ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2006) 12 S9

The ups and downs of nuclear receptor action in metabolic tissues

M Parker, E Kiskinis, M Christian, A Seth, D Debevec, D Nichol, J Steel & R White

Imperial College London, London, United Kingdom.

Nuclear receptors control developmental and physiological processes by regulating the transcription of gene networks in specific cells. This is achieved by the recruitment of coactivators and corepressors that lead to chromatin remodelling and alterations in gene transcription. RIP140 is a ligand dependant corepressor for nuclear receptors that plays key roles in adipose tissue and muscle to regulate energy homeostasis.

RIP140 regulates carbohydrate and lipid metabolism in white adipocytes by controlling the expression of metabolic gene programmes. The absence of the corepressor leads to the upregulation of genes that promote catabolism, an increase in energy expenditure and the loss of fat stores from adipose tissue. Studies in brown and white adipocytes suggest that the repression of metabolic genes by RIP140 is achieved by its recruitment to peroxisome proliferator activated receptors and to estrogen related receptors. The repressor acts as a scaffold protein bridging the nuclear receptors with chromatin remodelling enzymes that lead to a marked increase in repressive histone marks and a reduction in activation marks in the vicinity of target genes. In muscle, RIP140 induces a switch from type 2 to type I muscle fibres with a corresponding increase in mitochondrial biogenesis and oxidative capacity. We are in the process of determining the precise mechanism by which the corepressor is recruited to distinct nuclear receptors and the enzymes that lead to chromatin remodelling and repression of target genes.

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