Thiazolidinediones: metabolic actions in vitro

Fürnsinn, Clemens; Waldhäusl, W.

doi:10.1007/s00125-002-0899-1

Cited by 87 publications

(59 citation statements)

References 162 publications

(231 reference statements)

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“…Specific coactivator recruitment by S 26948. The ligand-binding domain of PPAR␥ interacts with cofactors such as DRIP205, CBP, PGC-1␣, GRIP1, and SRC-1 (47,48). GST pull-down experiments were first carried out to assess the affinity of PPAR␥ for GST fusion proteins with the indicated cofactors ( Fig.…”

Section: Resultsmentioning

confidence: 99%

S 26948

et al. 2007

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OBJECTIVE-Rosiglitazone displays powerful antidiabetes benefits but is associated with increased body weight and adipogenesis. Keeping in mind the concept of selective peroxisome proliferator-activated receptor (PPAR)␥ modulator, the aim of this study was to characterize the properties of a new PPAR␥ ligand, S 26948, with special attention in body-weight gain.RESEARCH DESIGN AND METHODS-We used transient transfection and binding assays to characterized the binding characteristics of S 26948 and GST pull-down experiments to investigate its pattern of coactivator recruitment compared with rosiglitazone. We also assessed its adipogenic capacity in vitro using the 3T3-F442A cell line and its in vivo effects in ob/ob mice (for antidiabetes and antiobesity properties), as well as the homozygous human apolipoprotein E2 knockin mice (E2-KI) (for antiatherogenic capacity).RESULTS-S 26948 displayed pharmacological features of a high selective ligand for PPAR␥ with low potency in promoting adipocyte differentiation. It also displayed a different coactivator recruitment profile compared with rosiglitazone, being unable to recruit DRIP205 or PPAR␥ coactivator-1␣. In vivo experiments showed that S 26948 was as efficient in ameliorating glucose and lipid homeostasis as rosiglitazone, but it did not increase body and white adipose tissue weights and improved lipid oxidation in liver. In addition, S 26948 represented one of the few molecules of the PPAR␥ ligand class able to decrease atherosclerotic lesions.CONCLUSIONS-These findings establish S 26948 as a selective PPAR␥ ligand with distinctive coactivator recruitment and gene expression profile, reduced adipogenic effect, and improved biological responses in vivo.

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Section: Resultsmentioning

confidence: 99%

S 26948

et al. 2007

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“…The most characteristic structure of glitazones is the thiazolidinedione ring resulting in a family of related compounds based on the structure of sidechains. 20 Whether these can be manipulated to produce compounds that activate only certain aspects of the PPARc receptor or to focus on non-PPARc pathways remains to be fully explored.…”

Section: History and Pharmacologymentioning

confidence: 99%

Therapeutic trials in nonalcoholic steatohepatitis: Insulin sensitizers and related methodological issues

2010

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Insulin sensitizers are attractive candidate therapies for nonalcoholic steatohepatitis mainly because of the strong association between this disease and insulin resistance. This review provides a critical overview of the mechanisms of action, clinical trial results, and safety issues of metformin and glitazones in nonalcoholic steatohepatitis. It also highlights methodological challenges for trial design and proposes endpoints for future proof of principle, registrational, and postmarketing trials. (HEPATOLOGY 2010;52:2206-2215 N onalcoholic steatohepatitis (NASH) is emerging as the next big therapeutic challenge in hepatology. 1 Currently the top cause of newly identified chronic liver diseases, NASH has potential for fibrosis, cirrhosis decompensation, and hepatocellular carcinoma. Not all individuals with metabolic risk factors will experience these adverse outcomes and identifying those at risk is critical. Prognostic markers for progression have mostly been derived from histological studies. Compared to steatosis alone or to steatosis and minimal inflammation, the coexistence of inflammation, cell injury (ballooning), and steatosis, a pathological aggregate labeled steatohepatitis, is associated with a significant increase in overall mortality and in liver-related mortality. The degree of inflammation is the best predictor of fibrosis progression, 2 a widely accepted surrogate for hard endpoints such as cirrhosis, endstage liver disease, and possibly hepatocellular carcinoma.Insulin resistance (IR) is consistently found in patients with NASH in both cross-sectional and longitudinal studies. Moreover, there is a stepwise increase in the severity of IR and its phenotypic complications (clustered as elements of the metabolic syndrome) between normal liver, isolated steatosis, and steatohepatitis that has prompted speculation that IR might contribute to liver damage. Logically, most therapeutic trials focused on insulin sensitizers (IS) as candidate therapies.The aim of this report is to critically review the results of trials of metformin and glitazones for NASH. We highlight methodological challenges for trial design and propose endpoints for future proof of principle, registrational, and postmarketing trials.

