Selective Modulators of PPAR-<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>γ</mml:mi></mml:math>Activity: Molecular Aspects Related to Obesity and Side-Effects

Zhang, Fang; Lavan, Brian E.; Gregoire, Francine M.

doi:10.1155/2007/32696

Cited by 104 publications

(105 citation statements)

References 56 publications

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“…PPAR␥ agonism by electrophilic NO 2 -FA manifests unique binding kinetics and induces conformational changes in PPAR␥ that result in coregulator interactions unique to these inflammatory by-products. These properties suggest that NO 2 -FA might induce physiological responses that differ from Rosi (22,32,36,37). These findings also support that the pro-adipogenic actions of Rosi, i.e.…”

Section: Discussionsupporting

confidence: 71%

“…Rosi recruits and displaces a specific pattern of coregulators upon PPAR␥ binding, inducing a biological response characteristic of full PPAR␥ agonists. In contrast, binding of partial agonists induces a modified coregulator-PPAR␥ interaction pattern that differentially transactivates target genes (37). Although OA-NO 2 and Rosi both bind PPAR␥ with high affinity, distinctively different coregulator protein interactions result.…”

Section: Discussionmentioning

confidence: 99%

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Covalent Peroxisome Proliferator-activated Receptor γ Adduction by Nitro-fatty Acids

Schöpfer

Cole

Groeger

et al. 2010

Journal of Biological Chemistry

153

155

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The peroxisome proliferator-activated receptor-␥ (PPAR␥) binds diverse ligands to transcriptionally regulate metabolism and inflammation. Activators of PPAR␥ include lipids and antihyperglycemic drugs such as thiazolidinediones (TZDsThe rapidly expanding global burden of type II diabetes mellitus (DM) 3 and the concomitant increased risk for cardiovascular disease (1, 2) have motivated better understanding of relevant cell signaling pathways and potential therapeutic strategies. One major characteristic of metabolic syndrome and DM is insulin resistance, leading to hyperglycemia and dyslipidemia. Following initial clinical use of TZDs as anti-hyperglycemic agents to treat DM in the late 1990s, the nuclear receptor PPAR␥ was discovered as their molecular target. This receptor is expressed primarily in adipose tissue, muscle, and macrophages, where it regulates glucose uptake, lipid metabolism/ storage, and cell proliferation/differentiation (3-5). Thus, PPAR␥ ligands and allied downstream signaling events play a pivotal role in both the development and treatment of DM (6, 7). This is underscored by the observation that mutations in the C-terminal helix 12 of the ligand-binding domain (LBD) of PPAR␥ (e.g. P467L or V290M) are linked with severe insulin resistance and the onset of juvenile DM (8).The oxidizing inflammatory milieu contributing to the pathogenesis of obesity, diabetes, and cardiovascular disease also promotes diverse biomolecule oxidation, nitrosation, and nitration reactions by O 2 and ⅐ NO-derived species. Although oxidized fatty acids typically propagate proinflammatory conditions, the recently detected class of NO 2 -FA act as anti-inflammatory mediators. Nitroalkene derivatives of oleic acid (OA-NO 2 ) and linoleic acid (LNO 2 ) have been detected in healthy human blood and murine cardiac tissue. The levels of free/unesterified OA-NO 2 are ϳ1-3 nM in human plasma (9, 10), with OA-NO 2 produced at increased rates and present at higher concentrations during inflammatory and metabolic stress (11-13). The signaling actions of NO 2 -FA are primarily ascribed to the electrophilic olefinic carbon situated ␤ to the electron-withdrawing NO 2 substituent, facilitating kinetically rapid and reversible Michael addition with nucleophilic amino acids (i.e. Cys and His) (14). NO 2 -FA adduction of proteins and GSH occurs in model systems and clinically, with this reaction

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Section: Discussionsupporting

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Covalent Peroxisome Proliferator-activated Receptor γ Adduction by Nitro-fatty Acids

Schöpfer

Cole

Groeger

et al. 2010

Journal of Biological Chemistry

153

155

View full text Add to dashboard Cite

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“…Importantly, SPPARMs also selectively regulate PPARγ target gene transcription in response to specific cofactor recruitment. [18][19][20] In present report, the insulin sensitizing properties of C333h were further confirmed in diabetic db/db mice and insulin resistant obese MSG rats. In db/db mice, C333H was at least as effective as the full PPARγ agonist rosiglitazone in ameliorating the glucose intolerance and increasing ISI.…”

Section: Discussionsupporting

confidence: 72%

C333H Ameliorated Insulin Resistance through Selectively Modulating Peroxisome Proliferator-Activated Receptor γ in Brown Adipose Tissue of db/db Mice

