The genetic ablation of SRC-3 protects against obesity and improves insulin sensitivity by reducing the acetylation of PGC-1α
Open accessAbstract
Transcriptional control of metabolic circuits requires coordination between specific transcription factors and coregulators and is often deregulated in metabolic diseases. We characterized here the mechanisms through which the coactivator SRC-3 controls energy homeostasis. SRC-3 knock-out mice present a more favorable metabolic profile relative to their wild-type littermates. This metabolic improvement in SRC-3 −/− mice is caused by an increase in mitochondrial function and in energy expenditure as a consequence of activation of PGC-1α. By controlling the expression of the only characterized PGC-1α acetyltransferase GCN5, SRC-3 induces PGC-1α acetylation and consequently inhibits its activity. Interestingly, SRC-3 expression is induced by caloric excess, resulting in the inhibition of PGC-1α activity and energy expenditure, whereas caloric restriction reduces SRC-3 levels leading to enhanced PGC-1α activity and energy expenditure. Collectively, these data suggest that SRC-3 is a critical link in a cofactor network that uses PGC-1α as an effector to control mitochondrial function and energy homeostasis.
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HFD in mice leads to hyperacetylated, inactive PGC-1α.
“Indeed, HFD in mice leads to hyperacetylated, inactive, PGC-1α (Coste et al, 2008).”
From Mitochondrial response to nutrient availability and its role in metabolic disease (2014) · cites this paper as Coste et al, 2008
Cites
Mootha, V. K., Lindgren, C. M., Eriksson, K.-F., Subramanian, A., Sihag, S., Lehar, J., Puigserver, P., Carlsson, E., Ridderstråle, M., Laurila, E., et al. (2003) · Nature Genetics · doi:10.1038/ng1180 · Cited by 10,197 · see citing works
Self-citationLagouge, M., Argmann, C., Gerhart-Hines, Z., Meziane, H., Lerin, C., Daussin, F., Messadeq, N., Milne, J., Lambert, P., Elliott, P., et al. (2006) · Cell · doi:10.1016/j.cell.2006.11.013 · Cited by 4,057 · see citing works
Self-citationA Cold-Inducible Coactivator of Nuclear Receptors Linked to Adaptive Thermogenesis
Puigserver, P., Wu, Z., Park, C. W., Graves, R., Wright, M., & Spiegelman, B. M. (1998) · Cell · doi:10.1016/s0092-8674(00)81410-5 · Cited by 3,864 · see citing works
Self-citationNutrient control of glucose homeostasis through a complex of PGC-1α and SIRT1
Rodgers, J. T., Lerin, C., Haas, W., Gygi, S. P., Spiegelman, B. M., & Puigserver, P. (2005) · Nature · doi:10.1038/nature03354 · Cited by 3,160 · see citing works
Self-citationMetabolic control through the PGC-1 family of transcription coactivators
Lin, J., Handschin, C., & Spiegelman, B. M. (2005) · Cell Metabolism · doi:10.1016/j.cmet.2005.05.004 · Cited by 2,130 · cited 1× · see citing works
“Mitochondrial activation in the absence of SRC-3 was caused by the deacetylation and increase in activity of the PPAR coactivator-1 (PGC-1 ), which coordinates mitochondrial function (11, 12).”
BackgroundMitochondrial dysfunction in the elderly: possible role in insulin resistance
Petersen, K. F., Befroy, D., Dufour, S., Dziura, J., Ariyan, C., Rothman, D. L., DiPietro, L., Cline, G. W., & Shulman, G. I. (2003) · Science · doi:10.1126/science.1082889 · Cited by 2,107 · see citing works
Patti, M. E., Butte, A. J., Crunkhorn, S., Cusi, K., Berria, R., Kashyap, S., Miyazaki, Y., Kohane, I., Costello, M., Saccone, R., et al. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1032913100 · Cited by 1,952 · see citing works
The Sir2 Family of Protein Deacetylases
Blander, G., & Guarente, L. (2004) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.73.011303.073651 · Cited by 1,480 · see citing works
Schoonjans, K., Peinado‐Onsurbe, J., Lefebvre, A. M., Heyman, R. A., Briggs, M., Deeb, S., Staels, B., & Auwerx, J. (1996) · The EMBO Journal · doi:10.1002/j.1460-2075.1996.tb00918.x · Cited by 1,173 · see citing works
Self-citationRosenfeld, M. G., Lunyak, V. V., & Glass, C. K. (2006) · Genes & Development · doi:10.1101/gad.1424806 · Cited by 952 · see citing works
Coregulator Function: A Key to Understanding Tissue Specificity of Selective Receptor Modulators
Smith, C. L., & O’Malley, B. W. (2004) · Endocrine Reviews · doi:10.1210/er.2003-0023 · Cited by 931 · see citing works
Self-citationCipolat, S., Rudka, T., Hartmann, D., Costa, V., Serneels, L., Craessaerts, K., Metzger, K., Frezza, C., Annaert, W. G., D'adamio, L., et al. (2006) · Cell · doi:10.1016/j.cell.2006.06.021 · Cited by 735 · see citing works
Sparks, L. M., Xie, H., Koza, R. A., Mynatt, R., Hulver, M. W., Bray, G. A., & Smith, S. R. (2005) · Diabetes · doi:10.2337/diabetes.54.7.1926 · Cited by 629 · cited 1× · see citing works
“Our data are fully in line with a recent report indicating that an HF diet attenuates gene pathways necessary for OXPHOS and mitochondrial biogenesis and provides a mechanistic explanation for the observed phenotype in that study (24).”
