Muscle-specific PPARγ-deficient mice develop increased adiposity and insulin resistance but respond to thiazolidinediones
Open accessAbstract
Activation of peroxisome proliferator-activated receptor gamma (PPARgamma) by thiazolidinediones (TZDs) improves insulin resistance by increasing insulin-stimulated glucose disposal in skeletal muscle. It remains debatable whether the effect of TZDs on muscle is direct or indirect via adipose tissue. We therefore generated mice with muscle-specific PPARgamma knockout (MuPPARgammaKO) using Cre/loxP recombination. Interestingly, MuPPARgammaKO mice developed excess adiposity despite reduced dietary intake. Although insulin-stimulated glucose uptake in muscle was not impaired, MuPPARgammaKO mice had whole-body insulin resistance with a 36% reduction (P < 0.05) in the glucose infusion rate required to maintain euglycemia during hyperinsulinemic clamp, primarily due to dramatic impairment in hepatic insulin action. When placed on a high-fat diet, MuPPARgammaKO mice developed hyperinsulinemia and impaired glucose homeostasis identical to controls. Simultaneous treatment with TZD ameliorated these high fat-induced defects in MuPPARgammaKO mice to a degree identical to controls. There was also altered expression of several lipid metabolism genes in the muscle of MuPPARgammaKO mice. Thus, muscle PPARgamma is not required for the antidiabetic effects of TZDs, but has a hitherto unsuspected role for maintenance of normal adiposity, whole-body insulin sensitivity, and hepatic insulin action. The tissue crosstalk mediating these effects is perhaps due to altered lipid metabolism in muscle.
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PPARγ deficient mice exhibit impaired M2 macrophage function and susceptibility to diet-induced inflammation and insulin resistance.
“Studies in PPARγ deficient mice exhibit impaired M2 macrophage function and susceptibility to diet-induced inflammation and insulin resistance [29,65–67].”
From Macrophage polarization: an opportunity for improved outcomes in biomaterials and regenerative medicine (2012) · cites this paper as [67]
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Cites
The adipocyte-secreted protein Acrp30 enhances hepatic insulin action
Berg, A. H., Combs, T. P., Du, X., Brownlee, M., & Scherer, P. E. (2001) · Nature Medicine · doi:10.1038/90992 · Cited by 2,526 · see citing works
Hayashi, T., Hirshman, M. F., Kurth, E. J., Winder, W. W., & Goodyear, L. J. (1998) · Diabetes · doi:10.2337/diabetes.47.8.1369 · Cited by 774 · see citing works
Self-citationMatsusue, K., Haluzı́k, M., Lambert, G. C., Yim, S.-H., Gavrilova, O., Ward, J. M., Brewer, B., Reitman, M. L., & Gonzalez, F. J. (2003) · Journal of Clinical Investigation · doi:10.1172/jci200317223 · Cited by 636 · see citing works
Self-citationMetzger, D., Clifford, J., Chiba, H., & Chambon, P. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.15.6991 · Cited by 570 · cited 1× · see citing works
“To study the functional role of PPARγ in skeletal muscle, we conditionally disrupted the PPARγ gene in skeletal muscle using Cre/loxP–mediated DNA recombination (30) by crossing PPARγ-loxP mice with MCK-Cre mice.”
MethodWang, J., Wilhelmsson, H., Graff, C., Li, H., Oldfors, A., Rustin, P., Brüning, J. C., Kahn, C. R., Clayton, D. A., Barsh, G. S., et al. (1999) · Nature Genetics · doi:10.1038/5089 · Cited by 435 · see citing works
Self-citationKim, J. K., Michael, M. D., Previs, S. F., Peroni, O. D., Mauvais-Jarvis, F., Neschen, S., Kahn, B. B., Kahn, C. R., & Shulman, G. I. (2000) · Journal of Clinical Investigation · doi:10.1172/jci8305 · Cited by 331 · see citing works
Self-citationGlucose toxicity and the development of diabetes in mice with muscle-specific inactivation of GLUT4
Kim, J. K., Zisman, A., Fillmore, J. J., Peroni, O. D., Kotani, K., Perret, P., Zong, H., Dong, J., Kahn, C. R., Kahn, B. B., et al. (2001) · Journal of Clinical Investigation · doi:10.1172/jci10294 · Cited by 202 · cited 2× · see citing works
“The glucose homeostasis defect in M-G4KO mice is more severe, and they develop secondary insulin resistance in liver and adipose tissue mediated by glucose toxicity (45).”
BackgroundMethodSelf-citationBlaak, E. E., van Aggel-Leijssen, D. P., Wagenmakers, A. J., Saris, W. H., & van Baak, M. A. (2000) · Diabetes · doi:10.2337/diabetes.49.12.2102 · Cited by 178 · see citing works
Blaak, E. E., Wagenmakers, A. J. M., Glatz, J. F. C., Wolffenbuttel, B. H. R., Kemerink, G. J., Langenberg, C. J. M., Heidendal, G. A. K., & Saris, W. H. M. (2000) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.2000.279.1.e146 · Cited by 140 · see citing works
Glucose toxicity and the development of diabetes in mice with muscle-specific inactivation of GLUT4
Kim, J. K., Zisman, A., Fillmore, J. J., et al. (2001) · Journal of Clinical Investigation · doi:10.1172/jci200110294 · Cited by 22 · see citing works
Flagged first, then by citations
Research works printed but not linked: 2
- Wahl, G.M., Stern, M., and Stark, G.R. 1979. Efficient transfer of large DNA fragments from agarose gels to diazobenzyloxymethyl-paper and rapid hybridization by using dextran sulfate. Proc. Natl. Acad. Sci. U. S. A. 76:3683-3687.
- Leone, T.C., Weinheimer, C.J., and Kelly, D.P. 1999. A critical role for the peroxisome proliferator-activated receptor alpha (PPARalpha) in the cellular fasting response: the PPARalpha-null mouse as a model of fatty acid oxidation disorders. Proc. Natl. Acad. Sci. U. S. A. 96:7473-7478.
Cited by
Sorted by citations
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
Self-citationPPARγ signaling and metabolism: the good, the bad and the future
Ahmadian, M., Suh, J. M., Hah, N., Liddle, C., Atkins, A. R., Downes, M., & Evans, R. M. (2013) · Nature Medicine · doi:10.1038/nm.3159 · Cited by 2,016 · see citing works
den Besten, G., Bleeker, A., Gerding, A., van Eunen, K., Havinga, R., van Dijk, T. H., Oosterveer, M. H., Jonker, J. W., Groen, A. K., Reijngoud, D.-J., et al. (2015) · Diabetes · doi:10.2337/db14-1213 · Cited by 1,125 · see citing works
The Human Obesity Gene Map: The 2005 Update
Rankinen, T., