Endocrine Abstracts

Nuclear receptors regulate many developmental processes and a vast array of physiological responses. They control the expression of subsets of specific genes by recruiting co-factors that can function either as co-activators or co-repressors to either stimulate or repress gene transcription. Using the ligand-binding domain of the estrogen receptor as bait we identified a receptor interacting protein of MW 140Kd that we called RIP140. Examination of RIP140 null mice showed two clear phenotypes: firstly, female mice were completely infertile due to ovulatory failure and secondly, both sexes were extremely lean even when fed a high fat diet. The failure to ovulate was caused by impaired amphiregulin signalling in cumulus cells leading to defective luteinisation. The resistance of the mice to obesity when fed a high fat diet was the result of fibre-type switching in muscle tissue and an increase in the number of brown/beige fat cells in adipose tissue, both of which led to an increase in energy expenditure. Clearly RIP140 regulates transcription of one or more genes involved in these physiological processes and much of my research in later years focussed on unravelling the underlying molecular mechanisms. One remarkable finding was that RIP140 could act as either a co-activator or a co-repressor in different biological processes. For example, in ovulation it functions as a co-activator to stimulate transcription from amphiregulin target genes in cumulus cells. On the other hand, in metabolic processes it functions as a co-repressor by competing with PGC1, a strong co-activator for PPAR receptors. Thus RIP140 emerged as a clinical target for interfering with ovulation or controlling obesity, but the complexity of the molecular mechanisms involved has hindered progress in this endeavour.