Differential Roles of Insulin Receptor Substrates in Brown Adipocyte Differentiation
Open accessAbstract
Insulin promotes adipocyte differentiation via a complex signaling network involving multiple insulin receptor substrates (IRSs). In cultured brown preadipocytes, expression of IRS-1 and IRS-2 mRNAs and proteins was at relatively high levels before and after differentiation into mature fat cells, while IRS-3 transcript was not detectable in preadipocytes but increased during the course of differentiation, and IRS-4 mRNA was barely detected in both states. To determine more precisely the roles of various IRS proteins in adipogenesis, we established and characterized brown preadipocyte cell lines from wild-type and IRS knockout (KO) animals. While wild-type, IRS-2 KO, and IRS-4 KO cells fully differentiated into mature adipocytes, IRS-3 KO cells showed a moderate defect in differentiation and IRS-1 KO cells exhibited a severe defect in the process. Cells lacking both IRS-1 and IRS-3 completely failed to differentiate. Expression of the adipogenic markers peroxisome proliferator-activated receptor gamma (PPARgamma), CCAAT/enhancer-binding protein alpha, fatty acid synthase, glucose transporter 4, and the transcription factor signal transducer and activator of transcription 5, as well as the brown-fat-specific markers PPARgamma coactivator 1 alpha and uncoupling protein 1, mirrored the differentiation pattern. Reconstitution of the IRS-1 KO cells with IRS-1 and IRS-4, but not IRS-2 or IRS-3, compensated for the lack of differentiation in IRS-1 KO cells. A chimeric molecule containing the N terminus of IRS-1 and the C terminus of IRS-2, but not one with the N terminus of IRS-2 and the C terminus of IRS-1, also rescued differentiation. Expression of Wnt 10a, a molecule known to inhibit adipogenesis, was dramatically increased in the IRS-1 KO cells, and this could be reduced by overexpression of IRS-1 or IRS-4, which was correlated with restoration of differentiation. These data indicate that both IRS-1 and -3 play important roles in the differentiation of brown adipocytes and that the N terminus of IRS-1 is more important for this function of the molecule. Although IRS-4 is not essential for the process, overexpression of IRS-4 can compensate for the deficiency in differentiation in IRS-1 KO cells.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Brown preadipocytes lacking IRS-1 display a severe defect in differentiation.
“Brown preadipocytes lacking the insulin receptor substrate (IRS)-1 display a severe defect in differentiation 109; and IRS-2 null brown adipocytes have impaired glucose uptake function 110.”
From Cellular bioenergetics as a target for obesity therapy (2010) · cites this paper as [109]
The insulin/IGF-1 signaling system exerts an essential role in brown fat differentiation and function.
“In addition, the insulin/IGF-1 signaling system also exerts an essential role in brown fat differentiation and function (Figure 3).”
From Cellular bioenergetics as a target for obesity therapy (2010) · cites this paper as [109]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
A 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
Understanding Adipocyte Differentiation
Gregoire, F. M., Smas, C. M., & Sul, H. S. (1998) · Physiological Reviews · doi:10.1152/physrev.1998.78.3.783 · Cited by 2,358 · see citing works
Morgenstern, J. P., & Land, H. (1990) · Nucleic Acids Research · doi:10.1093/nar/18.12.3587 · Cited by 2,099 · see citing works
Puigserver, P., & Spiegelman, B. M. (2003) · Endocrine Reviews · doi:10.1210/er.2002-0012 · Cited by 2,076 · see citing works
Transcriptional regulation of adipogenesisPreprint
Rosen, E. D., Walkey, C. J., Puigserver, P., & Spiegelman, B. M. (2000) · Genes & Development · doi:10.1101/gad.14.11.1293 · Cited by 1,902 · see citing works
Inhibition of Adipogenesis by Wnt Signaling
Ross, S. E., Hemati, N., Longo, K. A., Bennett, C. N., Lucas, P. C., Erickson, R. L., & MacDougald, O. A. (2000) · Science · doi:10.1126/science.289.5481.950 · Cited by 1,876 · see citing works
Disruption of IRS-2 causes type 2 diabetes in mice