ResultSRC-1 and TIF2 Control Energy Balance between White and Brown Adipose Tissues
Picard, F., Géhin, M., Annicotte, J., Rocchi, S., Champy, M., O’Malley, B. W., Chambon, P., & Auwerx, J. H. (2002) · Cell · doi:10.1016/s0092-8674(02)01169-8 · Cited by 444 · see citing works
Self-citationLerin, C., Rodgers, J. T., Kalume, D. E., Kim, S.-H., Pandey, A., & Puigserver, P. (2006) · Cell Metabolism · doi:10.1016/j.cmet.2006.04.013 · Cited by 443 · see citing works
Self-citationTakahashi, H., McCaffery, J. M., Irizarry, R. A., & Boeke, J. D. (2006) · Molecular Cell · doi:10.1016/j.molcel.2006.05.040 · Cited by 438 · see citing works
Biological control through regulated transcriptional coactivators
Spiegelman, B. M., & Heinrich, R. (2004) · Cell · doi:10.1016/j.cell.2004.09.037 · Cited by 377 · see citing works
Torres‐Arzayus, M. I., de Mora, J. F., Yuan, J., Vázquez, F., Bronson, R. T., Rué, M., Sellers, W. R., & Brown, M. A. (2004) · Cancer Cell · doi:10.1016/j.ccr.2004.06.027 · Cited by 377 · see citing works
Transcriptional coregulators in the control of energy homeostasis
Feige, J. N., & Auwerx, J. (2007) · Trends in Cell Biology · doi:10.1016/j.tcb.2007.04.001 · Cited by 325 · see citing works
Self-citationThe Expanding Cosmos of Nuclear Receptor Coactivators
Lonard, D. M., & O’Malley, B. W. (2006) · Cell · doi:10.1016/j.cell.2006.04.021 · Cited by 317 · see citing works
Self-citationOncogenic steroid receptor coactivator-3 is a key regulator of the white adipogenic program
Louet, J., Coste, A., Amazit, L., Tannour‐Louet, M., Wu, R., Tsai, S. Y., Tsai, M., Auwerx, J. H., & O’Malley, B. W. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0608711103 · Cited by 114 · see citing works
Self-citationCritical roles of the p160 transcriptional coactivators p/CIP and SRC-1 in energy balance
Wang, Z., Qi, C., Krones, A., Woodring, P. J., Zhu, X., Reddy, J. K., Evans, R. M., Rosenfeld, M. G., & Hunter, T. R. (2006) · Cell Metabolism · doi:10.1016/j.cmet.2006.01.002 · Cited by 103 · see citing works
Rheostat Control of Gene Expression by Metabolites
Ladurner, A. G. (2006) · Molecular Cell · doi:10.1016/j.molcel.2006.09.002 · Cited by 95 · see citing works
Absence of the steroid receptor coactivator‐3 induces B‐cell lymphoma
Coste, A., Antal, M. C., Chan, S. H., Kastner, P., Mark, M. P., O’Malley, B. W., & Auwerx, J. H. (2006) · The EMBO Journal · doi:10.1038/sj.emboj.7601106 · Cited by 67 · see citing works
Self-citationImproving metabolism by increasing energy expenditure
Auwerx, J. H. (2006) · Nature Medicine · doi:10.1038/nm0106-44 · Cited by 26 · see citing works
Self-citation
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Houtkooper, R. H., Pirinen, E., & Auwerx, J. (2012) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3293 · Cited by 2,008 · see citing works
Self-citationPGC-1α, SIRT1 and AMPK, an energy sensing network that controls energy expenditure
Cantó, C., & Auwerx, J. (2009) · Current Opinion in Lipidology · doi:10.1097/mol.0b013e328328d0a4 · Cited by 1,624 · see citing works
Self-citationRegulation of pgc-1α, a nodal regulator of mitochondrial biogenesis
Fernandez-Marcos, P. J., & Auwerx, J. (2011) · The American Journal of Clinical Nutrition · doi:10.3945/ajcn.110.001917 · Cited by 1,237 · see citing works
Self-citationAdaptive thermogenesis in adipocytes: Is beige the new brown?
