Rosiglitazone Increases the Expression of Peroxisome Proliferator-Activated Receptor-γ Target Genes in Adipose Tissue, Liver, and Skeletal Muscle in the Sheep Fetus in Late Gestation

Exposure to maternal overnutrition increases the expression of peroxisome proliferator-activated receptor-gamma (PPAR gamma) in adipose tissue before birth, and it has been proposed that the precocial activation of PPAR gamma target genes may lead to increased fat deposition in postnatal life. In this study, we determined the effect of intrafetal administration of a PPAR gamma agonist, rosiglitazone, on PPAR gamma target gene expression in fetal adipose tissue as well indirect actions of rosiglitazone on fetal liver and skeletal muscle. Osmotic pumps containing rosiglitazone (n = 7) or vehicle (15% ethanol, n = 7) were implanted into fetuses at 123-126 d gestation (term = 150 +/- 3 d gestation). At 137-141 d gestation, tissues were collected and mRNA expression of PPAR gamma, lipoprotein lipase (LPL), adiponectin, and glycerol-3-phosphate dehydrogenase (G3PDH) in adipose tissue, PPAR alpha and PPAR gamma-coactivator 1 alpha (PGC1 alpha) in liver and muscle and phosphoenol pyruvate carboxykinase (PEPCK) in liver determined by quantitative real-time RT-PCR. Plasma insulin concentrations were lower in rosiglitazone-treated fetuses (P < 0.02). Rosiglitazone treatment resulted in increased expression of LPL and adiponectin mRNA (P < 0.01) in fetal adipose tissue. The expression of PPAR alpha mRNA in liver (P < 0.05) and PGC1 alpha mRNA (P < 0.02) in skeletal muscle were also increased by rosiglitazone treatment. Rosiglitazone treatment increased expression of PPAR alpha target genes within fetal adipose tissue and also had direct or indirect actions on the fetal liver and muscle. The effects of activating PPAR alpha in fetal adipose tissue mimic those induced by prenatal overnutrition, and it is therefore possible that activation of PPAR alpha may be the initiating mechanism in the pathway from prenatal overnutrition to postnatal obesity. (Endocrinology 150: 4287-4294, 2009)