PPAR-gamma: A multifaceted transcription factor important in diabetes, cardiovascular disease, and cancer

Peroxisome proliferator-activated receptor gamma (PPAR-gamma) is a nutrient-sensing transcription factor that associates with cardiovascular diseases and metabolic disorders. Its agonists, the thiazolidinediones (TZDs), are clinically used to treat type 2 diabetes. This thesis investigated the multifaceted functions of PPAR-gamma and the pharmacology of TZDs in insulin sensitivity, glucose homeostasis, adipogenesis, blood pressure regulation, tumorigenesis, and cardiac growth.; We rescued the embryonic lethality of generalized PPAR-gamma deficiency using Cre-LoxP technology to preserve PPAR-gamma expression in the placenta (MORE-PGKO mice). These mice demonstrated that PPAR-gamma is required to maintain normal adiposity, insulin sensitivity, and blood pressure.; Administration of rosiglitazone, a TZD, to these PPAR-gamma deficiency mice improved glucose homeostasis in both males and females. In females, rosiglitazone stimulated fat growth and was sufficient to improve insulin sensitivity. Vaspin, but not likely leptin or adiponectin, is a candidate adipokine that is responsible for this insulin-sensitizing effect. In males, glucose homeostasis was improved independently of adipose tissue and insulin-sensitivity likely by improving beta-cell function. Surprisingly, rosiglitazone treatment of male MORE-PGKO mice led to the development liver tumors, suggesting a tumor suppressor function of PPAR-gamma.; To directly determine the role of PPAR-gamma in cardiac growth, we developed a cardiomyocyte-specific PPAR-gamma knockout (CM-PGKO) mouse model. Cardiomyocyte PPAR-gamma was required to suppress cardiac growth, embryonic gene expression, and nuclear-factor-kappa-B activity in vivo. Rosiglitazone induced cardiac hypertrophy at least partially independent of PPAR-gamma in cardiomyocytes and through different mechanisms from CM-PGKO. These data may provide guidance for designing new drugs with fewer cardiac side effects.; In order to distinguish TZDs' intrinsic effects on cardiomyocytes from their blood pressure-lowering effects, we monitored pressure overload (POL) and found that systolic pressure at later stages was the major determinant of cardiac hypertrophy. In contrast to pioglitazone and troglitazone, rosiglitazone did not inhibit POL-induced cardiac hypertrophy. Future studies comparing multiple TZDs are needed to understand the pharmacology of this effect and to explore the role of PPAR-gamma in POL-induced cardiac hypertrophy.