Withers, D., Gutiérrez, J., Towery, H., Burks, D., Ren, J.-M., Previs, S., Zhang, Y., Bernal, D., Pons, S., Shulman, G., et al. (1998) · Nature · doi:10.1038/36116 · Cited by 1,850 · see citing works
Alternative pathway of insulin signalling in mice with targeted disruption of the IRS-1 gene
Araki, E., Lipes, M. A., Patti, M.-E., Brüning, J. C., Haag III, B., Johnson, R. S., & Kahn, C. R. (1994) · Nature · doi:10.1038/372186a0 · Cited by 1,252 · see citing works
Self-citationIRS proteins and the common path to diabetes
White, M. F. (2002) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00514.2001 · Cited by 925 · see citing works
Regulation of Wnt Signaling during Adipogenesis
Bennett, C. N., Ross, S. E., Longo, K. A., Bajnok, L., Hemati, N., Johnson, K. W., Harrison, S. D., & MacDougald, O. A. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m204527200 · Cited by 743 · see citing works
Prusty, D., Park, B.-H., Davis, K. E., & Farmer, S. R. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m207776200 · Cited by 528 · see citing works
Kb, S. (1965) · PubMed · Cited by 461 · see citing works
Adipocyte Differentiation: From Fibroblast to Endocrine Cell
Gregoire, F. M. (2001) · Experimental Biology and Medicine · doi:10.1177/153537020122601106 · Cited by 433 · see citing works
Specific Inhibitors of p38 Mitogen-activated Protein Kinase Block 3T3-L1 Adipogenesis
Engelman, J. A., Lisanti, M. P., & Scherer, P. E. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.48.32111 · Cited by 360 · see citing works
Adipogenesis: forces that tip the scales
MacDougald, O. A., & Mandrup, S. (2002) · Trends in Endocrinology and Metabolism · doi:10.1016/s1043-2760(01)00517-3 · Cited by 355 · see citing works
Structure of the IRS-1 PTB Domain Bound to the Juxtamembrane Region of the Insulin Receptor
Eck, M. J., Dhe‐Paganon, S., Trüb, T., Nolte, R. T., & Shoelson, S. E. (1996) · Cell · doi:10.1016/s0092-8674(00)81236-2 · Cited by 323 · see citing works
T RANSCRIPTIONAL C ONTROL OF A DIPOGENESIS
Rangwala, S. M., & Lazar, M. A. (2000) · Annual Review of Nutrition · doi:10.1146/annurev.nutr.20.1.535 · Cited by 319 · see citing works
Molecular regulation of adipocyte differentiation
Cowherd, R. M., Lyle, R., & McGehee, R. E. (1999) · Seminars in Cell and Developmental Biology · doi:10.1006/scdb.1998.0276 · Cited by 271 · see citing works
Klein, J. C., Faßhauer, M., Ito, M., Lowell, B. B., Benito, M., & Kahn, C. R. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.49.34795 · Cited by 239 · see citing works
Self-citationFantin, V. R., Wang, Q., Lienhard, G. E., & Keller, S. R. (2000) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.2000.278.1.e127 · Cited by 224 · see citing works
Adipogenesis and fat-cell function in obesity and diabetes
Camp, H. S., Ren, D., & Leff, T. (2002) · Trends in Molecular Medicine · doi:10.1016/s1471-4914(02)02396-1 · Cited by 214 · see citing works
Essential Role of Insulin Receptor Substrate 1 (IRS-1) and IRS-2 in Adipocyte Differentiation
Miki, H., Yamauchi, T., Suzuki, R., Komeda, K., Tsuchida, A., Kubota, N., Terauchi, Y., Kamon, J., Kaburagi, Y., Matsui, J., et al. (2001) · Molecular and Cellular Biology · doi:10.1128/mcb.21.7.2521-2532.2001 · Cited by 214 · see citing works
Rui, L., Fisher, T. L., Thomas, J., & White, M. F. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m105332200 · Cited by 210 · see citing works
Insulin Receptor Substrate 3 Is Not Essential for Growth or Glucose Homeostasis
Liu, S. C. H., Wang, Q., Lienhard, G. E., & Keller, S. R. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.25.18093 · Cited by 189 · see citing works
Fasshauer, M., Klein, J., Ueki, K., Kriauciunas, K. M., Benito, M., White, M. F., & Kahn, C. R. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m004046200 · Cited by 176 · see citing works
Self-citationEssential Role of Insulin Receptor Substrate 1 in Differentiation of Brown Adipocytes
Faßhauer, M., Klein, J. C., Kriauciunas, K. M., Ueki, K., Benito, M., & Kahn, C. R. (2001) · Molecular and Cellular Biology · doi:10.1128/mcb.21.1.319-329.2001 · Cited by 171 · see citing works