Wu, J., Cohen, P., & Spiegelman, B. M. (2013) · Genes & Development · doi:10.1101/gad.211649.112 · Cited by 828 · see citing works
Transcriptional integration of mitochondrial biogenesis
Scarpulla, R. C., Vega, R. B., & Kelly, D. P. (2012) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2012.06.006 · Cited by 798 · see citing works
Mitochondrial biogenesis and dynamics in the developing and diseased heart
Dorn, G. W., Vega, R. B., & Kelly, D. P. (2015) · Genes & Development · doi:10.1101/gad.269894.115 · Cited by 470 · see citing works
Targeting Sirtuin 1 to Improve Metabolism: All You Need Is NAD+?
Cantó, C., & Auwerx, J. (2012) · Pharmacological Reviews · doi:10.1124/pr.110.003905 · Cited by 433 · see citing works
Self-citationPharmacological approaches to restore mitochondrial function
Andreux, P. A., Houtkooper, R. H., & Auwerx, J. (2013) · Nature Reviews Drug Discovery · doi:10.1038/nrd4023 · Cited by 383 · see citing works
Self-citationProtein acetylation in metabolism – metabolites and cofactors
Menzies, K. J., Zhang, H., Katsyuba, E., & Auwerx, J. (2016) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2015.181 · Cited by 331 · see citing works
Self-citationPhilp, A., Chen, A., Lan, D., Meyer, G. A., Murphy, A. N., Knapp, A. E., Olfert, I. M., McCurdy, C. E., Marcotte, G. R., Hogan, M. C., et al. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.261685 · Cited by 184 · see citing works
Gurd, B. J. (2011) · Applied Physiology, Nutrition, and Metabolism · doi:10.1139/h11-070 · Cited by 171 · see citing works
Mitochondrial response to nutrient availability and its role in metabolic disease
Gao, A. W., Cantó, C., & Houtkooper, R. H. (2014) · EMBO Molecular Medicine · doi:10.1002/emmm.201303782 · Cited by 148 · see citing works
Goedeke, L., Salerno, A., Ramírez, C. M., Guo, L., Allen, R. M., Yin, X., Langley, S. R., Esau, C., Wanschel, A., Fisher, E. A., et al. (2014) · EMBO Molecular Medicine · doi:10.15252/emmm.201404046 · Cited by 145 · see citing works
- Authors
- Coste, A., Louet, J.-F., Lagouge, M., Lerin, C., Antal, M. C., Meziane, H., Schoonjans, K., Puigserver, P., O'Malley, B. W., & Auwerx, J.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030;
- Dana Farber Cancer Institute and Department of Cell Biology Harvard Medical School, Boston, MA 02115;
- Phénotypage et ingénierie précliniques des systèmes d’organismes modèles (FR)
- Institut Clinique de la Souris, 67404 Illkirch, France; and
- Harvard University (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2008-11-04
- Volume
- 105
- Issue
- 44
- Pages
- 17187-17192
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2579399
- OpenAlex
- W2078252528
- Cited by
- 205
- References
- 25
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 13 · 2023: 9 · 2022: 5 · 2021: 6 · 2020: 10 · 2019: 8 · 2018: 5 · 2017: 13 · 2016: 16 · 2015: 12 · 2014: 18 · 2013: 19 · 2012: 20
- FWCI
- 10.61
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- Funders
- Institut National de la Santé et de la Recherche Médicale
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-59820, P01DK059820)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD 07857, R01HD007857)
- Topics
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- 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
- Keywords
- SRC-3, PGC-1α, protein acetylation, GCN5, transcriptional coactivator, obesity, insulin sensitivity, energy homeostasis, mitochondrial function, energy expenditure, caloric restriction, caloric excess, metabolic disorders
- MeSH terms
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, p300-CBP-Associated Factor, Acetylation, Animals, Energy Metabolism, Insulin Resistance, Male, Mice, Inbred C57BL, Mitochondria, Obesity, Transcription Factors, Trans-Activators, Mice, Knockout, Caloric Restriction, p300-CBP Transcription Factors, Mice, Histone Acetyltransferases, Nuclear Receptor Coactivator 3
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