ABSTRACT
The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) is essential for placental development. Here, we show that the mucin gene Muc1 is a PPARgamma target, whose expression is lost in PPARgamma null placentas. During differentiation of trophoblast stem cells, PPARgamma is strongly induced, and Muc1 expression is upregulated by the PPARgamma agonist rosiglitazone. Muc1 promoter is activated strongly and specifically by liganded PPARgamma but not PPARalpha or PPARdelta. A PPAR binding site (DR1) in the proximal Muc1 promoter acts as a basal silencer in the absence of PPARgamma, and its cooperation with a composite upstream enhancer element is both necessary and sufficient for PPARgamma-dependent induction of Muc1. In the placenta, MUC1 protein is localized exclusively to the apical surface of the labyrinthine trophoblast around maternal blood sinuses, resembling its luminal localization on secretory epithelia. Last, variably penetrant maternal blood sinus dilation in Muc1-deficient placentas suggests that Muc1 regulation by PPARgamma contributes to normal placental development but also that the essential functions of PPARgamma in the organ are mediated by other targets.
Subject(s)
Gene Expression Regulation, Developmental , Mucin-1/genetics , PPAR gamma/metabolism , Transcription, Genetic , Trophoblasts/metabolism , Animals , Binding Sites , Cells, Cultured , Crosses, Genetic , Electrophoretic Mobility Shift Assay , Enhancer Elements, Genetic , Female , Fluorescent Dyes , Genes, Reporter , Hypoglycemic Agents/pharmacology , Ligands , Luciferases/metabolism , Mice , Mice, Inbred C57BL , Microscopy, Fluorescence , PPAR gamma/agonists , Pregnancy , Promoter Regions, Genetic , Rosiglitazone , Stem Cells/cytology , Thiazolidinediones/pharmacology , Trophoblasts/cytology , Up-RegulationABSTRACT
Syndrome X, typified by obesity, insulin resistance (IR), dyslipidemia, and other metabolic abnormalities, is responsive to antidiabetic thiazolidinediones (TZDs). Peroxisome proliferator-activated receptor (PPAR) gamma, a target of TZDs, is expressed abundantly in adipocytes, suggesting an important role for this tissue in the etiology and treatment of IR. Targeted deletion of PPARgamma in adipose tissue resulted in marked adipocyte hypocellularity and hypertrophy, elevated levels of plasma free fatty acids and triglyceride, and decreased levels of plasma leptin and ACRP30. In addition, increased hepatic glucogenesis and IR were observed. Despite these defects, blood glucose, glucose and insulin tolerance, and insulin-stimulated muscle glucose uptake were all comparable to those of control mice. However, targeted mice were significantly more susceptible to high-fat diet-induced steatosis, hyperinsulinemia, and IR. Surprisingly, TZD treatment effectively reversed liver IR, whereas it failed to lower plasma free fatty acids. These results suggest that syndrome X may be comprised of separable PPARgamma-dependent components whose origins and therapeutic sites may reside in distinct tissues.
Subject(s)
Adipose Tissue/physiology , Insulin Resistance/genetics , Intercellular Signaling Peptides and Proteins , Liver/physiology , Muscle, Skeletal/physiology , Receptors, Cytoplasmic and Nuclear/deficiency , Receptors, Cytoplasmic and Nuclear/genetics , Transcription Factors/deficiency , Transcription Factors/genetics , Adipocytes/physiology , Adiponectin , Adipose Tissue/drug effects , Animals , Hypoglycemic Agents/pharmacology , Leptin/blood , Lipodystrophy/genetics , Liver/drug effects , Liver Function Tests , Metabolic Syndrome/genetics , Mice , Mice, Knockout , Muscle, Skeletal/drug effects , Organ Specificity , Proteins/metabolism , Rosiglitazone , Thiazolidinediones/pharmacologyABSTRACT
Targeting of the nuclear prostaglandin receptor peroxisome proliferator-activated receptor delta (PPARdelta) by homologous recombination results in placental defects and frequent (>90%) midgestation lethality. Surviving PPARdelta(-/-) mice exhibit a striking reduction in adiposity relative to wild-type levels. This effect is not reproduced in mice harboring an adipose tissue-specific deletion of PPARdelta, and thus likely reflects peripheral PPARdelta functions in systemic lipid metabolism. Finally, we observe that PPARdelta is dispensable for polyp formation in the intestine and colon of APC(min) mice, inconsistent with its recently proposed role in the establishment of colorectal tumors. Together, these observations reveal specific roles for PPARdelta in embryo development and adipocyte physiology, but not cancer.
