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Skeletal muscle and insulin regulated genes

ABSTRACT: Insulin action in target tissues involved precise regulation of gene expression. To define the set of insulin-regulated genes in human skeletal muscle, we analyzed the global changes in mRNA levels during a 3-h hyperinsulinemic euglycemic clamp in vastus lateralis muscle of six healthy subjects. Using 29,308 cDNA element microarrays, we found that the mRNA expression of 762 genes, including 353 expressed sequence tags, was significantly modified during insulin infusion. 478 were up-regulated and 284 down-regulated. Most of the genes with known function are novel targets of insulin. They are involved in the transcriptional and translational regulation (29%), intermediary and energy metabolisms (14%), intracellular signaling (12%), and cytoskeleton and vesicle traffic (9%). Other categories consisted of genes coding for receptors, carriers, and transporters (8%), components of the ubiquitin/proteasome pathways (7%) and elements of the immune response (5.5%). These results thus define a transcriptional signature of insulin action in human skeletal muscle. They will help to better define the mechanisms involved in the reduction of insulin effectiveness in pathologies such as type 2 diabetes mellitus, a disease characterized by defective regulation of gene expression in response to insulin. An all pairs experiment design type is where all labeled extracts are compared to every other labeled extract. Keywords: all_pairs

ORGANISM(S): Homo sapiens

PROVIDER: GSE3881 | GEO | 2005/12/21

SECONDARY ACCESSION(S): PRJNA94123

REPOSITORIES: GEO

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Project description:Identification and validation of the pathways and functions regulated by the orphan nuclear receptor, ROR alpha1, in skeletal muscle The retinoic acid receptor-related orphan receptor (ROR) alpha has been demonstrated to regulate lipid metabolism. We were interested in the physiologically relevant roles, and pathways regulated by RORalpha1 action in skeletal muscle. This major mass organ accounts for ~40% of the total body mass, and significant levels of lipid catabolism, glucose disposal and energy expenditure. We utilized the strategy of targeted muscle specific expression of a truncated (dominant negative) RORalphaâDE in transgenic mice, to investigate RORalpha1 signalling (and function) in this peripheral tissue. Expression profiling and pathway analysis indicated that RORalpha regulated genes involved in: (i) lipid and carbohydrate metabolism, cardiovascular and metabolic disease; and (ii) the LXR nuclear receptor signaling pathway and, (iii) the Akt and AMPK signaling cascades. This analysis was extensively validated by rigorous qPCR analysis using TaqMan Low Density Arrays, coupled to rigorous statistical analysis (with Empirical Bayes, and Benjamini-Hochberg). Moreover, westerns and metabolic profiling were utilized to validate the genes, proteins and pathways (lipogenic, Akt, AMPK and fatty acid oxidation) involved in the regulation of metabolism by RORalph1. The identified genes and pathways were in concordance with the demonstration of hyperglycemia, glucose intolerance, attenuated insulin stimulated phosphorylation of Akt, and impaired glucose uptake in the transgenic heterozygous Tg-RORalphaâDE animals. In conclusion, we propose that RORalpha1 is involved in regulating the Akt2-AMPK signalling pathways in the context of lipid homeostasis in skeletal muscle. Total RNA was compared from quadriceps femoris of both transgenic and wild type mice. Transgenic mice contained a truncated version of human RORalpha1 (RORalpha1delDE) where the entire E region and part of the hinge/D region have been removed. This transgene is driven by a skeletal muscle specific human skeletal alpha-actin (HSA) promoter.

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Skeletal muscle and insulin regulated genes

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