Role of nuclear receptor corepressor RIP140 in metabolic syndrome.
Bottom Line: Moreover, white adipocytes with targeted disruption of RIP140 express genes characteristic of brown fat including CIDEA and UCP1 while skeletal muscles show a shift in fibre type composition enriched in more oxidative fibres.Thus, RIP140 is a potential therapeutic target in metabolic disorders.This article is part of a Special Issue entitled: Translating nuclear receptors from health to disease.
Affiliation: Institute of Reproductive and Developmental Biology, Imperial College London, Faculty of Medicine, Hammersmith Campus 158 Du Cane Road, W12 0NN, UK. firstname.lastname@example.orgShow MeSH
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Mentions: The pathways underlying the metabolic syndrome are interlinked in a complex network and an effective approach to treatment may need to target multiple points. For example, TDZ treatment, which activates PPARγ to reduce inflammation and promote adipogenesis and enhances adiponectin secretion to increase lipid oxidation [117,118], is often prescribed in conjunction with metformin to reduce gluconeogenesis in the liver, improve glucose uptake in peripheral tissue and overall insulin sensitivity. The evidence accumulated form studying RIP140 suggests that targeting the function of this cofactor for treatment of metabolic disorders would be of particular value since it would also have multiple beneficial consequences (Fig. 3). As detailed above, RIP140 mice have a hypermetabolic phenotype, largely as a result of upregulation of genes involved in FA β-oxidation, oxidative phosphorylation, TCA cycle and mitochondrial biogenesis in adipose tissue and muscle [37,75]. This causes WAT to function in a manner akin to BAT to expend stored fat for thermogenesis, while in skeletal muscle the proportion of type I oxidative fibres, where TAGs are mainly used as fuel, is increased. Consequently, lipids are removed from the circulation, and both visceral and subcutaneous fat depots are reduced . The upregulation of UCP1 in WAT  may also limit the amount of ROS produced by the mitochondria  to prevent inhibition of insulin signalling. Absence of RIP140 may have an additional protective effect on insulin signalling by preventing downregulation and inhibition of GLUT4 . Impairing RIP140 function would protect against hepatic steatosis during a lipid challenge by promoting gluconeogenesis and reducing lipogenesis. Here, downregulation of SREBP1c and FAS restricts de novo FA synthesis , therefore reducing both TAG and sphingolipid biosynthetic pathways and the production of harmful intermediates. Furthermore, absence of RIP140 in macrophages would decrease the inflammation associated with obesity and insulin resistance . The net results are improved lipid partitioning (decrease in circulating and ectopic load), decrease in adipose tissue size to allow it to regain normal lipid homeostatic function, and consequently, improved insulin sensitivity. The phenotype of RIP140 mice is proof of principle that targeting RIP140 might constitute a successful approach for the treatment of metabolic syndrome. Although caution must be exercised since RIP140 function is essential for female fertility [28,121,122], this might not necessarily be a priority since metabolic disorders prevail at an age past sexual reproduction. Drugs seldom approach 100% efficiency, however, even a 50% inhibition of RIP140 activity would be beneficial, since heterozygous mice challenged with a high-fat diet also display improved metabolic parameters at a level intermediate between wild-type and animals [74,75].
Affiliation: Institute of Reproductive and Developmental Biology, Imperial College London, Faculty of Medicine, Hammersmith Campus 158 Du Cane Road, W12 0NN, UK. email@example.com