Glycerol-3-Phosphate Acyltransferase 1 Deficiency in ob/ob Mice Diminishes Hepatic Steatosis but Does Not Protect Against Insulin Resistance or Obesity
Open accessAbstract
OBJECTIVE: Hepatic steatosis is strongly associated with insulin resistance, but a causal role has not been established. In ob/ob mice, sterol regulatory element binding protein 1 (SREBP1) mediates the induction of steatosis by upregulating target genes, including glycerol-3-phosphate acyltransferase-1 (Gpat1), which catalyzes the first and committed step in the pathway of glycerolipid synthesis. We asked whether ob/ob mice lacking Gpat1 would have reduced hepatic steatosis and improved insulin sensitivity. RESEARCH DESIGN AND METHODS: Hepatic lipids, insulin sensitivity, and hepatic insulin signaling were compared in lean (Lep+/?), lean-Gpat1−/−, ob/ob (Lepob/ob), and ob/ob-Gpat1−/− mice. RESULTS: Compared with ob/ob mice, the lack of Gpat1 in ob/ob mice reduced hepatic triacylglycerol (TAG) and diacylglycerol (DAG) content 59 and 74%, respectively, but increased acyl-CoA levels. Despite the reduction in hepatic lipids, fasting glucose and insulin concentrations did not improve, and insulin tolerance remained impaired. In both ob/ob and ob/ob-Gpat1−/− mice, insulin resistance was accompanied by elevated hepatic protein kinase C-ε activation and blunted insulin-stimulated Akt activation. CONCLUSIONS: These results suggest that decreasing hepatic steatosis alone does not improve insulin resistance, and that factors other than increased hepatic DAG and TAG contribute to hepatic insulin resistance in this genetically obese model. They also show that the SREBP1-mediated induction of hepatic steatosis in ob/ob mice requires Gpat1.
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Some mouse models of obesity and non-insulin-dependent diabetes have also shown a dissociation between fatty liver and glucose tolerance.
“A similar dissociation was already reported in some murine models of obesity and non-insulin dependent diabetes mellitus [44,45].”
From Vasopressin and hydration play a major role in the development of glucose intolerance and hepatic steatosis in obese rats (2015) · cites this paper as [44]
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Cites
Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT Method
Livak, K. J., & Schmittgen, T. D. (2001) · Methods · doi:10.1006/meth.2001.1262 · Cited by 180,860 · see citing works
A SIMPLE METHOD FOR THE ISOLATION AND PURIFICATION OF TOTAL LIPIDES FROM ANIMAL TISSUES
Folch, J., Lees, M., & Stanley, G. H. S. (1957) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)64849-5 · Cited by 65,189 · see citing works
Positional cloning of the mouse obese gene and its human homologue
Zhang, Y., Proenca, R., Maffei, M., Barone, M., Leopold, L., & Friedman, J. M. (1994) · Nature · doi:10.1038/372425a0 · Cited by 13,419 · see citing works
Mutation of the mouse klotho gene leads to a syndrome resembling ageing
Kuro-o, M., Matsumura, Y., Aizawa, H., Kawaguchi, H., Suga, T., Utsugi, T., Ohyama, Y., Kurabayashi, M., Kaname, T., Kume, E., et al. (1997) · Nature · doi:10.1038/36285 · Cited by 3,837 · see citing works
Obesity and insulin resistance
Kahn, B. B., & Flier, J. S. (2000) · Journal of Clinical Investigation · doi:10.1172/jci10842 · Cited by 3,283 · see citing works
Cellular mechanisms of insulin resistance
Shulman, G. I. (2000) · Journal of Clinical Investigation · doi:10.1172/jci10583 · Cited by 2,714 · see citing works
