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

Mootha, Vamsi K.; Lindgren, Cecilia M.; Eriksson, Karl-Fredrik; Subramanian, Aravind; Sihag, Smita; Lehár, Joseph; Puigserver, Pere; Carlsson, Enar; Ridderstråle, Martin; Laurila, Esa; Houstis, Nicholas E.; Daly, Mark J.; Patterson, Nick; Mesirov, Jill P.; Golub, Todd R.; Tamayo, Pablo; Spiegelman, Bruce M.; Lander, Eric S.; Hirschhorn, Joel N.; Altshuler, David; Groop, Leif

doi:10.1038/ng1180

Cited by 8,224 publications

(6,991 citation statements)

References 32 publications

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“…We focused on differentially expressed protein‐coding genes defined as those having an absolute log fold change greater than 1 and adjusted p‐value less than 0.05 (Supporting Information Table S1). Mouse genes were mapped to human orthologs using Mouse Genome Informatics orthology reports, and pathway analysis was performed based on Gene Set Enrichment Analysis (GSEA) (Mootha et al, 2003). …”

Section: Resultsmentioning

confidence: 99%

SIRT1 deacetylase in aging‐induced neuromuscular degeneration and amyotrophic lateral sclerosis

et al. 2018

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SIRT1 is an NAD+‐dependent deacetylase that functions in a variety of cells and tissues to mitigate age‐associated diseases. However, it remains unknown if SIRT1 also acts to prevent pathological changes that accrue in motor neurons during aging and amyotrophic lateral sclerosis (ALS). In this study, we show that SIRT1 expression decreases in the spinal cord of wild‐type mice during normal aging. Using mouse models either overexpressing or lacking SIRT1 in motor neurons, we found that SIRT1 slows age‐related degeneration of motor neurons’ presynaptic sites at neuromuscular junctions (NMJs). Transcriptional analysis of spinal cord shows an overlap of greater than 90% when comparing alterations during normal aging with changes during ALS, revealing a substantial upregulation in immune and inflammatory response genes and a downregulation of synaptic transcripts. In addition, overexpressing SIRT1 in motor neurons delays progression to end‐stage disease in high copy SOD1G93A mice. Thus, our findings suggest that there are parallels between ALS and aging, and interventions to impede aging may also slow the progression of this devastating disease.

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Section: Resultsmentioning

confidence: 99%

SIRT1 deacetylase in aging‐induced neuromuscular degeneration and amyotrophic lateral sclerosis

et al. 2018

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“…gene expression data from liver, muscle, and heart tissue using GSEA (gene set enrichment analysis) (Mootha et al ., 2003; Subramanian et al ., 2005); unfortunately, adipose gene expression information was not available from the AGEMAP study, and an insufficient number of samples were available from the Pearson et al . study for GSEA.…”

Section: Resultsmentioning

confidence: 99%

Sex‐ and tissue‐specific changes in mTOR signaling with age in C57 BL /6J mice

et al. 2015

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SummaryInhibition of the mTOR (mechanistic Target Of Rapamycin) signaling pathway robustly extends the lifespan of model organisms including mice. The precise molecular mechanisms and physiological effects that underlie the beneficial effects of rapamycin are an exciting area of research. Surprisingly, while some data suggest that mTOR signaling normally increases with age in mice, the effect of age on mTOR signaling has never been comprehensively assessed. Here, we determine the age‐associated changes in mTORC1 (mTOR complex 1) and mTORC2 (mTOR complex 2) signaling in the liver, muscle, adipose, and heart of C57BL/6J.Nia mice, the lifespan of which can be extended by rapamycin treatment. We find that the effect of age on several different readouts of mTORC1 and mTORC2 activity varies by tissue and sex in C57BL/6J.Nia mice. Intriguingly, we observed increased mTORC1 activity in the liver and heart tissue of young female mice compared to male mice of the same age. Tissue and substrate‐specific results were observed in the livers of HET3 and DBA/2 mouse strains, and in liver, muscle and adipose tissue of F344 rats. Our results demonstrate that aging does not result in increased mTOR signaling in most tissues and suggest that rapamycin does not promote lifespan by reversing or blunting such an effect.

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“…Heilbronn et al (13) have demonstrated that different biomarkers of mitochondrial biogenesis and metabolism are reduced in overweight and obese insulin-resistant subjects. Two other studies using cDNA microarrays have reported that mitochondrial metabolism in both muscle and adipocytes is disturbed in subjects with insulin resistance, type 2 diabetes and even in subjects with family history for diabetes (28,32). Both trials found a decrease in the expression of a subset of genes involved in mitochondrial oxidative metabolism, suggesting that impaired regulation of mitochondrial function could be an important mechanism linked to obesity and the metabolic syndrome.…”

Section: Discussionmentioning

confidence: 96%

Orchestrated downregulation of genes involved in oxidative metabolic pathways in obese vs. lean high-fat young male consumers

Marrades

González‐Muniesa

Arteta³

et al. 2010

J Physiol Biochem

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There are major variations in the susceptibility to weight gain among individuals under similar external influences (decreased physical activity and excessive calorie intake), depending on the genetic background. In the present study, we performed a microarray analysis and RT-PCR validations in order to find out differential gene expression in subcutaneous abdominal adipose tissue from two groups of subjects that despite living in similar environmental conditions such as a habitual high fat dietary intake (energy as fat >40%) and similar moderate physical activity, some of them were successfully "resistant" (lean) to weight gain, while others were "susceptible" to fat deposition (obese). The classification of up-and down-regulated genes into different categories together with the analysis of the altered biochemical pathways, revealed a coordinated downregulation of catabolic pathways operating in the mitochondria: fatty acid oxidation (P=0.008), TCA cycle (P=0.001) and electron transport chain (P=0.012). At the same time, glucose metabolism (P=0.010) and fatty acid biosynthesis (P=0.011) pathways were also downregulated in obese compared to lean subjects. In conclusion, our data showed an orchestrated downregulation of nuclear-encoded mitochondrial gene expression. These genes are involved in cellular respiration and oxidative metabolism pathways, and could play a role in the susceptibility to weight gain in some individuals.

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

Cited by 8,224 publications

References 32 publications

SIRT1 deacetylase in aging‐induced neuromuscular degeneration and amyotrophic lateral sclerosis

SIRT1 deacetylase in aging‐induced neuromuscular degeneration and amyotrophic lateral sclerosis

Sex‐ and tissue‐specific changes in mTOR signaling with age in C57 BL /6J mice

Orchestrated downregulation of genes involved in oxidative metabolic pathways in obese vs. lean high-fat young male consumers

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