Self-citationde Mora, J. F., Porrás, A., Ahn, N. G., & Santos, E. (1997) · Molecular and Cellular Biology · doi:10.1128/mcb.17.10.6068 · Cited by 171 · see citing works
Magun, R., Burgering, B. M. T., Coffer, P. J., Pardasani, D., Lin, Y.-T., Chabot, J., & Sorisky, A. (1996) · Endocrinology · doi:10.1210/endo.137.8.8754791 · Cited by 167 · see citing works
The Expression and Regulation of STATs during 3T3-L1 Adipocyte Differentiation
Stephens, J. M., Morrison, R. F., & Pilch, P. F. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.18.10441 · Cited by 157 · see citing works
Sakaue, H., Ogawa, W., Matsumoto, M., Kuroda, S., Takata, M., Sugimoto, T., Spiegelman, B. M., & Kasuga, M. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.44.28945 · Cited by 148 · see citing works
Klein, J. C., Faßhauer, M., Klein, H. H., Benito, M., & Kahn, C. R. (2002) · BioEssays · doi:10.1002/bies.10058 · Cited by 136 · see citing works
Self-citationLipoatrophic diabetes in Irs1−/−/Irs3−/− double knockout micePreprint
Laustsen, P. G., Michael, M. D., Crute, B. E., Cohen, S. E., Ueki, K., Kulkarni, R. N., Keller, S. R., Lienhard, G. E., & Kahn, C. R. (2002) · Genes & Development · doi:10.1101/gad.1034802 · Cited by 131 · see citing works
Self-citationEngelman, J. A., Berg, A. H., Lewis, R. Y., Lin, A., Lisanti, M. P., & Scherer, P. E. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.50.35630 · Cited by 122 · see citing works
Insulin Receptor Substrate 3 (IRS-3) and IRS-4 Impair IRS-1- and IRS-2-Mediated Signaling
Tsuruzoe, K., Emkey, R., Kriauciunas, K. M., Ueki, K., & Kahn, C. R. (2001) · Molecular and Cellular Biology · doi:10.1128/mcb.21.1.26-38.2001 · Cited by 113 · see citing works
Self-citationHarmon, A. W., Patel, Y. M., & Harp, J. B. (2002) · Biochemical Journal · doi:10.1042/bj20020300 · Cited by 106 · see citing works
Tseng, Y.-H., Ueki, K., Kriauciunas, K. M., & Kahn, C. R. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m202932200 · Cited by 96 · see citing works
Self-citationFunctional differentiation of white and brown adipocytes
Klaus, S. (1997) · BioEssays · doi:10.1002/bies.950190307 · Cited by 82 · see citing works
Valverde, Á. M., Arribas, M., Mur, C., et al. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m209363200 · Cited by 75 · see citing works
Regulation of adipocyte differentiation
Koutníková, H., & Auwerx, J. H. (2001) · Annals of Medicine · doi:10.3109/07853890108995966 · Cited by 75 · see citing works
Cloning, Tissue Expression, and Chromosomal Location of the Mouse Insulin Receptor Substrate 4 Gene
Fantin, V. R., Lavan, B. E., Wang, Q., Jenkins, N. A., Gilbert, D. J., Copeland, N. G., Keller, S. R., & Lienhard, G. E. (1999) · Endocrinology · doi:10.1210/endo.140.3.6578 · Cited by 75 · see citing works
Harp, J. B., Franklin, D. M., Vanderpuije, A. A., & Gimble, J. M. (2001) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.2001.4460 · Cited by 69 · see citing works
Gagnon, A., Chen, C. S., & Sorisky, A. (1999) · Diabetes · doi:10.2337/diabetes.48.4.691 · Cited by 61 · see citing works
Moulin, K., Truel, N., André, M., ARNAULD, E., Nibbelink, M. M., Cousin, B., Dani, C., Pénicaud, L., & Casteilla, L. (2001) · Biochemical Journal · doi:10.1042/bj3560659 · Cited by 59 · see citing works
Adrenoceptors, Uncoupling Proteins, and Energy Expenditure
Collins, S., Cao, W., Daniel, K. W., Dixon, T. M., Medvedev, A. V., Onuma, H., & Surwit, R. S. (2001) · Experimental Biology and Medicine · doi:10.1177/153537020122601104 · Cited by 28 · see citing works
In Vitro Binding and Phosphorylation of Insulin Receptor Substrate 1 by the Insulin Receptor
Backer, J., Wjasow, C., & Zhang, Y. (1997) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1997.t01-1-00091.x · Cited by 27 · see citing works
Aubert, J., Belmonte, N., & Dani, C. (1999) · Cellular and Molecular Life Sciences · doi:10.1007/s000180050450 · Cited by 21 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- [36]Rangwala, S. M., and M. A. Lazar. 2000. Transcriptional control of adipogenesis. Annu. Rev. Nutr. 20:535-559. [DOI] [PubMed] [Google Scholar]
Cited by
Sorted by citations
Adipocyte differentiation from the inside out
