Dominant negative mutations in human PPARγ associated with severe insulin resistance, diabetes mellitus and hypertension
Abstract
Thiazolidinediones are a new class of antidiabetic agent that improve insulin sensitivity and reduce plasma glucose and blood pressure in subjects with type 2 diabetes. Although these agents can bind and activate an orphan nuclear receptor, peroxisome proliferator-activated receptor gamma (PPARgamma), there is no direct evidence to conclusively implicate this receptor in the regulation of mammalian glucose homeostasis. Here we report two different heterozygous mutations in the ligand-binding domain of PPARgamma in three subjects with severe insulin resistance. In the PPARgamma crystal structure, the mutations destabilize helix 12 which mediates transactivation. Consistent with this, both receptor mutants are markedly transcriptionally impaired and, moreover, are able to inhibit the action of coexpressed wild-type PPARgamma in a dominant negative manner. In addition to insulin resistance, all three subjects developed type 2 diabetes mellitus and hypertension at an unusually early age. Our findings represent the first germline loss-of-function mutations in PPARgamma and provide compelling genetic evidence that this receptor is important in the control of insulin sensitivity, glucose homeostasis and blood pressure in man.
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Two dominant negative PPARγ mutations explain less than 4% of cases in a cohort of markedly insulin-resistant subjects.
“in a cohort of markedly insulin-resistant subjects, two different dominant negative mutations of the peroxisome proliferator activating receptor gamma (PPARγ ) receptor could only explain less than 4% of these cases [20]”
From The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of type 2 diabetes (2003) · cites this paper as [20]
Known genetic mutations associated with insulin resistance are rare in healthy subjects across populations.
“Examination of groups of healthy subjects in a number of different populations has shown that known genetic mutations associated with insulin resistance are rare [20, 39, 40, 41, 42, 43, 44].”
From The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of type 2 diabetes (2003) · cites this paper as [20]
Insulin sensitivity is influenced by genetics, age, acute exercise, physical fitness, dietary nutrients, medications, obesity and body fat distribution.
“insulin sensitivity is influenced by a number of different factors such as genetics [20], age [21, 22], acute exercise [23], physical fitness [24], dietary nutrients [25], medications [26, 27, 28], obesity [9, 10, 29, 30, 31, 32] and body fat distribution [31, 33, 34, 35, 36, 37, 38].”
From The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of type 2 diabetes (2003) · cites this paper as [20]
Cites
Matthews, D. R., Hosker, J. P., Rudenski, A. S., Naylor, B. A., Treacher, D. F., & Turner, R. C. (1985) · Diabetologia · doi:10.1007/bf00280883 · Cited by 31,502 · see citing works
Lehmann, J. M., Moore, L. B., Smith-Oliver, T. A., Wilkison, W. O., Willson, T. M., & Kliewer, S. A. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.22.12953 · Cited by 3,626 · see citing works
Stimulation of adipogenesis in fibroblasts by PPARγ2, a lipid-activated transcription factor
Tontonoz, P., Hu, E., & Spiegelman, B. M. (1994) · Cell · doi:10.1016/0092-8674(94)90006-x · Cited by 3,533 · see citing works
15-Deoxy-Δ12,14-Prostaglandin J2 is a ligand for the adipocyte determination factor PPARγ
FORMAN, B. M., Tontonoz, P., Chen, J., Brun, R. P., Spiegelman, B. M., & Evans, R. M. (1995) · Cell · doi:10.1016/0092-8674(95)90193-0 · Cited by 2,858 · see citing works
Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-γ
Nolte, R. T., Wisely, G. B., Westin, S. K., Cobb, J. E., Lambert, M. H., Kurokawa, R., Rosenfeld, M. G., Willson, T. M., Glass, C. K., & Milburn, M. V. (1998) · Nature · doi:10.1038/25931 · Cited by 1,955 · see citing works
PPAR-gamma: adipogenic regulator and thiazolidinedione receptor.