Self-citationYu, C., Chen, Y., Cline, G. W., Zhang, D., Zong, H., Wang, Y., Bergeron, R., Kim, J. K., Cushman, S. W., Cooney, G. J., et al. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m200958200 · Cited by 1,561 · see citing works
Self-citationMechanism of hepatic insulin resistance in non-alcoholic fatty liver disease
Samuel, V. T., Liu, Z.-X., Qu, X., Elder, B. D., Bilz, S., Befroy, D., Romanelli, A. J., & Shulman, G. I. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m313478200 · Cited by 1,322 · see citing works
Self-citationGriffin, M. E., Marcucci, M. J., Cline, G. W., Bell, K., Barucci, N., Lee, D., Goodyear, L. J., Kraegen, E. W., White, M. F., & Shulman, G. I. (1999) · Diabetes · doi:10.2337/diabetes.48.6.1270 · Cited by 1,267 · see citing works
Self-citationHolland, W. L., Brozinick, J. T., Wang, L.-P., Hawkins, E. D., Sargent, K. M., Liu, Y., Narra, K., Hoehn, K. L., Knotts, T. A., Siesky, A., et al. (2007) · Cell Metabolism · doi:10.1016/j.cmet.2007.01.002 · Cited by 1,232 · see citing works
The glycemic index: methodology and clinical implications
Wolever, T., Jenkins, D., Jenkins, A., & Josse, R. (1991) · The American Journal of Clinical Nutrition · doi:10.1093/ajcn/54.5.846 · Cited by 1,168 · see citing works
Disordered lipid metabolism and the pathogenesis of insulin resistance.
Savage, D. B., Petersen, K. F., & Shulman, G. I. (2007) · Physiological Reviews · doi:10.1152/physrev.00024.2006 · Cited by 1,107 · see citing works
Self-citationLoss of stearoyl–CoA desaturase-1 function protects mice against adiposity
Ntambi, J. M., Miyazaki, M., Stoehr, J. P., Hong, L., Kendziorski, C. M., Yandell, B. S., Song, Y., Cohen, P., Friedman, J. M., & Attie, A. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.132384699 · Cited by 1,096 · see citing works
Enzymes of triacylglycerol synthesis and their regulation
Coleman, R. (2003) · Progress in Lipid Research · doi:10.1016/s0163-7827(03)00051-1 · Cited by 961 · see citing works
Self-citationPetersen, K. F., Dufour, S., Befroy, D., Lehrke, M., Hendler, R. E., & Shulman, G. I. (2005) · Diabetes · doi:10.2337/diabetes.54.3.603 · Cited by 911 · see citing works
Self-citationTissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance
Kim, J. K., Fillmore, J. J., Chen, Y., Yu, C., Moore, I. K., Pypaert, M., Lutz, E. P., Kako, Y., Velez-Carrasco, W., Goldberg, I. J., et al. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.121164498 · Cited by 753 · see citing works
Self-citationShimomura, I., Bashmakov, Y. K., & Horton, J. D. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.42.30028 · Cited by 704 · see citing works
Crucial role of a long-chain fatty acid elongase, Elovl6, in obesity-induced insulin resistance
Matsuzaka, T., Shimano, H., Yahagi, N., Kato, T., Atsumi, A., Yamamoto, T., Inoue, N., Ishikawa, M., Okada, S., Ishigaki, N., et al. (2007) · Nature Medicine · doi:10.1038/nm1662 · Cited by 542 · see citing works
Dissociation of Hepatic Steatosis and Insulin Resistance in Mice Overexpressing DGAT in the Liver
Monetti, M., Levin, M. C., Watt, M. J., Sajan, M. P., Marmor, S., Hubbard, B. K., Stevens, R. D., Bain, J. R., Newgard, C. B., Farese, R. V., et al. (2007) · Cell Metabolism · doi:10.1016/j.cmet.2007.05.005 · Cited by 511 · see citing works
Samuel, V. T., Liu, Z.-X., Wang, A., Beddow, S. A., Geisler, J. G., Kahn, M., Zhang, X.-M., Monia, B. P., Bhanot, S., & Shulman, G. I. (2007) · Journal of Clinical Investigation · doi:10.1172/jci30400 · Cited by 497 · see citing works