Zhang

Cui

Zhou

et al. 2013

Biological & Pharmaceutical Bulletin

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Peroxisome proliferator-activated receptor γ (PPARγ) is a unique target for insulin sensitizer agents. These drugs have been used for the clinical treatment of type 2 diabetes for almost twenty years. However, serious safety issues are associated with the PPARγ agonist thiazolidinediones (TZDs). Selective PPARγ modulators (SPPARMs) which retain insulin sensitization without TZDs-like side effects are emerging as a promising new generation of insulin sensitizers. C333H is a novel structure compound synthesized by our laboratory. In diabetic rodent models, C333H has insulin-sensitizing and glucose-lowering activity comparable to that of TZDs, and causes no significant increase in body weight or adipose tissue weight in db/db mice. In diabetic db/db mice, C333H elevated circulating high molecular weight adiponectin isoforms, decreased PPARγ 273 serine phosphorylation in brown adipose tissue and selectively modulated the expression of a subset of PPARγ target genes in adipose tissue. In vitro, C333H weakly recruited coactivator and weakly dissociated corepressor activity. These findings suggest that C333H has similar properties to SPPARMs and may be a potential therapeutic agent for the treatment of type 2 diabetes.Key words C333H; peroxisome proliferator-activated receptor γ (PPAR γ); insulin resistance; selective PPARγ modulator; type 2 diabetes Thiazolidinediones (TZDs) are unique insulin sensitizing drugs used for the treatment of type 2 diabetes and other metabolic syndromes associated with insulin resistance. 1)The γ subtype of peroxisome proliferator activated receptors (PPARγ) acts as target for TZDs and is key regulator of glucose homeostasis and adipocyte differentiation. As a nuclear receptor, PPARγ firstly interacts with retinoid X receptor α (RXRα) to form a heterodimer, which in turn recruits specific coactivators or corepressors depending on physiological environment. It then binds to specific response elements (PPREs) within promoter region of target genes to control gene transcription.2) However, the unwanted effects of TZDs including body weight gain, edema, increased risks of congestive heart failure, and increased rate of bone fracture restrict the clinical usage of these drugs.It has been known for several years that the insulin sensitizing effects can be obtained by PPARγ ligands without the risk of TZDs-like side effects. Genetic and epidemic studies have shown that the side effects of TZDs are closely related to overactivation of PPARγ, whereas physiologically appropriate PPARγ activity is beneficial in terms of reducing insulin resistance and other risks associated with type 2 diabetes. 3-5)More recently, it has been reported that the inhibition of CDK5 mediated PPARγ 273 serine phosphorylation, rather than PPARγ agonism and lipogenic effects, constitutes the key target for insulin sensitization and the antidiabetic effects of PPARγ agonists.6) The same workers reported that a nonagonist PPARγ ligand, SR1664, inhibited PPARγ 273 serine phosphorylation, and enhanced insulin sensitivity withou...

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“…Severe side effects of TZDs, including weight gain and fluid retention, occur rapidly in both humans and mice (12,27,28). As shown in Fig.…”

Section: Discussionmentioning

confidence: 99%

A Novel Non-agonist Peroxisome Proliferator-activated Receptor γ (PPARγ) Ligand UHC1 Blocks PPARγ Phosphorylation by Cyclin-dependent Kinase 5 (CDK5) and Improves Insulin Sensitivity

Choi

Kim

Koh

et al. 2014

Journal of Biological Chemistry

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Background: PPAR␥ ligands can be used in numerous metabolic syndromes. Results: A novel non-agonist PPAR␥ ligand, UHC1 exhibited great beneficial effects on glucose metabolism and anti-inflammatory response. Conclusion: UHC1 shows anti-diabetic action by blocking CDK5-mediated PPAR␥ phosphorylation. Significance: UHC1 can be a novel therapeutic agent for use in type 2 diabetes and related metabolic disorders.

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Selective Modulators of PPAR-γActivity: Molecular Aspects Related to Obesity and Side-Effects

Cited by 104 publications

References 56 publications

Covalent Peroxisome Proliferator-activated Receptor γ Adduction by Nitro-fatty Acids

Covalent Peroxisome Proliferator-activated Receptor γ Adduction by Nitro-fatty Acids

C333H Ameliorated Insulin Resistance through Selectively Modulating Peroxisome Proliferator-Activated Receptor γ in Brown Adipose Tissue of db/db Mice

A Novel Non-agonist Peroxisome Proliferator-activated Receptor γ (PPARγ) Ligand UHC1 Blocks PPARγ Phosphorylation by Cyclin-dependent Kinase 5 (CDK5) and Improves Insulin Sensitivity

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