An Antidiabetic Thiazolidinedione Is a High Affinity Ligand for Peroxisome Proliferator-activated Receptor γ (PPARγ)

Lehmann, Jürgen; Moore, Linda B.; Smith-Oliver, Tracey; Wilkison, William O.; Willson, Timothy M.; Kliewer, Steven A.

doi:10.1074/jbc.270.22.12953

Cited by 3,355 publications

(2,380 citation statements)

References 27 publications

Supporting

Mentioning

2,269

Contrasting

Unclassified

Order By: Relevance

“…Currently, two PPAR agonist classes are in widespread use, the thiazolidinediones (TZDs) which activate PPAR and increase insulin sensitivity, and the fibrates (gemfibrozil, fenofibrate) which activate PPAR to reduce hepatic triglyceride production and increase hepatic fatty acid oxidation (Harris and Kletzien 1994;Forman et al 1995;Lehmann et al 1995;Willson et al 1996a). In vivo, PPAR and ligands appear to be naturally occurring fatty acids and eicosanoid arachidonic acid metabolites (Forman et al 1997).…”

Section: Pparsmentioning

confidence: 99%

Nuclear receptors, mitochondria and lipid metabolism

2008

View full text Add to dashboard Cite

Lipid metabolism is a continuum from emulsification and uptake of lipids in the intestine to cellular uptake and transport to compartments such as mitochondria. Whether fats are shuttled into lipid droplets in adipose tissue or oxidized in mitochondria and peroxisomes depends on metabolic substrate availability, energy balance and endocrine signaling of the organism. Several members of the nuclear hormone receptor superfamily are lipid-sensing factors that affect all aspects of lipid metabolism. The physiologic actions of glandular hormones (e.g. thyroid, mineralocorticoid and glucocorticoid), vitamins (e.g. vitamins A and D) and reproductive hormones (e.g. progesterone, estrogen and testosterone) and their cognate receptors are well established. The peroxisome proliferator activated receptors (PPARs) and Liver X receptors (LXRs), acting in concert with PPARγ Coactivator 1α (PGC-1α), have been shown to regulate insulin sensitivity and lipid handling. These receptors are the focus of intense pharmacologic studies to expand the armamentarium of small molecule ligands to treat diabetes and the metabolic syndrome (hypertension, insulin resistance, hyperglycemia, dyslipidemia, and obesity). Recently, additional partners of PGC-1α have moved to the forefront of metabolic research, the Estrogen-related Receptors (ERRs). Although no endogenous ligands for these receptors have been identified, phenotypic analyses of knockout mouse models demonstrate an important role for these molecules in substrate sensing and handling as well as mitochondrial function.

show abstract

Section: Pparsmentioning

confidence: 99%

Nuclear receptors, mitochondria and lipid metabolism

2008

View full text Add to dashboard Cite

show abstract

“…It was later determined that thiazolidinedione-type anti-diabetic agents act as potent PPARγ ligands 48 . This was soon followed by the discovery of the first endogenously produced PPARγ ligand, the prostaglandin J 2 metabolite, 15-deoxy-Δ 12,14 -PGJ 2 (15d-PGJ 2 ) 49, 50.…”

Section: Evidence That Oxidized Gpc Are Native Pparγ Ligandsmentioning

confidence: 99%

Oxidized glycerophosphocholines as biologically active mediators for ultraviolet radiation-mediated effects

Konger

Marathe

Yao

et al. 2008

Prostaglandins & Other Lipid Mediators

View full text Add to dashboard Cite

Ultraviolet light radiation (UVR) has profound effects upon human skin. Yet, the exact targets for UVR are unclear. Inasmuch as UVR is a known pro-oxidative stressor, one potential target for UVR could be oxidatively modified glycerophosphocholines (GPC). Importantly, recent studies demonstrate that these oxidized GPCs (ox-GPC) are potent agonists for the platelet-activating factor receptor and peroxisome proliferator-activated receptor gamma. This review discusses these new biologically active lipids and their down-stream receptor targets that provide a unique system of biosensors for detecting and responding to UVR photo-oxidation.

show abstract

“…Lehman and colleagues were subsequently the first to identify peroxisome proliferator-activated receptor g (PPARg) as a molecular target for TZDs. 8 Binding affinities of TZDs for PPARg were also shown to correlate with the potency of their antidiabetic action, suggesting that the insulin-sensitizing effect of TZDs are mediated through activation of PPARg. 9 Identification of a dominant-negative mutation in the PPARg gene in two families with an inherited form of type 2 diabetes further underscores the importance of this transcription factor in insulin sensitivity.…”

Section: Pparc Is the Primary Target Transcription Factor For Tzdsmentioning

confidence: 99%

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

2005

View full text Add to dashboard Cite

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.

show abstract

An Antidiabetic Thiazolidinedione Is a High Affinity Ligand for Peroxisome Proliferator-activated Receptor γ (PPARγ)

Cited by 3,355 publications

References 27 publications

Nuclear receptors, mitochondria and lipid metabolism

Nuclear receptors, mitochondria and lipid metabolism

Oxidized glycerophosphocholines as biologically active mediators for ultraviolet radiation-mediated effects

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

Contact Info

Product

Resources

About