Spiegelman, B. M. (1998) · Diabetes · doi:10.2337/diabetes.47.4.507 · Cited by 1,730 · see citing works
Deeb, S. S., Fajas, L., Nemoto, M., Pihlajamäki, J., Mykkänen, L., Kuusisto, J., Laakso, M., Fujimoto, W., & Auwerx, J. (1998) · Nature Genetics · doi:10.1038/3099 · Cited by 1,319 · see citing works
Role of CBP/P300 in nuclear receptor signalling
Chakravarti, D., LaMorte, V. J., Nelson, M. C., Nakajima, T., Schulman, I. G., Juguilon, H., Montminy, M., & Evans, R. M. (1996) · Nature · doi:10.1038/383099a0 · Cited by 930 · see citing works
Danielian, P. S., White, R., Lees, J. A., & Parker, M. G. (1992) · The EMBO Journal · doi:10.1002/j.1460-2075.1992.tb05141.x · Cited by 800 · see citing works
Willson, T. M., Cobb, J. E., Cowan, D. J., Wiethe, R. W., Correa, I. D., Prakash, S. R., Beck, K. D., Moore, L. B., Kliewer, S. A., & Lehmann, J. M. (1996) · Journal of Medicinal Chemistry · doi:10.1021/jm950395a · Cited by 638 · see citing works
Sensitization of diabetic and obese mice to insulin by retinoid X receptor agonists
Mukherjee, R., Davies, P. J., Crombie, D. L., Bischoff, E. D., Cesario, R. M., Jow, L., Hamann, L. G., Boehm, M. F., Mondon, C. E., Nadzan, A. M., et al. (1997) · Nature · doi:10.1038/386407a0 · Cited by 598 · see citing works
Adams, M., Reginato, M. J., Shao, D., Lazar, M. A., & Chatterjee, K. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.8.5128 · Cited by 549 · see citing works
Obesity Associated with a Mutation in a Genetic Regulator of Adipocyte Differentiation
Ristow, M., Müller‐Wieland, D., Pfeiffer, A. F. H., Krone, W., & Kahn, C. R. (1998) · New England Journal of Medicine · doi:10.1056/nejm199810013391403 · Cited by 544 · see citing works
Loss-of-Function Mutations in PPARγ Associated with Human Colon Cancer
Sarraf, P., Mueller, E., Smith, W. M., Wright, H. M., Kum, J. B., Aaltonen, L. A., de la Chapelle, A., Spiegelman, B. M., & Eng, C. (1999) · Molecular Cell · doi:10.1016/s1097-2765(01)80012-5 · Cited by 506 · see citing works
Thiazolidinediones: a new class of antidiabetic drugs
Day, C. (1999) · Diabetic Medicine · doi:10.1046/j.1464-5491.1999.00023.x · Cited by 435 · see citing works
Marx, N., Bourcier, T., Sukhova, G. K., Libby, P., & Plutzky, J. (1999) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.19.3.546 · Cited by 362 · see citing works
Beamer, B. A., Yen, C., Andersen, R. E., Muller, D., Elahi, D., Cheskin, L. J., Andres, R., Roth, J., & Shuldiner, A. R. (1998) · Diabetes · doi:10.2337/diabetes.47.11.1806 · Cited by 293 · see citing works
DiRenzo, J., Söderström, M., Kurokawa, R., Ogliastro, M.-H., Ricote, M., Ingrey, S., Hörlein, A., Rosenfeld, M. G., & Glass, C. K. (1997) · Molecular and Cellular Biology · doi:10.1128/mcb.17.4.2166 · Cited by 281 · see citing works
Enhancement of insulin sensitivity by troglitazone lowers blood pressure in diabetic hypertensives
Ogihara, T., Rakugi, H., IKEGAMI, H., Mikami, H., & Masuo, K. (1995) · American Journal of Hypertension · doi:10.1016/0895-7061(95)96214-5 · Cited by 274 · see citing works
Young, P. W., Buckle, D. R., Cantello, B. C. C., Chapman, H., Clapham, J. C., Coyle, P. J., Haigh, D., Hindley, R. M., Holder, J. C., Kallender, H., et al. (1998) · PubMed · Cited by 229 · see citing works
Satoh, H., Tsukamoto, K., Hashimoto, Y., et al. (1999) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1998.0126 · Cited by 182 · see citing works
Collingwood, T. N., Adams, M., Tone, Y., & Chatterjee, K. (1994) · Molecular Endocrinology · doi:10.1210/mend.8.9.7838159 · Cited by 149 · see citing works
Morris, C., Aubert, D., Legrand, C., Pain, B., & Samarut, J. (1991) · Cell · doi:10.1016/0092-8674(91)90068-a · Cited by 145 · see citing works
Acerini, C. L., Ahmed, M. L., Ross, K. M., Sullivan, P. B., Bird, G., & Dunger, D. B. (1998) · Diabetic Medicine · doi:10.1002/(sici)1096-9136(199801)15:1 · Cited by 137 · see citing works
Maturity-onset diabetes of the young
Fajans, S. S., Bell, G. I., Bowden, D. W., Halter, J. B., & Polonsky, K. S. (1994) · Life Sciences · doi:10.1016/0024-3205(94)90052-3 · Cited by 118 · see citing works
