Endocrine Abstracts (2009) 20 S28.1

Diverse actions of the nuclear receptor corepressor RIP140 in metabolic regulation

Malcolm Parker, Mark Christian, Evangelos Kiskinis, Asmaa Fritah, Ariel Poliandri, Jenny Steel, Magnus Hallberg, Birger Herzog, Asha Seth, Steven Dilworth & Roger White

Faculty of Medicine, Imperial College London, Institute of Reproductive & Developmental Biology, London W12 0NN, UK.

PGC1 and RIP140 are key regulators of nuclear receptor signalling that control metabolic gene expression in adipose tissue, liver and muscle. PGC1 promotes whereas RIP140 represses the expression of a network of catabolic genes in adipose and muscle. Thus mice devoid of RIP140 accumulate less fat in adipose tissue and liver while mitochondrial biogenesis and respiration is increased in type 2 muscle fibres; as a consequence, the mice maintain their insulin sensitivity as they age or are fed a high fat diet. Expression profiling indicates RIP140 suppresses the expression of genes in adipose and muscle that are involved in energy expenditure, including fatty acid oxidation, oxidative phosphorylation and mitochondrial biogenesis but is necessary for the expression of genes involved in lipogenesis and triglyceride storage. Analysis of cultured adipocytes and myofibres after in vitro differentiation demonstrates that RIP140 functions as a corepressor for PPARs and ERRs. Analysis of the UCP1 gene, which is de-repressed in white adipose tissue, indicates that the repression of metabolic genes is achieved by the recruitment of a combination of histone modifying enzymes and DNA methyl transferases which leads to methylation of specific histone residues and DNA. Interestingly, many of the metabolic genes repressed by RIP140 are activated by the coactivator PGC1. It appears that these two cofactors function to remodel chromatin in the vicinity of metabolic genes and thereby regulate their transcription through mutually antagonistic mechanisms including post translational modifications.