Effects of PPAR Ligands on Ectopic Fat Accumulation and Inflammation

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.

Inclusion Criteria:

- Impaired glucose tolerance and/or impaired fasting glucose and/or metabolic syndrome

- Age 18-65

- BMI 28-38

Exclusion Criteria:

- Renal insufficiency: creatinine.1.4

- Liver disease: ALT.2x normal, congestive heart failure, history of documented
coronary artery disease, concomitant use HMG CoA-reductase inhibitors (statins)

- Concurrent use of ASA, steroids and other anti-inflammatory agents