PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes

  title={PGC-1$\alpha$-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes},
  author={Vamsi K. Mootha and Cecilia M. Lindgren and K. -F. Eriksson and Aravind Subramanian and Smita Sihag and Joseph Leh{\'a}r and Pere Puigserver and Emma Carlsson and Martin Ridderstr{\aa}le and Esa Laurila and Nicholas E Houstis and Mark J. Daly and Nick J. Patterson and Jill P. Mesirov and Todd R. Golub and Pablo Tamayo and Bruce M Spiegelman and Eric S. Lander and Joel N. Hirschhorn and David M Altshuler and Leif C. Groop},
  journal={Nature Genetics},
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… 

Genes involved in oxidative phosphorylation are coordinately upregulated with fasting hyperglycaemia in livers of patients with type 2 diabetes

The results indicate that upregulation of genes involved in OXPHOS in the liver, which are regulated by different mechanisms from genes in the skeletal muscle, is associated with fasting hyperglycaemia in patients with type 2 diabetes.

Errα and Gabpa/b specify PGC-1α-dependent oxidative phosphorylation gene expression that is altered in diabetic muscle

The results illustrate the dissection of gene regulatory networks in a complex mammalian system, elucidate the mechanism of PGC-1α action in the OXPHOS pathway, and suggest that Errα agonists may ameliorate insulin-resistance in individuals with type 2 diabetes mellitus.

Exercise, Gene Regulation, and Cardiometabolic Disease

This chapter will detail genes which are misregulated in cardiometabolic disease and how the aberrant expression of these genes results in metabolic issues and highlight that exercise can positively influence several of the same molecular pathways that are negatively affected in CMD.

PGC-1α: a potent transcriptional cofactor involved in the pathogenesis of type 2 diabetes

How PGC-1α links cellular glucose metabolism, insulin sensitivity and mitochondrial function, and why defects in P GC-1 α expression and regulation may contribute to the pathophysiology of type 2 diabetes in humans are considered.

Decreased expression of genes involved in oxidative phosphorylation in human pancreatic islets from patients with type 2 diabetes

Pancreatic islets from patients with T2D show decreased expression of a set of OXPHOS genes, which may lead to impaired insulin secretion.

Physiological insights gained from gene expression analysis in obesity and diabetes.

Microarray technology permits the interrogation of nearly all expressed genes under a wide range of conditions. Patterns of gene expression in response to obesity and diabetes have yielded important

PGC-1alpha and ERRalpha target gene downregulation is a signature of the failing human heart.

Tissue-specific regulation of metabolic pathways through the transcriptional coactivator PGC1-α

The fact that PGC-1α controls important metabolic pathways in several tissues suggests that it can be a therapeutic target for antiobesity or diabetes drugs.

PGC-1alpha-mediated regulation of gene expression and metabolism: implications for nutrition and exercise prescriptions.

  • C. BentonD. WrightA. Bonen
  • Biology
    Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme
  • 2008
It is speculated that optimal targeting of PGC-1alpha upregulation, whether by diet, exercise, or a combination of both, could represent effective prophylactic or therapeutic means to improve insulin sensitivity.

Obesity Upregulates Genes Involved in Oxidative Phosphorylation in Livers of Diabetic Patients

Obesity may affect the pathophysiology of type 2 diabetes by upregulating genes involved in OXPHOS in association with insulin resistance markers and the expression of genesinvolved in hepatic gluconeogenesis and ROS generation.



Gene expression profile in skeletal muscle of type 2 diabetes and the effect of insulin treatment.

Several candidate genes for muscle insulin resistance, complications associated with poor glycemic control, and effects of insulin treatment in people with type 2 diabetes are identified.

Large-scale analysis of the human and mouse transcriptomes

  • A. SuM. Cooke J. Hogenesch
  • Biology
    Proceedings of the National Academy of Sciences of the United States of America
  • 2002
This work generated and analyzed gene expression from 91 human and mouse samples across a diverse array of tissues, organs, and cell lines to reveal insights into molecular and physiological gene function, mechanisms of transcriptional regulation, disease etiology, and comparative genomics.

A genetic variation in the PGC-1 gene could confer insulin resistance and susceptibility to Type II diabetes

The results of this study suggested that the PGC-1 gene might be implicated in the pathogenesis of Type II diabetes.

Microarray profiling of skeletal muscle tissues from equally obese, non-diabetic insulin-sensitive and insulin-resistant Pima Indians

Differentially expressed genes in chromosomal regions with linkage to diabetes and insulin resistance serve as new diabetes susceptibility genes, particularly in skeletal muscle tissues of Pima Indians.

Global functional profiling of gene expression.

Onto-Express is developed as a novel tool able to automatically translate lists of differentially regulated genes into functional profiles characterizing the impact of the condition studied, and was able to identify correctly all biological processes postulated by the original authors, as well as discover novel relevant mechanisms.

Transcriptional co-activator PGC-1α drives the formation of slow-twitch muscle fibres

Using fibre-type-specific promoters, it is shown in cultured muscle cells that PGC-1α activates transcription in cooperation with Mef2 proteins and serves as a target for calcineurin signalling, which has been implicated in slow fibre gene expression.