The goal of this study is to determine why some obese individuals develop insulin resistance and others do not. We hypothesize that an impairment in differentiation of fat cells (adipocytes) is responsible for the development of insulin resistance in select obese individuals. This study will evaluate obese individuals at baseline with respect to characteristics of adipocytes, including gene expression, and will then entail randomizing subjects to either weight loss or treatment with an insulin sensitizing drug (pioglitazone). Changes in insulin resistance will be associated with changes in adipocyte morphology and gene expression.

Healthy overweight/obese individuals will be screened for insulin resistance. Both insulin resistant individuals and insulin sensitive individuals (to serve as controls) will be eligible to enroll. Fat cel biopsy and CT scan of the abdomen is required at baseline and after an intervention with either weight loss or pioglitazone (drug to improve insulin resistance). Subjects will repeat insulin resistance test after the intervention as well. Subjects will learn much about their metabolism in this study, and will have an opportunity to improve their insulin resistance.

Inclusion Criteria:

• nondiabetic defined as fasting plasma glucose < 126 mg/dL
• body mass index 27 to 35 kg/m2
• no major organ diseases
• able to come to Stanford for regular clinical research center visits
• English speaking or has own translator

Exclusion Criteria:

• pregnancy/lactation
• history of eating disorder or major psychiatric illness
• allergy to thiazolidinedione
• elevation of liver enzymes (> 2.5 times upper normal limit)