Molecular Scanning of the Insulin Receptor Gene in Syndromes of Insulin Resistance
Krook, A., Kumar, S., Laing, I., et al. (1994) · Diabetes · doi:10.2337/diab.43.3.357 · Cited by 105 · see citing works
Young, P. W., Buckle, D. R., Cantello, B. C. C., Chapman, H., Clapham, J. C., Coyle, P. J., Haigh, D., Hindley, R. M., Holder, J. C., Kallender, H., et al. (1998) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(24)37268-4 · Cited by 101 · see citing works
Expression of Peroxisome Proliferator-Activated Receptor γ (PPARγ) in Rat Aortic Smooth Muscle Cells
Iijima, K., Yoshizumi, M., Ako, J., Eto, M., Kim, S., Hashimoto, M., Sugimoto, N., Liang, Y.-Q., Sudoh, N., Toba, K., et al. (1998) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1998.8794 · Cited by 85 · see citing works
Lilly Lecture: Syndromes of Insulin Resistance: From Patient to Gene and Back Again
Flier, J. S. (1992) · Diabetes · doi:10.2337/diab.41.9.1207 · Cited by 74 · see citing works
Nakamura, Y., Ohya, Y., Onaka, U., et al. (1998) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0701669 · Cited by 68 · see citing works
Whitehead, J. P., Humphreys, P. J., Krook, A., et al. (1998) · Diabetes · doi:10.2337/diabetes.47.5.837 · Cited by 39 · see citing works
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The hormone resistin links obesity to diabetes
Steppan, C. M., Bailey, S. T., Bhat, S., Brown, E. J., Banerjee, R. R., Wright, C. M., Patel, H. R., Ahima, R. S., & Lazar, M. A. (2001) · Nature · doi:10.1038/35053000 · Cited by 4,755 · see citing works
The mechanisms of action of PPARs
Berger, J., & Moller, D. E. (2002) · Annual Review of Medicine · doi:10.1146/annurev.med.53.082901.104018 · Cited by 2,659 · see citing works
Kahn, S. E. (2003) · Diabetologia · doi:10.1007/s00125-002-1009-0 · Cited by 2,166 · see citing works
Fat and Beyond: The Diverse Biology of PPARγ
Tontonoz, P., & Spiegelman, B. M. (2008) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.77.061307.091829 · Cited by 2,085 · see citing works
The common PPARγ Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes
Altshuler, D., Hirschhorn, J. N., Klannemark, M., Lindgren, C. M., Vohl, M.-C., Nemesh, J., Lane, C. R., Schaffner, S. F., Bolk, S., Brewer, C., et al. (2000) · Nature Genetics · doi:10.1038/79216 · Cited by 1,766 · see citing works
Molecular Mechanisms of Human Hypertension
Lifton, R. P., Gharavi, A. G., & Geller, D. S. (2001) · Cell · doi:10.1016/s0092-8674(01)00241-0 · Cited by 1,686 · see citing works
Adipose tissue expandability, lipotoxicity and the Metabolic Syndrome — An allostatic perspective
Virtue, S., & Vidal-Puig, A. (2010) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2009.12.006 · Cited by 1,013 · see citing works
Varga, T., Czimmerer, Z., & Nagy, L. (2011) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2011.02.014 · Cited by 933 · see citing works
Delépine, M., Nicolino, M., Barrett, T., Golamaully, M., Mark Lathrop, G., & Julier, C. (2000) · Nature Genetics · doi:10.1038/78085 · Cited by 813 · see citing works
Havel, P. J. (2002) · Current Opinion in Lipidology · doi:10.1097/00041433-200202000-00008 · Cited by 575 · see citing works
Contribution of adipogenesis to healthy adipose tissue expansion in obesity
Vishvanath, L., & Gupta, R. K. (2019) · Journal of Clinical Investigation · doi:10.1172/jci129191 · Cited by 558 · see citing works
The role of mitochondria in the pathogenesis of type 2 diabetes
Patti, M.-E., & Corvera, S. (2010) · Endocrine Reviews · doi:10.1210/er.2009-0027 · Cited by 551 · see citing works
Christensen (2008) · doi:10.1016/s1043-4526(08)00401-4 · Cited by 504 · see citing works
Diabetes mellitus and genetically programmed defects in β-cell function
Bell, G. I., & Polonsky, K. S. (2001) · Nature · doi:10.1038/414788a · Cited by 475 · see citing works
Impaired adipogenesis and dysfunctional adipose tissue in human hypertrophic obesity
Hammarstedt, A., Gogg, S., Hedjazifar, S., Nerstedt, A., & Smith, U. (2018) · Physiological Reviews · doi:10.1152/physrev.00034.2017 · Cited by 462 · see citing works
