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

Maura Agostini; Erik Schoenmakers; Catherine Mitchell; Istvan Szatmari; David Savage; Aaron Smith; Odelia Rajanayagam; Robert Semple; Jian'an Luan; Louise Bath; Anthony Zalin; Mourad Labib; Sudhesh Kumar; Helen Simpson; Dirk Blom; David Marais; John Schwabe; Inês Barroso; Richard Trembath; Nicholas Wareham; Laszlo Nagy; Mark Gurnell; Stephen O'Rahilly; Krishna Chatterjee

doi:10.1016/j.cmet.2006.09.003

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

Maura Agostini, Erik Schoenmakers, Catherine Mitchell, Istvan Szatmari, David Savage, Aaron Smith, Odelia Rajanayagam, Robert Semple, Jian'an Luan, Louise Bath, Anthony Zalin, Mourad Labib, Sudhesh Kumar, Helen Simpson, Dirk Blom, David Marais, John Schwabe, Inês Barroso, Richard Trembath, Nicholas WarehamLaszlo Nagy, Mark Gurnell, Stephen O'Rahilly, Krishna Chatterjee

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134 Scopus citations

Abstract

PPARγ is essential for adipogenesis and metabolic homeostasis. We describe mutations in the DNA and ligand binding domains of human PPARγ in lipodystrophic, severe insulin resistance. These receptor mutants lack DNA binding and transcriptional activity but can translocate to the nucleus, interact with PPARγ coactivators and inhibit coexpressed wild-type receptor. Expression of PPARγ target genes is markedly attenuated in mutation-containing versus receptor haploinsufficent primary cells, indicating that such dominant-negative inhibition operates in vivo. Our observations suggest that these mutants restrict wild-type PPARγ action via a non-DNA binding, transcriptional interference mechanism, which may involve sequestration of functionally limiting coactivators.

Original language	English (US)
Pages (from-to)	303-311
Number of pages	9
Journal	Cell Metabolism
Volume	4
Issue number	4
DOIs	https://doi.org/10.1016/j.cmet.2006.09.003
State	Published - Oct 2006
Externally published	Yes

ASJC Scopus subject areas

Physiology
Molecular Biology
Cell Biology

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Agostini, M., Schoenmakers, E., Mitchell, C., Szatmari, I., Savage, D., Smith, A., Rajanayagam, O., Semple, R., Luan, J., Bath, L., Zalin, A., Labib, M., Kumar, S., Simpson, H., Blom, D., Marais, D., Schwabe, J., Barroso, I., Trembath, R., ... Chatterjee, K. (2006). Non-DNA binding, dominant-negative, human PPARγ mutations cause lipodystrophic insulin resistance. Cell Metabolism, 4(4), 303-311. https://doi.org/10.1016/j.cmet.2006.09.003

Agostini, M, Schoenmakers, E, Mitchell, C, Szatmari, I, Savage, D, Smith, A, Rajanayagam, O, Semple, R, Luan, J, Bath, L, Zalin, A, Labib, M, Kumar, S, Simpson, H, Blom, D, Marais, D, Schwabe, J, Barroso, I, Trembath, R, Wareham, N, Nagy, L, Gurnell, M, O'Rahilly, S & Chatterjee, K 2006, 'Non-DNA binding, dominant-negative, human PPARγ mutations cause lipodystrophic insulin resistance', Cell Metabolism, vol. 4, no. 4, pp. 303-311. https://doi.org/10.1016/j.cmet.2006.09.003