Rosen, E. D., & MacDougald, O. A. (2006) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2066 · Cited by 2,607 · see citing works
PRDM16 controls a brown fat/skeletal muscle switch
Seale, P., Bjork, B., Yang, W., Kajimura, S., Chin, S., Kuang, S., Scimè, A., Devarakonda, S., Conroe, H. M., Erdjument-Bromage, H., et al. (2008) · Nature · doi:10.1038/nature07182 · Cited by 2,347 · see citing works
Developmental Origin of Fat: Tracking Obesity to Its Source
Gesta, S., Tseng, Y.-H., & Kahn, C. R. (2007) · Cell · doi:10.1016/j.cell.2007.10.004 · Cited by 1,508 · see citing works
Self-citationAdipogenesis and metabolic health
Ghaben, A. L., & Scherer, P. E. (2019) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-018-0093-z · Cited by 1,395 · see citing works
Transcriptional Control of Brown Fat Determination by PRDM16
Seale, P., Kajimura, S., Yang, W., Chin, S., Rohas, L. M., Uldry, M., Tavernier, G., Langin, D., & Spiegelman, B. M. (2007) · Cell Metabolism · doi:10.1016/j.cmet.2007.06.001 · Cited by 1,174 · see citing works
New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure
Tseng, Y.-H., Kokkotou, E., Schulz, T. J., Huang, T. L., Winnay, J. N., Taniguchi, C. M., Tran, T. T., Suzuki, R., Espinoza, D. O., Yamamoto, Y., et al. (2008) · Nature · doi:10.1038/nature07221 · Cited by 1,099 · see citing works
Self-citationCellular bioenergetics as a target for obesity therapy
Tseng, Y.-H., Cypess, A. M., & Kahn, C. R. (2010) · Nature Reviews Drug Discovery · doi:10.1038/nrd3138 · Cited by 591 · see citing works
Self-citationGenetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile
Kilpeläinen, T. O., Zillikens, M. C., Stančákova, A., Finucane, F. M., Ried, J. S., Langenberg, C., Zhang, W., Beckmann, J. S., Luan, J., Vandenput, L., et al. (2011) · Nature Genetics · doi:10.1038/ng.866 · Cited by 335 · see citing works
Tseng, Y.-H., Butte, A. J., Kokkotou, E., Yechoor, V. K., Taniguchi, C. M., Kriauciunas, K. M., Cypess, A. M., Niinobe, M., Yoshikawa, K., Patti, M. E., et al. (2005) · Nature Cell Biology · doi:10.1038/ncb1259 · Cited by 222 · see citing works
Self-citationRegulatory circuits controlling white versus brown adipocyte differentiation
Hansen, J. B., & Kristiansen, K. (2006) · Biochemical Journal · doi:10.1042/bj20060402 · Cited by 178 · see citing works
Brown adipose tissue: Development, metabolism and beyond
Schulz, T. J., & Tseng, Y.-H. (2013) · Biochemical Journal · doi:10.1042/bj20130457 · Cited by 173 · see citing works
Boucher, J., Mori, M. A., Lee, K. Y., Smyth, G., Liew, C. W., Macotela, Y., Rourk, M., Bluher, M., Russell, S. J., & Kahn, C. R. (2012) · Nature Communications · doi:10.1038/ncomms1905 · Cited by 142 · see citing works
Self-citation
- Authors
- Tseng, Y.-H., Kriauciunas, K. M., Kokkotou, E., & Kahn, C. R.
- Affiliations
- Joslin Diabetes Center (US)
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2004-03-01
- Volume
- 24
- Issue
- 5
- Pages
- 1918-1929
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC350563
- OpenAlex
- W2149340540
- Cited by
- 173
- References
- 46
- Citations by year
- 2026: 3 · 2025: 9 · 2024: 1 · 2023: 3 · 2022: 5 · 2021: 4 · 2020: 13 · 2019: 8 · 2018: 10 · 2017: 13 · 2016: 10 · 2015: 6 · 2014: 6 · 2013: 8 · 2012: 10
- FWCI
- 5.36
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK055545, DK 33201, F32DK101183, DK101183, R01DK033201, DK55545)
- Topics
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- insulin receptor substrate, brown adipocyte differentiation, adipogenesis, IRS-1, insulin receptor substrate 2, insulin receptor substrate 3, WNT10A, PPARγ, C/EBPα, UCP1, PPARγ coactivator-1α, insulin signaling
- MeSH terms
- Animals, Adipose Tissue, Brown, Cell Differentiation, Cells, Cultured, Humans, Insulin, Phosphoproteins, Phosphorylation, Receptor, Insulin, RNA, Messenger, Tyrosine, Biomarkers, Adipocytes, Mice, Knockout, Mitogen-Activated Protein Kinases, MAP Kinase Signaling System, Intracellular Signaling Peptides and Proteins, Adaptor Proteins, Signal Transducing, Mice, Insulin Receptor Substrate Proteins
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
