Endocrine Abstracts

Nuclear Receptors control many developmental and physiological processes by regulating the expression of networks of genes. Their ability to activate or repress gene transcription depends on the recruitment of coactivators and corepressors that function as scaffolds for the binding of chromatin remodelling enzymes. RIP140 is a ligand dependant corepressor for most, if not all, nuclear receptors with key roles in energy homeostasis and reproduction.

RIP140 regulates carbohydrate and lipid metabolism by regulating metabolic gene programmes in adipose tissue and in muscle. Mice devoid of RIP140 are extremely lean, exhibit resistance to high fat diet-induced obesity and are protected against insulin resistance as they age or are fed high fat diets. It appears that peroxisome proliferator activated receptors and estrogen related receptors repress the expression of gene networks in metabolic tissues that would otherwise disrupt energy homeostasis by recruiting the RIP140 corepressor. As a consequence, chromatin remodelling enzymes are recruited to the promoters of target genes and this leads to epigenetic changes which prevents their transcription.

Mice lacking RIP140 also fail to ovulate following the pre-ovulatory surge of luteinising hormone although the process of luteinisation still occurs. This phenotype closely resembles that of the luteinised unruptured follicle syndrome often associated with infertility in women. The ovulatory failure is due to a primary defect within the ovary itself and our recent studies indicate that it is likely to reflect an alteration in the expression of genes involved in granulosa cell expansion and follicular rupture. We are now in the process of identifying direct RIP140 target genes in the ovary and will address the extent to which the function of RIP140 is conserved in different tissues or varies according to the endocrine response.