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

abstract = "PPARγ is essential for adipogenesis and metabolic homeostasis. We describe mutations in the DNA and ligand binding domains of human PPARγ in lipodystrophic, severe insulin resistance. These receptor mutants lack DNA binding and transcriptional activity but can translocate to the nucleus, interact with PPARγ coactivators and inhibit coexpressed wild-type receptor. Expression of PPARγ target genes is markedly attenuated in mutation-containing versus receptor haploinsufficent primary cells, indicating that such dominant-negative inhibition operates in vivo. Our observations suggest that these mutants restrict wild-type PPARγ action via a non-DNA binding, transcriptional interference mechanism, which may involve sequestration of functionally limiting coactivators.",

author = "Maura Agostini and Erik Schoenmakers and Catherine Mitchell and Istvan Szatmari and David Savage and Aaron Smith and Odelia Rajanayagam and Robert Semple and Jian'an Luan and Louise Bath and Anthony Zalin and Mourad Labib and Sudhesh Kumar and Helen Simpson and Dirk Blom and David Marais and John Schwabe and In{\^e}s Barroso and Richard Trembath and Nicholas Wareham and Laszlo Nagy and Mark Gurnell and Stephen O'Rahilly and Krishna Chatterjee",

note = "Funding Information: We would like to thank the Imaging Department (Royal Orthopaedic Hospital, Stanmore) for supplying control MRI data and Teturou Satoh (Gunma University) for providing PDIP1α ahead of publication. This work was supported by the Wellcome Trust (V.K.K.C., S.O.R., L.N., I.B., D.B.S.) and the Medical Research Council (N.J.W., J.W.R.S.). ",

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doi = "10.1016/j.cmet.2006.09.003",

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AU - Agostini, Maura

AU - Schoenmakers, Erik

AU - Mitchell, Catherine

AU - Szatmari, Istvan

AU - Savage, David

AU - Smith, Aaron

AU - Rajanayagam, Odelia

AU - Semple, Robert

AU - Luan, Jian'an

AU - Bath, Louise

AU - Zalin, Anthony

AU - Labib, Mourad

AU - Kumar, Sudhesh

AU - Simpson, Helen

AU - Blom, Dirk

AU - Marais, David

AU - Schwabe, John

AU - Barroso, Inês

AU - Trembath, Richard

AU - Wareham, Nicholas

AU - Nagy, Laszlo

AU - Gurnell, Mark

AU - O'Rahilly, Stephen

AU - Chatterjee, Krishna

N1 - Funding Information: We would like to thank the Imaging Department (Royal Orthopaedic Hospital, Stanmore) for supplying control MRI data and Teturou Satoh (Gunma University) for providing PDIP1α ahead of publication. This work was supported by the Wellcome Trust (V.K.K.C., S.O.R., L.N., I.B., D.B.S.) and the Medical Research Council (N.J.W., J.W.R.S.).

PY - 2006/10

Y1 - 2006/10

N2 - PPARγ is essential for adipogenesis and metabolic homeostasis. We describe mutations in the DNA and ligand binding domains of human PPARγ in lipodystrophic, severe insulin resistance. These receptor mutants lack DNA binding and transcriptional activity but can translocate to the nucleus, interact with PPARγ coactivators and inhibit coexpressed wild-type receptor. Expression of PPARγ target genes is markedly attenuated in mutation-containing versus receptor haploinsufficent primary cells, indicating that such dominant-negative inhibition operates in vivo. Our observations suggest that these mutants restrict wild-type PPARγ action via a non-DNA binding, transcriptional interference mechanism, which may involve sequestration of functionally limiting coactivators.

AB - PPARγ is essential for adipogenesis and metabolic homeostasis. We describe mutations in the DNA and ligand binding domains of human PPARγ in lipodystrophic, severe insulin resistance. These receptor mutants lack DNA binding and transcriptional activity but can translocate to the nucleus, interact with PPARγ coactivators and inhibit coexpressed wild-type receptor. Expression of PPARγ target genes is markedly attenuated in mutation-containing versus receptor haploinsufficent primary cells, indicating that such dominant-negative inhibition operates in vivo. Our observations suggest that these mutants restrict wild-type PPARγ action via a non-DNA binding, transcriptional interference mechanism, which may involve sequestration of functionally limiting coactivators.

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

Abstract

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