Self-citationSavage, D. B. (2006) · Journal of Clinical Investigation · doi:10.1172/jci27300 · Cited by 447 · see citing works
Metabolic Significance of Nonalcoholic Fatty Liver Disease in Nonobese, Nondiabetic Adults
Kim, H. J., Kim, H. J., Lee, K. E., Kim, D. J., Kim, S. K., Ahn, C. W., Lim, S., Kim, K. R., Lee, H. C., Huh, K. B., et al. (2004) · Archives of Internal Medicine · doi:10.1001/archinte.164.19.2169 · Cited by 434 · see citing works
Liver-Specific Inhibition of ChREBP Improves Hepatic Steatosis and Insulin Resistance in ob/ob Mice
Dentin, R., Benhamed, F., Hainault, I., Fauveau, V., Foufelle, F., Dyck, J. R. B., Girard, J. R., & Postic, C. (2006) · Diabetes · doi:10.2337/db06-0200 · Cited by 429 · see citing works
Choi, C. S., Savage, D. B., Kulkarni, A., Yu, X. X., Liu, Z.-X., Morino, K., Kim, S., Distefano, A., Samuel, V. T., Neschen, S., et al. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m704213200 · Cited by 383 · see citing works
Self-citationYahagi, N., Shimano, H., Hasty, A. H., Matsuzaka, T., Ide, T., Yoshikawa, T., Amemiya-Kudo, M., Tomita, S., Okazaki, H., Tamura, Y., et al. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m201584200 · Cited by 370 · see citing works
The Physiology of Obese-Hyperglycemic Mice [ob/obMice]
Lindström, P. (2007) · The Scientific World JOURNAL · doi:10.1100/tsw.2007.117 · Cited by 353 · see citing works
Livingstone, D. E. W., Jones, G. C., Smith, K., Jamieson, P. M., Andrew, R., Kenyon, C. J., & Walker, B. R. (2000) · Endocrinology · doi:10.1210/endo.141.2.7297 · Cited by 348 · see citing works
Yu, X. X., Murray, S. F., Pandey, S., Booten, S. L., Bao, D., Song, X., Kelly, S., Chen, S., McKay, R. A., Monia, B. P., et al. (2005) · Hepatology · doi:10.1002/hep.20783 · Cited by 303 · see citing works
Glycerol-3-phosphate acyltransferases: Rate limiting enzymes of triacylglycerol biosynthesis
Wendel, A. A., Lewin, T. M., & Coleman, R. (2008) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2008.10.010 · Cited by 292 · see citing works
Self-citationHepatic triacylglycerol accumulation and insulin resistance
Nagle, C. A., Klett, E. L., & Coleman, R. A. (2009) · Journal of Lipid Research · doi:10.1194/jlr.r800053-jlr200 · Cited by 272 · see citing works
Self-citationNeschen, S., Morino, K., Hammond, L. E., Zhang, D., Liu, Z.-X., Romanelli, A. J., Cline, G. W., Pongratz, R. L., Zhang, X.-M., Choi, C. S., et al. (2005) · Cell Metabolism · doi:10.1016/j.cmet.2005.06.006 · Cited by 261 · see citing works
Self-citationKim, J. K., Gimeno, R. E., Higashimori, T., Kim, H., Choi, H., Punreddy, S., Mozell, R. L., Tan, G., Stricker‐Krongrad, A., Hirsch, D. J., et al. (2004) · Journal of Clinical Investigation · doi:10.1172/jci18917 · Cited by 244 · see citing works
Self-citationKim, J. K., Gimeno, R. E., Higashimori, T., Kim, H., Choi, H., Punreddy, S., Mozell, R. L., Tan, G., Stricker‐Krongrad, A., Hirsch, D. J., et al. (2004) · Journal of Clinical Investigation · doi:10.1172/jci200418917 · Cited by 212 · see citing works
Self-citationHereditary Diabetes in Genetically Obese Mice
Mayer, J., Bates, M. W., & Dickie, M. M. (1951) · Science · doi:10.1126/science.113.2948.746 · Cited by 209 · see citing works
Hammond, L. E., Gallagher, P. A., Wang, S., Hiller, S., Kluckman, K. D., Posey-Marcos, E. L., Maeda, N., & Coleman, R. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.23.8204-8214.2002 · Cited by 198 · see citing works
