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This version published online on June 11, 2009
Endocrinology, doi:10.1210/en.2009-0462
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Submitted on April 13, 2009
Accepted on May 29, 2009

Rosiglitazone increases the expression of Peroxisome Proliferator-Activated Receptor-{gamma} target genes in adipose tissue, liver and skeletal muscle in the sheep fetus in late gestation

B S Muhlhausler*, J L Morrison, and I C McMillen

Early Origins of Adult Health Research Group, Sansom Research Institute, University of South Australia, Australia

* To whom correspondence should be addressed. E-mail: Beverly.Muhlhausler{at}unisa.edu.au.

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% EtOH, n=7) were implanted into fetuses at 123–126 d gestation (term=150 ± d gestation). At 137–141d 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} (PGC-1{alpha}) in liver and muscle and phosphoenolpyruvate (PEPCK) in liver determined by qRT-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 PGC-1{alpha} mRNA (P<0.02) in skeletal muscle were also increased by rosiglitazone treatment.

Rosiglitazone treatment increased expression of PPAR{gamma} target genes within fetal adipose tissue and also had direct or indirect actions on the fetal liver and muscle. The effects of activating PPAR{gamma} in fetal adipose tissue mimic those induced by prenatal overnutrition, and it is therefore possible that activation of PPAR{gamma} may be the initiating mechanism in the pathway from prenatal overnutrition to postnatal obesity.
Key words: PPAR{gamma} • adipose tissue • muscle • liver






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