Non-DNA binding, dominant-negative, human PPARγ mutations cause lipodystrophic insulin resistance

Agostini, Maura; Schoenmakers, Erik; Mitchell, Catherine; Szatmári, István; Savage, David B.; Smith, Aaron G.; Rajanayagam, Odelia; Semple, Robert K.; Luan, Jian’an; Bath, Louise; Zalin, A. M.; Labib, M; Kumar, Sudhesh; Simpson, Helen; Blom, Dirk; Marais, David; Schwabe, John W. R.; Barroso, Inês; Trembath, Richard C.; Wareham, Nicholas J.; Nagy, László; Gurnell, Mark; O’Rahilly, Stephen; Chatterjee, Krishna

doi:10.1016/j.cmet.2006.09.003

Cited by 170 publications

(160 citation statements)

References 67 publications

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“…Finally, as mentioned above, point mutations in the ligand or DNA-binding domain of PPAR are associated with severe insulin resistance in human subjects [26,27]. The majority of data also supports the conclusion that WAT is the principal tissue responsible for the therapeutic effects of TZDs although extra-adipose actions also contribute to improved insulin sensitivity.…”

Section: Ppar and Insulin Resistancesupporting

confidence: 57%

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PPARs and adipocyte function

Christodoulides

Vidal-Puig

2010

Molecular and Cellular Endocrinology

114

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Abstract:For long viewed as passive lipid storage depots, adipocytes are now recognised as key players in the pathogenesis of insulin resistance and metabolic disease. In parallel, the last two decades of research have seen the emergence of transcription factors of the peroxisome proliferator-activated receptor (PPAR) family as central regulators of lipid and glucose homeostasis and molecular targets for drugs to treat hyper-lipidaemia and type 2 diabetes mellitus. In this review we discuss the characteristics of PPARs and the role of the different isotypes in adipocyte biology.

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Section: Ppar and Insulin Resistancesupporting

confidence: 57%

“…Naturally occurring PPAR mutations in human subjects also support an important role for this transcription factor in WAT development [26,27]. Specifically, individuals carrying dominant-negative mutations in PPAR display partial lipodystrophy concomitant with insulin resistance, dys-lipidaemia, and hypertension.…”

Section: Ppar and Adipocyte Biologymentioning

confidence: 96%

PPARs and adipocyte function

Christodoulides

Vidal-Puig

2010

Molecular and Cellular Endocrinology

114

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“…For P12A, the variant is very common, but the magnitude of effect on disease risk is modest (20% decreased risk of T2D) (3). In rare families with syndromic lipodystrophy, loss-of-function (LOF) mutations in PPARG that prohibit adipocyte differentiation in vitro, have been found that segregate with lipodystophy, insulin resistance, and T2D (4,5). The magnitude of effect on individual and cellular phenotypes is strong, but the mutations are extremely rare.…”

mentioning

confidence: 99%

Rare variants in PPARG with decreased activity in adipocyte differentiation are associated with increased risk of type 2 diabetes

Majithia

Flannick

Shahinian

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

152

113

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Significance Genome sequencing of individuals in the population reveals new mutations in almost every protein coding gene; interpreting the consequence of these mutations for human health and disease remains challenging. We sequenced the gene PPARG , a target of antidiabetic drugs, in nearly 20,000 individuals with and without type 2 diabetes (T2D). We identified 49 previously unidentified protein-altering mutations, characterized their cellular function in human cells, and discovered that nine of these mutations cause loss-of-function (LOF). The individuals who carry these nine LOF mutations have a sevenfold increased risk of T2D, whereas individuals carrying mutations we classify as benign have no increased risk of T2D.

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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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Non-DNA binding, dominant-negative, human PPARγ mutations cause lipodystrophic insulin resistance

Cited by 170 publications

References 67 publications

PPARs and adipocyte function

PPARs and adipocyte function

Rare variants in PPARG with decreased activity in adipocyte differentiation are associated with increased risk of type 2 diabetes

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

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