Gupta, R. K., Mepani, R. J., Kleiner, S., Lo, J. C., Khandekar, M. J., Cohen, P., Frontini, A., Bhowmick, D. C., Ye, L., Cinti, S., et al. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.01.010 · Cited by 426 · see citing works
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Clark, R. B. (2002) · Journal of Leukocyte Biology · doi:10.1189/jlb.71.3.388 · Cited by 337 · see citing works
Sarjeant, K., & Stephens, J. M. (2012) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a008417 · Cited by 328 · see citing works
Musso, C., Cochran, E., Moran, S. A., Skarulis, M. C., Oral, E. A., Taylor, S., & Gorden, P. (2004) · Medicine · doi:10.1097/01.md.0000133625.73570.54 · Cited by 264 · see citing works
Jeremic, N., Chaturvedi, P., & Tyagi, S. C. (2017) · Journal of Cellular Physiology · doi:10.1002/jcp.25450 · Cited by 211 · see citing works
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Faraci, F. M. (2011) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.01310.2010 · Cited by 196 · see citing works
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Schopfer, F. J., Cole, M. P., Groeger, A. L., Chen, C.-S., Khoo, N. K. H., Woodcock, S. R., Golin-Bisello, F., Motanya, U. N., Li, Y., Zhang, J., et al. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.091512 · Cited by 171 · see citing works
Structural basis for the assembly of the SMRT/NCoR core transcriptional repression machinery
Oberoi, J., Fairall, L., Watson, P. J., Yang, J.-C., Czimmerer, Z., Kampmann, T., Goult, B. T., Greenwood, J. A., Gooch, J. T., Kallenberger, B. C., et al. (2011) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.1983 · Cited by 165 · see citing works
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Roche, H. M. (2005) · Proceedings of The Nutrition Society · doi:10.1079/pns2004405 · Cited by 113 · see citing works
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Damcott, C. M., Sack, P., & Shuldiner, A. R. (2003) · Endocrinology and Metabolism Clinics of North America · doi:10.1016/s0889-8529(03)00076-8 · Cited by 63 · see citing works
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Savage, D. B., Murgatroyd, P. R., Chatterjee, V. K., & O’Rahilly, S. (2005) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2004-1494 · Cited by 47 · see citing works
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- Authors
- Barroso, I., Gurnell, M., Crowley, V. E. F., Agostini, M., Schwabe, J. W., Soos, M. A., Maslen, G. L., Williams, T. D. M., Lewis, H., Schafer, A. J., Chatterjee, V. K. K., & O'Rahilly, S.
- Affiliations
- University of Cambridge (GB)
- Prince Philip Hospital (GB)
- Selly Oak Hospital (GB)
- Venue
- Nature
- Published
- 1999-12
- Volume
- 402
- Issue
- 6764
- Pages
- 880-883
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1488559297
- Cited by
- 1,368
- References
- 31
- Citations by year
- 2026: 18 · 2025: 20 · 2024: 23 · 2023: 24 · 2022: 35 · 2021: 38 · 2020: 41 · 2019: 39 · 2018: 38 · 2017: 47 · 2016: 47 · 2015: 46 · 2014: 44 · 2013: 43 · 2012: 52
- FWCI
- 24.46
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Leicester Research Archive (University of Leicester) (submittedVersion)
- Funders
- Wellcome Trust
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- PPARγ, dominant negative mutation, insulin resistance, type 2 diabetes, hypertension, thiazolidinediones, ligand-binding domain, helix 12, glucose homeostasis, nuclear receptors, transcriptional activation
- MeSH terms
- Rosiglitazone, Adult, Animals, Benzoxazoles, Binding Sites, Diabetes Mellitus, Type 2, Female, Genes, Dominant, Humans, Hypertension, Insulin Resistance, Ligands, Male, Middle Aged, Models, Molecular, Mutation, Nicotinic Acids, Phenylpropionates, Protein Conformation, Tetrahydronaphthalenes, Thiazoles, Transcription Factors, Receptors, Cytoplasmic and Nuclear, Receptors, Retinoic Acid, Thiazolidinediones, Retinoid X Receptors, Mice
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