| Background: Lipodystrophy (LD) is a major health problem in HIV-infected patients, who are treated with "highly active anti-retroviral therapy" (HAART); the prevalence is about 25 to 50%. LD is characterized by a redistribution of fat tissue, consisting of peripheral fat loss (particularly in the face and extrimities) and central fat storage (particularly intra-abdominal). LD is often accompanied by cardiovascular risk factors like insulin resistance, diabetes mellitus, hyperlipidemia and a disturbed endothelial function. Since HAART has resulted in a dramatic reduction of HIV-related morbidity and mortality, the metabolic and vascular complications of this therapy seem to determine the future picture. Peripheral fat loss possibly plays a central role in the etiology of LD. Protease inhibitors (PI) inhibit the differentiation of peripheral fat cells by inhibiting the expression of genes that are involved in fat cell differentiation. In addition, both PI and reverse transcription inhibitors (RTI) induce enhanced apoptosis of peripheral fat cells. A lower capacity for storage of triglycerides in peripheral fat cells possibly leads to a higher flux of free fatty acids to the liver, VLDL overproduction and central fat accumulation. Thiazolidinediones (TZD) are synthetic ligands for activation of the nuclear receptor 'peroxisome proliferator-activated receptor type gamma' (PPAR-g). This regulates the transcription of genes that are involved in the differentiation and proliferation of peripheral (and not of intra-abdominal) fat cells and stimulates insulin sensitivity. - Hypothesis: Our hypothesis is that TZD stimulate peripheral fat cell differentiation by modulating the expression of genes involved in fat cell differentiation. This results in an improvement of insulin sensitivity, hepatic fatty acid flux, fat distribution and eventually the cardiovascular risk profile. Other insulin sensitizers like metformine, will probably not improve fat cell differentiation and fat distribution. |