Self-citationSummers, S. A., & Nelson, D. H. (2005) · Diabetes · doi:10.2337/diabetes.54.3.591 · Cited by 185 · see citing works
Seppala-Lindroos, A. (2002) · Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.87.7.3023 · Cited by 168 · see citing works
Nagle, C. A., An, J., Shiota, M., Torres, T. P., Cline, G. W., Liu, Z., Wang, S., Catlin, R. L., Shulman, G. I., Newgard, C. B., et al. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m611550200 · Cited by 132 · see citing works
Self-citationQu, X.-Q., Seale, J., & Donnelly, R. (1999) · Journal of Endocrinology · doi:10.1677/joe.0.1620207 · Cited by 123 · see citing works
González-Baró, M. R., Lewin, T. M., & Coleman, R. (2006) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00553.2006 · Cited by 121 · see citing works
Self-citationLindén, D., William‐Olsson, L., Rhedin, M., Asztély, A.-K., Clapham, J. C., & Schreyer, S. A. (2004) · Journal of Lipid Research · doi:10.1194/jlr.m400010-jlr200 · Cited by 107 · see citing works
Hammond, L. E., Neschen, S., Romanelli, A. J., Cline, G. W., Ilkayeva, O., Shulman, G. I., Muoio, D. M., & Coleman, R. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m503181200 · Cited by 103 · see citing works
Self-citationShin, D. H., Paulauskis, J. D., Moustaïd, N., & Sul, H. S. (1991) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)54359-3 · Cited by 97 · see citing works
Morgan, K., Uyuni, A., Nandgiri, G., Mao, L., Castaneda, L., Kathirvel, E., French, S. W., & Morgan, T. R. M. (2008) · European Journal of Gastroenterology & Hepatology · doi:10.1097/meg.0b013e3282f9b203 · Cited by 87 · see citing works
Donnelly, R., Reed, M. J., Azhar, S., & Reaven, G. M. (1994) · Endocrinology · doi:10.1210/endo.135.6.7988419 · Cited by 82 · see citing works
A Simple Enzymatic Quantitative Analysis of Triglycerides in Tissues.
DANNO, H., JINCHO, Y., Budijanto, S., Furukawa, Y., & Kimura, S. (1992) · Journal of Nutritional Science and Vitaminology · doi:10.3177/jnsv.38.517 · Cited by 70 · see citing works
Grefhorst, A., Hoekstra, J., Derks, T. G. J., Ouwens, D. M., Baller, J. F. W., Havinga, R., Havekes, L. M., Romijn, J. A., & Kuipers, F. (2005) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00063.2005 · Cited by 67 · see citing works
Hepatic knockdown of mitochondrial GPAT1 in ob/ob mice improves metabolic profile
Xu, H., Wilcox, D. M., Nguyen, P., Voorbach, M. J., Suhar, T., Morgan, S. J., An, W., Ge, L., Green, J., Wu, Z., et al. (2006) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2006.08.071 · Cited by 64 · see citing works
Zinker, B. A., Mika, A. K., Nguyen, P., Wilcox, D. M., Öhman, L., von Geldern, T. W., Opgenorth, T. J., & Jacobson, P. B. (2007) · Metabolism · doi:10.1016/j.metabol.2006.10.021 · Cited by 48 · see citing works
Livingstone, D. E. W., Grassick, S. L., Currie, G. L., Walker, B. R., & Andrew, R. (2009) · Journal of Endocrinology · doi:10.1677/joe-09-0003 · Cited by 30 · see citing works
Yazdi, M., Ahnmark, A., William‐Olsson, L., Snaith, M. R., Turner, N. A., Osla, F., Wedin, M., Asztély, A.-K., Elmgren, A., Bohlooly‐Y, M., et al. (2008) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2008.02.156 · Cited by 23 · see citing works
Shin, O., da Costa, K.-A., Mar, M.-H. H., et al. (1997) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/s0167-4889(97)00064-5 · Cited by 11 · see citing works
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AMPK regulation of fatty acid metabolism and mitochondrial biogenesis: implications for obesity.