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“…The compounds exert their potent insulinsensitising action by interacting with, and activating, peroxisome proliferator-activated receptor γ (PPARγ), a nuclear receptor that is mainly expressed in adipose tissue. Along with their effects on white adipose tissue (WAT) adipokine production and extra-adipose actions [1,2], several lines of evidence suggest that one of the insulinsensitising mechanisms of thiazolidinediones is a reduction in circulating NEFAs, which protects non-adipose tissues against lipid overload and consequent insulin resistance (reviewed in [2]). Plasma concentrations of NEFAs represent the balance between their release from WAT and uptake by oxidative tissues, with a contribution from adipose reuptake.…”

Section: Introductionmentioning

confidence: 99%

PPARγ agonism increases rat adipose tissue lipolysis, expression of glyceride lipases, and the response of lipolysis to hormonal control

et al. 2006

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Aims/hypothesis The aim of this study was to investigate the effect and mechanisms of action of in vivo peroxisome proliferator-activated receptor γ (PPARγ) activation on white adipose tissue (WAT) lipolysis and NEFA metabolism. Materials and methods Study rats were treated for 7 days with 15 mg/kg of rosiglitazone per day; control rats were not treated. After a 6-h fast, lipolysis and levels of mRNA for lipases were assessed in explants from various adipose depots. Results Rosiglitazone markedly increased basal and noradrenaline (norepinephrine)-stimulated glycerol and NEFA release from WAT explants, and amplified their inhibition by insulin. Primary adipocytes isolated from PPARγ agonist-treated rats were also more responsive to noradrenaline stimulation expressed per cell, ruling out a contribution of an altered number of mature adipocytes in explants. Rosiglitazone concomitantly increased levels of mRNA transcripts for adipose triglyceride lipase (ATGL) and monoglyceride lipase (MGL) in subcutaneous and visceral WAT, and mRNA for hormone-sensitive lipase (HSL) in subcutaneous WAT. Lipase expression increased within 12 h of in vitro exposure of naïve explants to rosiglitazone, suggesting direct transcriptional activation. In parallel, chronic in vivo treatment with rosiglitazone lowered plasma NEFAs and exerted in WAT its expected stimulatory action on glycerol and NEFA recycling, and on the expression of genes involved in NEFA uptake and retention by WAT, such processes counteracting net NEFA export. Conclusions/interpretation These findings demonstrate that, in the face of its plasma NEFA-lowering action, PPARγ agonism stimulates WAT lipolysis, an effect that is compensated by lipid-retaining pathways. The results further suggest that PPARγ agonism stimulates lipolysis by increasing the lipolytic potential, including the expression levels of the genes encoding adipose triglyceride lipase and monoglyceride lipase.

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Thiazolidinediones: metabolic actions in vitro

Cited by 87 publications

References 162 publications

S 26948

S 26948

Therapeutic trials in nonalcoholic steatohepatitis: Insulin sensitizers and related methodological issues

PPARγ agonism increases rat adipose tissue lipolysis, expression of glyceride lipases, and the response of lipolysis to hormonal control

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