Journal ArticleDOI
PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes
Vamsi K. Mootha,Cecilia M. Lindgren,Cecilia M. Lindgren,Karl-Fredrik Eriksson,Aravind Subramanian,Smita Sihag,J. Lehar,Pere Puigserver,Emma Carlsson,Martin Ridderstråle,Esa Laurila,Nicholas E. Houstis,Mark J. Daly,Nick Patterson,Jill P. Mesirov,Todd R. Golub,Todd R. Golub,Pablo Tamayo,Bruce M. Spiegelman,Eric S. Lander,Joel N. Hirschhorn,Joel N. Hirschhorn,Joel N. Hirschhorn,David Altshuler,Leif Groop +24 more
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TLDR
An analytical strategy is introduced, Gene Set Enrichment Analysis, designed to detect modest but coordinate changes in the expression of groups of functionally related genes, which identifies a set of genes involved in oxidative phosphorylation whose expression is coordinately decreased in human diabetic muscle.Abstract:
DNA microarrays can be used to identify gene expression changes characteristic of human disease. This is challenging, however, when relevant differences are subtle at the level of individual genes. We introduce an analytical strategy, Gene Set Enrichment Analysis, designed to detect modest but coordinate changes in the expression of groups of functionally related genes. Using this approach, we identify a set of genes involved in oxidative phosphorylation whose expression is coordinately decreased in human diabetic muscle. Expression of these genes is high at sites of insulin-mediated glucose disposal, activated by PGC-1α and correlated with total-body aerobic capacity. Our results associate this gene set with clinically important variation in human metabolism and illustrate the value of pathway relationships in the analysis of genomic profiling experiments.read more
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Activation of nuclear receptor coactivator PGC-1α by arginine methylation
TL;DR: Peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), a tissue-specific and inducible transcriptional coActivator for several nuclear receptors, plays a key role in energy metabolism and is potentiated by arginine methylation by protein arginin methyltransferase 1 (PRMT1), another nuclear receptor coactivators.
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Increased lipid availability impairs insulin-stimulated ATP synthesis in human skeletal muscle
Attila Brehm,Martin Krššák,Albrecht Ingo Schmid,Peter Nowotny,Werner Waldhäusl,Michael Roden +5 more
TL;DR: Physiologically increased plasma FFA concentrations reduce insulin-stimulated muscle ATP synthase flux in parallel with induction of insulin resistance, and this results in reduced whole-body glucose metabolism.
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Decoding insulin resistance and metabolic syndrome for promising therapeutic intervention.
TL;DR: The thematic review section in this issue of the Journal of Endocrinology provides four review articles, discussing the disease mechanism of metabolic syndrome with the most recent research update from cell-based and animal studies, which address how insulin resistance in different organs contributes to metabolic syndrome at the molecular, biochemical, and physiological levels.
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Skeletal muscle fiber type: using insights from muscle developmental biology to dissect targets for susceptibility and resistance to muscle disease
TL;DR: These findings suggest that some muscle diseases may be treated by shifting fiber type characteristics either from slow to fast, or fast to slow phenotypes, depending on the disease.
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Targeting VEGF-B as a novel treatment for insulin resistance and type 2 diabetes
Carolina E. Hagberg,Annika Mehlem,Annelie Falkevall,Lars Muhl,Barbara C Fam,Henrik Ortsäter,Pierre Scotney,Daniel Nyqvist,Erik Samén,Li Lu,Sharon Stone-Elander,Joseph Proietto,Sofianos Andrikopoulos,Åke Sjöholm,Andrew D. Nash,Ulf Eriksson +15 more
TL;DR: In this article, the authors proposed VEGF-B antagonism as a novel pharmacological approach for type 2 diabetes, targeting the lipidtransport properties of the endothelium to improve muscle insulin sensitivity and glucose disposal.
References
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Journal ArticleDOI
Cluster analysis and display of genome-wide expression patterns
TL;DR: A system of cluster analysis for genome-wide expression data from DNA microarray hybridization is described that uses standard statistical algorithms to arrange genes according to similarity in pattern of gene expression, finding in the budding yeast Saccharomyces cerevisiae that clustering gene expression data groups together efficiently genes of known similar function.
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Molecular classification of cancer: class discovery and class prediction by gene expression monitoring.
Todd R. Golub,Todd R. Golub,Donna K. Slonim,Pablo Tamayo,Christine Huard,Michelle Gaasenbeek,Jill P. Mesirov,Hilary A. Coller,Mignon L. Loh,James R. Downing,Michael A. Caligiuri,Clara D. Bloomfield,Eric S. Lander +12 more
TL;DR: A generic approach to cancer classification based on gene expression monitoring by DNA microarrays is described and applied to human acute leukemias as a test case and suggests a general strategy for discovering and predicting cancer classes for other types of cancer, independent of previous biological knowledge.
Journal ArticleDOI
Significance analysis of microarrays applied to the ionizing radiation response
TL;DR: A method that assigns a score to each gene on the basis of change in gene expression relative to the standard deviation of repeated measurements is described, suggesting that this repair pathway for UV-damaged DNA might play a previously unrecognized role in repairing DNA damaged by ionizing radiation.
Journal ArticleDOI
A direct approach to false discovery rates
TL;DR: The calculation of the q‐value is discussed, the pFDR analogue of the p‐value, which eliminates the need to set the error rate beforehand as is traditionally done, and can yield an increase of over eight times in power compared with the Benjamini–Hochberg FDR method.
Journal ArticleDOI
Mechanisms Controlling Mitochondrial Biogenesis and Respiration through the Thermogenic Coactivator PGC-1
Zhidan Wu,Pere Puigserver,Ulf Andersson,Chen-Yu Zhang,Guillaume Adelmant,Vamsi K. Mootha,Amy E Troy,Saverio Cinti,Bradford B. Lowell,Richard C. Scarpulla,Bruce M. Spiegelman +10 more
TL;DR: PGC-1, a cold-inducible coactivator of nuclear receptors, stimulates mitochondrial biogenesis and respiration in muscle cells through an induction of uncoupling protein 2 (UCP-2) and through regulation of the nuclear respiratory factors (NRFs).
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