Reduced expression of PGC-1 and insulin-signaling molecules in adipose tissue is associated with insulin resistance

Hammarstedt, Ann; Jansson, Per‐Anders; Wesslau, Christian; Yang, Xiaolin; Smith, Ulf

doi:10.1016/s0006-291x(03)00014-7

Cited by 141 publications

(113 citation statements)

References 30 publications

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“…Because several different populations were used in the STOP-NIDDM trial, our data provides strong evidence that the Gly482Ser polymorphism of the PGC-1α gene contributes to the risk of type 2 diabetes. In agreement with this, the reduced expression of PGC-1α in adipose tissue has been associated with insulin resistance [51]. Moreover, recent studies have reported that down-regulation of the PGC-1α gene and coordinated changes in other genes involved in oxidative phosphorylation in man are associated with IGT, diabetes mellitus [35] and insulin resistance [37].…”

Section: Discussionmentioning

confidence: 61%

Common polymorphisms of the PPAR-?2 (Pro12Ala) and PGC-1? (Gly482Ser) genes are associated with the conversion from impaired glucose tolerance to type 2 diabetes in the STOP-NIDDM trial

et al. 2004

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Aim/hypothesis. We investigated the effects of the common polymorphisms in the peroxisome proliferator-activated receptor γ2 (PPAR-γ2; Pro12Ala) and in PPAR-γ coactivator 1α (PGC-1α; Gly482Ser) genes on the conversion from impaired glucose tolerance to type 2 diabetes in participants in the STOP-NIDDM trial. This trial aimed to study the effect of acarbose in the prevention of type 2 diabetes. Methods. Genotyping was performed in 770 study subjects whose DNA was available. The Gly482Ser variant in the PGC-1α gene was determined with the polymerase chain reaction amplification, Hpa II enzyme digestion, and gel electrophoresis. The Pro12Ala polymorphism of the PPAR-γ2 gene was determined by the polymerase chain reaction-singlestrand conformation polymorphism analysis. Results. The Pro12Pro genotype of the PPAR-γ2 gene predicted the conversion to diabetes in women in the acarbose group (odds ratio 2.89, 95% CI 1.20 to 6.96; p=0.018). The 482Ser allele of the PGC-1α gene had a significant interaction with the mode of treatment (p=0.012), and in the placebo group the 482Ser allele was associated with a 1.6-fold higher risk for type 2 diabetes compared to the Gly482Gly genotype (95% CI 1.06 to 2.33; p=0.023). Acarbose prevented the development of diabetes independently of the genotype of the PPAR-γ2 gene, but only the carriers of the 482Ser allele of the PGC-1α gene were responsive to acarbose treatment. Conclusion/interpretation. We conclude that the Pro12Pro genotype of the PPAR-γ2 gene and the 482Ser allele of the PGC-1α gene are associated with the conversion from impaired glucose tolerance to type 2 diabetes in the STOP-NIDDM trial.

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Section: Discussionmentioning

confidence: 61%

Common polymorphisms of the PPAR-?2 (Pro12Ala) and PGC-1? (Gly482Ser) genes are associated with the conversion from impaired glucose tolerance to type 2 diabetes in the STOP-NIDDM trial

et al. 2004

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“…Previous studies from this laboratory have shown an early association between adipose tissue dysfunction and insulin resistance [17][18][19][20][21]31].…”

Section: Discussionmentioning

confidence: 88%

“…3b), but there was no significant correlation between either plasma total or HMW adiponectin and the expression of GLUT4 mRNA or protein (data not shown). PGC-1 is expressed in human white adipose cells and the expression level is reduced in insulin resistance [21]. PGC-1 has also been found to increase GLUT4 expression in skeletal muscle [29].…”

Section: Resultsmentioning

confidence: 99%

“…In addition to these perturbations, we have identified other markers for dysregulated adipose tissue in insulin resistance suggesting impaired adipose cell differentiation, i.e. reduced expression of adiponectin and adipocyte P 2 (aP2), low circulating adiponectin levels, increased fat cell size [19,20] and a reduced expression of the PPARγ coactivator 1 (PGC-1) [21].…”

