Program in Molecular Medicine
3T3 Cells; Adaptor Proteins, Signal Transducing; Adipocytes; Animals; Citric Acid Cycle; Energy Metabolism; Glucose; Glycolysis; Mice; Mitochondria; Nuclear Proteins; *Oxidative Phosphorylation; Repressor Proteins
Cell Biology | Endocrinology
Using an siRNA-based screen, we identified the transcriptional corepressor RIP140 as a negative regulator of insulin-responsive hexose uptake and oxidative metabolism in 3T3-L1 adipocytes. Affymetrix GeneChip profiling revealed that RIP140 depletion upregulates the expression of clusters of genes in the pathways of glucose uptake, glycolysis, TCA cycle, fatty acid oxidation, mitochondrial biogenesis, and oxidative phosphorylation in these cells. Conversely, we show that reexpression of RIP140 in mouse embryonic fibroblasts derived from RIP140-null mice downregulates expression of many of these same genes. Consistent with these microarray data, RIP140 gene silencing in cultured adipocytes increased both conversion of [14C]glucose to CO2 and mitochondrial oxygen consumption. RIP140-null mice, previously reported to resist weight gain on a high-fat diet, are shown here to display enhanced glucose tolerance and enhanced responsiveness to insulin compared with matched wild-type mice upon high-fat feeding. Mechanistically, RIP140 was found to require the nuclear receptor ERRalpha to regulate hexose uptake and mitochondrial proteins SDHB and CoxVb, although it likely acts through other nuclear receptors as well. We conclude that RIP140 is a major suppressor of adipocyte oxidative metabolism and mitochondrial biogenesis, as well as a negative regulator of whole-body glucose tolerance and energy expenditure in mice.
DOI of Published Version
J Clin Invest. 2006 Jan;116(1):125-36. Epub 2005 Dec 22. Link to article on publisher's site
The Journal of clinical investigation
Powelka, Aimee M.; Seth, Asha; Virbasius, Joseph V.; Kiskinis, Evangelos; Nicoloro, Sarah M.; Guilherme, Adilson L.; Tang, Xiaoqing; Straubhaar, Juerg R.; Cherniack, Andrew D.; Parker, Malcolm G.; and Czech, Michael P., "Suppression of oxidative metabolism and mitochondrial biogenesis by the transcriptional corepressor RIP140 in mouse adipocytes" (2005). Open Access Articles. 994.