O’Neill, H. M., Holloway, G. P., & Steinberg, G. R. (2013) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2012.06.019 · Cited by 364 · see citing works
Knebel, B., Haas, J., Hartwig, S., Jacob, S., Köllmer, C., Nitzgen, U., Muller–Wieland, D., & Kotzka, J. (2012) · PLoS ONE · doi:10.1371/journal.pone.0031812 · Cited by 162 · see citing works
“Depletion of GPAT has been shown to improve hepatic steatosis and associated insulin resistance [46].”
BackgroundConti, R., Mannucci, E., Pessotto, P., Tassoni, E., Carminati, P., Giannessi, F., & Arduini, A. (2011) · Diabetes · doi:10.2337/db10-0346 · Cited by 98 · see citing works
Monsénégo, J., Mansouri, A., Akkaoui, M., Lenoir, V., Esnous, C., Fauveau, V., Tavernier, V., Girard, J., & Prip-Buus, C. (2012) · Journal of Hepatology · doi:10.1016/j.jhep.2011.10.008 · Cited by 91 · see citing works
Taveau, C., Chollet, C., Waeckel, L., Desposito, D., Bichet, D. G., Arthus, M.-F., Magnan, C., Philippe, E., Paradis, V., Foufelle, F., et al. (2015) · Diabetologia · doi:10.1007/s00125-015-3496-9 · Cited by 86 · see citing works
- Authors
- Wendel, A. A., Li, L. O., Li, Y., Cline, G. W., Shulman, G. I., & Coleman, R. A.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Yale University (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Coleman, Rosalind A.
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2010-03-03
- Volume
- 59
- Issue
- 6
- Pages
- 1321-1329
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- PMC
- PMC2874692
- OpenAlex
- W2140282855
- Cited by
- 63
- References
- 52
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 2 · 2023: 4 · 2022: 2 · 2021: 3 · 2020: 4 · 2019: 5 · 2018: 3 · 2017: 1 · 2016: 3 · 2015: 5 · 2014: 7 · 2013: 3 · 2012: 7
- FWCI
- 4.67
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Diabetes (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- American Heart Association
- National Institutes of Health (P30 DK, DK-34987)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30 DK56350, DK40936, U24DK59635, DK-056598, R01DK040936, U24DK059635, R56DK056598, R01DK056598, DK-007129, P30‐DK34987, T32DK007129, P30DK034987, P30DK056350)
- National Institute of Environmental Health Sciences (P30ES010126)
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Keywords
- GPAT1, hepatic steatosis, insulin resistance, ob/ob mice, SREBP1, glycerolipid biosynthesis, triglycerides, diacylglycerol, acyl-CoA, protein kinase C epsilon, Akt signaling, hepatic insulin signaling, obesity
- MeSH terms
- Animals, Crosses, Genetic, Fatty Liver, Glycerol-3-Phosphate O-Acyltransferase, Heterozygote, Humans, Insulin Resistance, Lipids, Mice, Obese, Obesity, RNA, Messenger, Triglycerides, Up-Regulation, Muscle, Skeletal, Reverse Transcriptase Polymerase Chain Reaction, Leptin, Mice, Sterol Regulatory Element Binding Protein 1
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