Adipose-specific peroxisome proliferator-activated receptor γ knockout causes insulin resistance in fat and liver but not in muscle

He, Weimin; Barak, Yaacov; Hevener, Andrea L.; Olson, Peter; Liao, Daiqing; Le, Jamie; Nelson, Michael C.; Ong, Estelita S.; Olefsky, Jerrold M.; Evans, Ronald M.

doi:10.1073/pnas.2536828100

Cited by 892 publications

(797 citation statements)

References 34 publications

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“…There is strong evidence to suggest that adipose tissue PPARγ does not mediate the entire range of therapeutic and adverse effects attributed to TZDs [48]. Instead, these agents appear to target organs such as the liver and skeletal muscle, where they elicit metabolic and cytotoxic responses.…”

Section: Discussionmentioning

confidence: 99%

Troglitazone causes acute mitochondrial membrane depolarisation and an AMPK-mediated increase in glucose phosphorylation in muscle cells

et al. 2005

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Aims/hypothesis: Troglitazone was the first thiazolidinedione (TZD) approved for clinical use, exerting hypoglycaemic effects related to its action as a ligand of the peroxisome proliferator-activated receptor γ receptor in adipocytes. However, emerging evidence suggests that mitochondrial function may be affected by troglitazone, and that skeletal muscle cells acutely respond to troglitazone by enhancing glucose uptake. The aim of the present study was to determine the cellular mechanisms by which troglitazone acutely stimulates glucose utilisation in skeletal muscle cells. Methods: L6 cells overexpressing GLUT4myc were incubated with troglitazone. Glucose uptake, transport and phosphorylation as well as AMP-activated protein kinase (AMPK) signalling and insulin signalling were examined. Changes in mitochondrial membrane potential were measured using the J-aggregate-forming dye JC-1. AMPK signalling was interfered with using AMPK α1/α2 siRNA. Results: Troglitazone acutely (in 10 min) reduced the mitochondrial membrane potential in L6GLUT4myc myotubes and robustly stimulated AMPK activity. Following 30 min of incubation with troglitazone or insulin, 2-deoxyglucose uptake was stimulated 1.5-and 2.1-fold respectively, and in cells treated with troglitazone, a 1.8-fold increase in the 2-deoxyglucose-6-phosphate:2-deoxyglucose ratio was observed. Moreover, contrary to insulin, troglitazone did not significantly stimulate 3-O-methylglucose uptake. Unlike insulin, troglitazone did not increase surface GLUT4myc content and did not increase IRS1-associated phosphatidylinositol 3-kinase activity or Akt phosphorylation on T308 and S473. Interestingly, interfering with troglitazone-induced activation of AMPK by decreasing the expression of the enzyme using siRNA inhibited the stimulation of 2-deoxyglucose uptake by the TZD. Conclusions/interpretation: We propose that troglitazone acutely increases glucose flux in muscle via an AMPK-mediated increase in glucose phosphorylation.

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Section: Discussionmentioning

confidence: 99%

Troglitazone causes acute mitochondrial membrane depolarisation and an AMPK-mediated increase in glucose phosphorylation in muscle cells

et al. 2005

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“…Ablation of PPARg in mature adipocytes results in improvements of hepatic insulin sensitivity in response to TZD treatment, but did not lower serum triglycerides and free fatty acids. 20 PPARg in b cells is not required for the antidiabetic actions of TZDs. 21 Mice lacking PPARg in the Adiponectin and PPARc agonist action M Bouskila et al liver respond to TZDs by lowering serum glucose, insulin, triglyceride and free fatty acid levels, and improve glucose and fat clearance rates.…”

Section: Pparc Is the Primary Target Transcription Factor For Tzdsmentioning

confidence: 98%

Adiponectin: a relevant player in PPARγ-agonist-mediated improvements in hepatic insulin sensitivity?

2005

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The potent insulin-sensitizing effects of peroxisome proliferator-activated receptor g (PPARg) agonists are well established. However, it is still a matter of intense debate as to which tissue(s) represent the most critical sites of action for PPARg agonists, and what the relevant target genes are that ultimately mediate the improvements in insulin sensitivity. The cell type with the highest levels of PPARg is the adipocyte, and as such the adipocyte is an excellent candidate cell to look for critical mediators of PPARg agonist action. Adiponectin, an adipocyte-specific secretory protein, is upregulated in response to PPARg agonist exposure, and its serum levels consequently increase significantly. Genetic, pharmacological and clinical studies have demonstrated potent insulin-sensitizing effects of adiponectin. Here, we summarize the evidence that implicates adiponectin as a critical mediator of PPARg-agonist-mediated improvements in insulin sensitivity, particularly in the context of PPARg-agonistmediated enhancements of hepatic insulin sensitivity.

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“…Mice containing PPAR␥ LoxP sites on a C57BL/6J mixed background (4 to 5 weeks of age) were kindly provided by Dr. Bruce Spiegelman (Dana Farber Cancer Institute, Boston, MA). 21 …”

Section: Animals and Models Of Liver Injurymentioning

confidence: 99%

Adiponectin Regulation of Stellate Cell Activation via PPARγ-Dependent and -Independent Mechanisms

Shafiei

Shetty

Scherer

et al. 2011

The American Journal of Pathology

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In this study, we elucidated the mechanism by which adiponectin modulates hepatic stellate cell activation and fibrogenesis. Adiponectin-overexpressing transgenic mice receiving thioacetamide were resistant to fibrosis, compared with controls. In contrast, adiponectin-null animals developed severe fibrosis. Expression of collagen ␣1(I) and ␣-smooth muscle actin (␣-SMA) mRNAs were significantly lower in adiponectin-overexpressing mice, compared with controls. In wild-type stellate cells exposed to a lentivirus encoding adiponectin, expression of peroxisome proliferator-activated receptor-␥ (PPAR␥), SREBP1c, and CEBP␣ mRNAs was significantly increased (3.2-, 4.1-, and 2.2-fold, respectively; n ‫؍‬ 3; P < 0.05, adiponectin virus versus control), consistent with possible activation of an adipogenic transcriptional program. Troglitazone, a PPAR␥ agonist, strongly suppressed upregulation of collagen ␣1(I) and ␣-SMA mRNA in stellate cells isolated from wild-type mice; however, stellate cells from adiponectin-null animals failed to respond to troglitazone. Furthermore, in isolated stellate cells in which PPAR␥ was depleted using an adenovirus-Cre-recombinase system and in which adiponectin was also overexpressed, collagen ␣1(I) and ␣-SMA were significantly inhibited. We conclude that the PPAR␥ effect on stellate cell activation and the fibrogenic cascade appears to be adiponectin-dependent; however, the inhibitory effect of adiponectin on stellate cell activation was not dependent on PPAR␥, suggesting the presence of PPAR␥-dependent as well as independent pathways in stellate cells.

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Adipose-specific peroxisome proliferator-activated receptor γ knockout causes insulin resistance in fat and liver but not in muscle

Cited by 892 publications

References 34 publications

Troglitazone causes acute mitochondrial membrane depolarisation and an AMPK-mediated increase in glucose phosphorylation in muscle cells

Troglitazone causes acute mitochondrial membrane depolarisation and an AMPK-mediated increase in glucose phosphorylation in muscle cells

Adiponectin: a relevant player in PPARγ-agonist-mediated improvements in hepatic insulin sensitivity?

Adiponectin Regulation of Stellate Cell Activation via PPARγ-Dependent and -Independent Mechanisms

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