lipid from muscle to adipocytes respectively. The combination of both medications will be particularly effective in reducing inflammation and muscle lipid accumulation.

In this study, IGT subjects will be randomized to treatment with PPAR ligand (fenofibrate), PPAR ligand (pioglitazone) or combination of both for 10 weeks. Baseline studies will include assessment of body composition, insulin sensitivity, muscle and fat biopsies. All studies will be repeated after treatment with fenofibrate, pioglitazone or combination of both.

Specific Aims (SA) are as follows:

SA 1. Insulin sensitivity and Intramyocellular lipid (IMCL) from muscle biopsy specimens will be measured in response to different treatments (PPAR , and combination of both ligands).

SA 2. The rate of fatty acid oxidation and the number of mitochondria in muscle will be measured in response to PPAR ligands.

SA 3. The anti-inflammatory effects of PPAR and ligands will be studied by the measurement of the number of adipose tissue macrophages and the rate of macrophages apoptosis in fat biopsy specimens. In addition, the plasma levels and expression of proinflammatory proteins will be studied in response to different treatment.

SA 4. The rate of SUMOylation of PPAR (a novel mechanism regulating anti-inflammatory effects of PPAR ligands) will be studied in response to PPAR , ligand or combination of both.

These studies are designed to examine fundamental clinical mechanisms underlying the metabolic syndrome and diabetes.

Potential Impact on Veterans Health Care: The national obesity/diabetes epidemic is magnified in the VA, and the cost of caring for these patients is enormous. This study will provide data on the mechanism of action of these drugs, which will improve our understanding of these drugs, impaired glucose tolerance, and treatment of metabolic syndrome. From the clinical perspective, this study uses drugs to treat patients with IGT, which is rapidly becoming recognized as a "disease" because of its association with coronary artery disease risk factors, and because of its high rate of progression to T2DM. If these drugs were shown to improve the care of patients, then they would eventually be a cost savings to the VA, either by choosing the less expensive drug, or by using the drug that delays the progression of the disease, and improves the care of the patient by preventing complications.