Section: Introductionmentioning

confidence: 99%

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Improved insulin sensitivity and adipose tissue dysregulation after short-term treatment with pioglitazone in non-diabetic, insulin-resistant subjects

et al. 2004

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Aims/hypothesis: We examined whether shortterm treatment with a thiazolidinedione improves insulin sensitivity in non-obese but insulin-resistant subjects and whether this is associated with an improvement in dysregulated adipose tissue (reduced expression of IRS-1, GLUT4, PPARγ co-activator 1 and markers of terminal differentiation) that we have previously documented to be associated with insulin resistance. Methods: Ten nondiabetic subjects, identified as having low IRS-1 and GLUT-4 protein in adipose cells as markers of insulin resistance, underwent 3 weeks of treatment with pioglitazone. The euglycaemic-hyperinsulinaemic clamp technique was used to measure insulin sensitivity before and after treatment. Serum samples were analysed for glucose, insulin, lipids, total and high-molecular-weight (HMW) adiponectin levels. Biopsies from abdominal subcutaneous adipose tissue were taken, cell size measured, mRNA and protein extracted and quantified using real-time RT-PCR and Western blot. Results: Insulin sensitivity was improved after 3 weeks treatment and circulating total as well as HMW adiponectin increased in all subjects, while no effect was seen on serum lipids. In the adipose cells, gene and protein expression of IRS-1 and PPARγ co-activator 1 remained unchanged, while adiponectin, adipocyte P 2, uncoupling protein 2, GLUT4 and liver X receptor-α increased. Insulin-stimulated tyrosine phosphorylation and p-ser-PKB/Akt increased, while no significant effect of thiazolidinedione treatment was seen on the inflammatory status of the adipose tissue in these non-obese subjects. Conclusions/interpretation: Short-term treatment with pioglitazone improved insulin sensitivity in the absence of any changes in circulating NEFA or lipid levels. Several markers of adipose cell differentiation, previously shown to be reduced in insulin resistance, were augmented, supporting the concept that insulin resistance in these individuals is associated with impaired terminal differentiation of the adipose cells.

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“…In addition, reduced adipose PGC-1α and an association between reduced PGC-1α mRNA levels and insulin resistance have been found in human subjects (25,26). Adipose mitochondria play an important role in fatty acid oxidation (FAO) and adaptive thermogenesis, key adipose-specific metabolic pathways that are regulated by PGC-1α (27).…”

mentioning

confidence: 99%

Development of insulin resistance in mice lacking PGC-1α in adipose tissues

Kleiner

Mepani

Laznik

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

265

209

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Reduced peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) expression and mitochondrial dysfunction in adipose tissue have been associated with obesity and insulin resistance. Whether this association is causally involved in the development of insulin resistance or is only a consequence of this condition has not been clearly determined. Here we studied the effects of adipose-specific deficiency of PGC-1α on systemic glucose homeostasis. Loss of PGC-1α in white fat resulted in reduced expression of the thermogenic and mitochondrial genes in mice housed at ambient temperature, whereas gene expression patterns in brown fat were not altered. When challenged with a high-fat diet, insulin resistance was observed in the mutant mice, characterized by reduced suppression of hepatic glucose output. Resistance to insulin was also associated with an increase in circulating lipids, along with a decrease in the expression of genes regulating lipid metabolism and fatty acid uptake in adipose tissues. Taken together, these data demonstrate a critical role for adipose PGC-1α in the regulation of glucose homeostasis and a potentially causal involvement in the development of insulin resistance.glucose metabolism | mitochondrial gene expression | thermogenesis | cold exposure | type 2 diabetes

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Reduced expression of PGC-1 and insulin-signaling molecules in adipose tissue is associated with insulin resistance

Cited by 141 publications

References 30 publications

Common polymorphisms of the PPAR-?2 (Pro12Ala) and PGC-1? (Gly482Ser) genes are associated with the conversion from impaired glucose tolerance to type 2 diabetes in the STOP-NIDDM trial

Common polymorphisms of the PPAR-?2 (Pro12Ala) and PGC-1? (Gly482Ser) genes are associated with the conversion from impaired glucose tolerance to type 2 diabetes in the STOP-NIDDM trial

Improved insulin sensitivity and adipose tissue dysregulation after short-term treatment with pioglitazone in non-diabetic, insulin-resistant subjects

Development of insulin resistance in mice lacking PGC-1α in adipose tissues

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