The transcriptional corepressor RIP140 regulates oxidative metabolism in skeletal muscle.

Nuclear receptor signaling plays an important role in energy metabolism. In this study we demonstrate that the nuclear receptor corepressor RIP140 is a key regulator of metabolism in skeletal muscle. RIP140 is expressed in a fiber type-specific manner, and manipulation of its levels in null, heterozygous, and transgenic mice demonstrate that low levels promote while increased expression suppresses the formation of oxidative fibers. Expression profiling reveals global changes in the expression of genes implicated in both myofiber phenotype and metabolic functions. Genes involved in fatty-acid oxidation, oxidative phosphorylation, and mitochondrial biogenesis are upregulated in the absence of RIP140. Analysis of cultured myofibers demonstrates that the changes in expression are intrinsic to muscle cells and that nuclear receptor-regulated genes are direct targets for repression by RIP140. Therefore RIP140 is an important signaling factor in the regulation of skeletal muscle function and physiology.

Multiple signaling defects in the absence of RIP140 impair both cumulus expansion and follicle rupture.

The nuclear receptor corepressor RIP140 is essential in the ovary for ovulation, but is not required for follicle growth and luteinization. To identify genes that may be subject to regulation by RIP140 or play a role in ovulation, we compared ovarian gene expression profiles in untreated immature wild-type and RIP140 null mice and after treatment with pregnant mare serum gonadotropin and human chorionic gonadotropin. Many genes involved in signaling, extracellular matrix formation, cell-cell attachment, and adhesion were aberrantly regulated in the absence of RIP140, varying according to the hormone status of the mice. Notable among these was the reduced expression of a number of genes that encode components of signaling pathways and matrix proteins required for cumulus expansion, a key remodeling process necessary for ovulation. Histological analysis confirmed that cumulus expansion in RIP140 null mice is reduced, oocyte detachment from the mural cell wall is impaired, and follicles fail to rupture in response to LH. Although the expression of many genes involved in cumulus cell expansion was reduced, there was a subset of genes involved in extracellular matrix formation and cell-cell interactions that was up-regulated and may interfere with ovarian tissue remodeling. We propose that widespread gene dysregulation in ovarian tissues in the absence of RIP140 leads to the anovulatory phenotype. This helps to define an important role for RIP140 in the regulation of multiple processes leading to ovulation.

Estrogenic activity of a polyphenolic extract of the leaves of Epimedium brevicornum.

The estrogenic activity of a polyphenolic extract of the leaves of Epimedium brevicornum and five fractions obtained by solid-phase extraction were investigated using estrogen-responsive bioassays, a yeast cell assay and the Ishikawa Var-I assay. The extract was found to exhibit significant estrogenic activity in both assays. Furthermore, bioassay-guided fractionation led to localisation of the estrogenicity in the relatively non-polar fractions of the polyphenolic extract.

Estrogenic and anticarcinogenic properties of kurarinone, a lavandulyl flavanone from the roots of Sophora flavescens.

Kurarinone, a lavandulyl flavanone, was isolated from a polyphenolic extract of the roots of Sophora flavescens using fractionation guided by estrogenic activity, which was determined by recombinant yeast and Ishikawa Var-I bioassays. Kurarinone showed weak estrogenic activity both in the yeast screen and in the Ishikawa Var-I assay with EC(50) values of 4.6 and 1.66 microM, respectively. Furthermore, kurarinone was found to have potent cytotoxic activity (IC(50) value = 22.2 microM) against human MCF-7/6 breast cancer cells in the sulforhodamine-B assay.

Nuclear receptor corepressor RIP140 regulates fat accumulation.

Nuclear receptors and their coactivators have been shown to function as key regulators of adipose tissue biology. Here we show that a ligand-dependent transcriptional repressor for nuclear receptors plays a crucial role in regulating the balance between energy storage and energy expenditure. Mice devoid of the corepressor protein RIP140 are lean, show resistance to high-fat diet-induced obesity and hepatic steatosis, and have increased oxygen consumption. Although the process of adipogenesis is unaffected, expression of certain lipogenic enzymes is reduced. In contrast, genes involved in energy dissipation and mitochondrial uncoupling, including uncoupling protein 1, are markedly increased. Therefore, the maintenance of energy homeostasis requires the action of a transcriptional repressor in white adipose tissue, and ligand-dependent recruitment of RIP140 to nuclear receptors may provide a therapeutic target in the treatment of obesity and related disorders.

Daucane phytoestrogens: a structure-activity study.

The estrogenic activity of a series of analogues of the daucane ester ferutinin (1a) modified at the acyl moiety was investigated in a yeast screen containing the human estrogen receptor alpha. Rather strict structure-activity relationships were observed. Thus, while the parent polyol (jaeschkeanadiol, 2a) was inactive, the presence of a p-hydroxybenzoyl moiety was necessary for activity in the yeast screen. Homologation and vinylation were both detrimental for activity, as were methylation of the p-hydroxyl substituent and the introduction of oxygen functions on the adjacent carbons.

Effects of perinatal octylphenol on ultrasound vocalization, behavior and reproductive physiology in rats.

A rodent diet containing paraffin wax was designed to administer the environmental estrogen octylphenol (OP) to nonpregnant, pregnant and lactating rats. The estrogenic activity of OP via this diet was first confirmed in ovariectomized adult animals: 20 mg OP/kg/day increased the mitoses in the vaginal epithelium, and 60 mg OP/kg/day stimulated mitoses in the uterine luminal epithelium. The effects on a variety of reproductive and nonreproductive parameters were then investigated in the offspring of dams fed OP (100-250 mg/kg/day during gestation and lactation). A number of modest reproductive and morphological effects observed in the offspring including decreased body weights in adults of both sexes, disrupted vaginal cyclicity and decreases in seminiferous tubule diameter and testis, kidney, spleen and ovary weights. Behavioral effects included increased sexual arousal in males, increased sexual motivation in females towards a female teaser and increased motor activity by females. Ultrasonic vocalizations by pups at Postnatal Day (PND) 7 were reduced in number and duration in both sexes. There were no effects of perinatal OP on ano-genital distance, prepuce separation, aggressive behavior or adult ultrasound vocalization. These observations confirm that the dietary intake of estrogenic amounts of OP during pregnancy and lactation can have a wide variety of effects in the offspring.