Dominant negative mutations in human PPARγ associated with severe insulin resistance, diabetes mellitus and hypertension

Barroso, Inês; Gurnell, Mark; Crowley, Vivion; Agostini, Maura; Schwabe, John W. R.; Soos, Maria A.; Maslen, G. Li; Williams, T. D. M.; Lewis, Helen M.; Schafer, Alan J.; Chatterjee, Krishna; O’Rahilly, Stephen

doi:10.1038/47254

Cited by 1,268 publications

(885 citation statements)

References 29 publications

(23 reference statements)

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“…25,26 Heterozygosity for either PPARg V290M or P467L was initially reported in nonlipodystrophic subjects with severe insulin resistance. 27 However, later re-evaluation of subjects with PPARg V290M or P467L showed loss of subcutaneous limb fat and atrophy of buttock fat, confirming that mutant PPARg causes lipodystrophy. 28 Heterozygosity for PPARg R425C was found in another patient who was ascertained based on a clinical diagnosis of partial lipodystrophy.…”

Section: Pparc Mutations In Partial Lipodystrophy (Fpld3)mentioning

confidence: 92%

Lessons from human mutations in PPARγ

Hegele

2005

Int J Obes

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Familial partial lipodystrophy (FPLD) is characterized by adipose tissue repartitioning with multiple metabolic disturbances, including insulin resistance and dyslipidemia. Classical FPLD results from mutations in LMNA encoding nuclear lamin A/C (FPLD2), but recently some families with partial lipodystrophy and normal LMNA sequence were found to have germline mutations in PPARg (FPLD3). For instance, all four affected subjects in a three-generation Canadian FPLD3 kindred ascertained based upon a clinical diagnosis of partial lipodystrophy were heterozygous for the PPARg F388L mutation, which altered a highly conserved residue within helix 8 of the predicted ligand-binding pocket of PPARg. The mutation was absent from normal subjects, and functional studies showed that the mutant receptor had significantly decreased basal transcriptional activity and impaired stimulation by rosiglitazone, with no evidence of a dominant-negative mechanism. Other reported FPLD3 patients with mutant PPARg were ascertained either directly based on a clinical diagnosis of lipodystrophy (R425C mutation), or based on insulin resistance with subsequent demonstration of lipodystrophy (V290M and P467L mutations). Compared to subjects with mutant LMNA, lipodystrophic subjects with mutant PPARg had less severe adipose involvement, together with more severe clinical and biochemical manifestations of insulin resistance, and more variable response to treatment with thiazolidinediones. Thus, rare natural mutations affecting PPARg ligand binding and/or transactivation functions cause partial lipodystrophy, with associated components that resemble the metabolic syndrome.

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Section: Pparc Mutations In Partial Lipodystrophy (Fpld3)mentioning

confidence: 92%

Lessons from human mutations in PPARγ

Hegele

2005

Int J Obes

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“…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. 10 The first clinically available TZD, troglitazone, has been associated with rare cases of idiosyncratic hepatotoxicity and was subsequently withdrawn from the European and US markets. Currently, two other TZDs are used for the treatment of type 2 diabetes in monotherapy or in combination with other antidiabetic drugs: rosiglitazone and pioglitazone.…”

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

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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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“…1) (Chan et al, 2010;Zieleniak et al, 2008). Single amino acid mutations within these functional domains result in severe defects in PPAR function that affect lipid metabolism and insulin resistance (Agostini et al, 2006;Barroso et al, 1999;Hegele et al, 2002;Ristow et al, 1998). PPAR heterodimerization with RXRs leads to binding of the peroxisome proliferator response element independent of ligand.…”

Section: Introductionmentioning

confidence: 99%

The Nuclear Receptor PPARs as Important Regulators of T-Cell Functions and Autoimmune Diseases

Choi¹,

Bothwell

2012

Molecules and Cells

147

111

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Members of the nuclear receptor superfamily function as transcription factors involved in innate and adaptive immunity as well as lipid metabolism. These highly conserved proteins participate in ligand-dependent or -independent regulatory mechanisms that affect gene expression. Peroxisome proliferator-activated receptors (PPARs), which include PPARα, PPARβ/δ, and PPARγ, are a group of nuclear receptor proteins that play diverse roles in cellular differentiation, development, and metabolism. Each PPAR subfamily is activated by different endogenous and synthetic ligands. Recent studies using specific ligand treatments and cell type-specific PPAR knockout mice have revealed important roles for these proteins in T-cell-related autoimmune diseases. Moreover, PPARs have been shown to regulate T-cell survival, activation, and CD4 + T helper cell differentiation into the Th1, Th2, Th17, and Treg lineages. Here, we review the studies that provide insight into the important regulatory roles of PPARs in T-cell activation, survival, proliferation, differentiation, and autoimmune disease.

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Dominant negative mutations in human PPARγ associated with severe insulin resistance, diabetes mellitus and hypertension

Cited by 1,268 publications

References 29 publications

Lessons from human mutations in PPARγ

Lessons from human mutations in PPARγ

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

The Nuclear Receptor PPARs as Important Regulators of T-Cell Functions and Autoimmune Diseases

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