 Our prior research has examined the pathogenesis and potential treatments for metabolic complications in people living with HIV. We have adopted the lipotoxicity hypothesis for Metabolic Syndrome X to explain the pathogenesis of impaired glucose tolerance IGT and fat redistribution in HIV: increased lipolysis and mobilization of lipids and free fatty acids from subcutaneous adipose depots leads to their excessive deposition in muscle and liver which contributes to dyslipidemia, insulin resistance, increased hepatic glucose output, and possibly visceral fat accumulation. Effective treatments have not been identified. Consensus groups recommend regular exercise and dietary modifications as primary and pharmacologic interventions as secondary treatments for the syndromes. We propose to test the efficacy of aerobic and weight lifting exercise training and an oral insulin-sensitizing agent pioglitazone as treatments for HIV-associated IGT and fat redistribution. We propose a 4-month, 2-group randomized study to evaluate the efficacy of pioglitazone and exercise pioglitazone in 40 men and 40 women living with HIV and IGT and fat redistribution. We will measure: insulin sensitivity, glucose disposal rate, hepatic glucose production rate 5hr-hyperinsulinemic euglycemic clamp with 6,6-2H2-glucose; whole-body and regional fat and muscle content 1H-MRI of the abdomen and thigh DEXA, soleus muscle and liver lipid content 1H-MRS, muscle and fat PPARgammaalpha mRNA and protein expression, serum lipid profiles, and serum adiponectin levels before and at the end of 4 months of treatment. We hypothesize that exercise training pioglitazone will be more effective than pioglitazone alone at improving insulin sensitivity, reducing visceral fat, liver and muscle lipid content, and increasing peripheral subcutaneous fat content in HIV-infected people. We hypothesize that combined treatment will be more effective because exercise training will activate PPARalpha expression in muscle and pioglitazone will activate PPARy expression in fat and muscle. We anticipate that this project will provide direct evidence that supports the combined use of exercise training and pioglitazone in people living with HIV and experiencing metabolic and anthropomorphic disorders that increase cardiovascular disease risk. 