Endocrine Abstracts (2007) 13 P162

The importance of gene repression for metabolic regulation in human fat

Daniel Morganstein, Birger Herzog, Roger White & Malcolm Parker


Imperial College, London, United Kingdom.


The nuclear receptor co-factor RIP140 has an essential role in metabolic regulation. Genetically manipulated mice lacking RIP140 show reduced fat accumulation, increased energy expenditure and increased insulin sensitivity. They gain less weight on high fat feeding than wild type littermates, and are protected from both age and high fat diet induced insulin resistance.

RIP140 is a repressor of transcription and in its absence metabolic gene networks are upregulated. This increases the activity of pathways including fatty acid β-oxidation, the tricyclic acid cycle and oxidative phosphorylation. Amongst the genes showing increased expression are UCP-1, CPT1b and CIDEA which are involved in thermogenesis. Changes are observed in metabolic tissues including white adipocytes and skeletal muscle.

Human and mouse RIP140 are highly conserved, and the exogenous expression of human RIP140 in cells derived from the RIP140 null mouse reverses the effects of gene deletion. However, it is not known if RIP140 serves a similar function in human adipose cells.

Using an shRNA approach we have found that the depletion of the co-repressor from human sub-cutaneous adipocytes also alters metabolic gene expression. Amongst the specific genes upregulated were UCP-1 and CPT1b, which are RIP140 targets in mouse adipose tissue.

Analysis of human adipogenesis when fetal mesenchymal stem cells are induced to differentiate indicates that the expression of RIP140 falls rapidly following induction, before the cells gain expression of pre-adipocyte markers. Therefore, it is possible that RIP140 is functioning either to maintain the stem cell state, or acting to regulate the process of commitment to the adipogenic lineage. This will be addressed by manipulating RIP140 levels in the stem cells.

In conclusion the function of RIP140 in fat appears to be conserved between mouse and human, suggesting that nuclear receptor-RIP140 signalling may be a useful therapeutic target for obesity and diabetes.

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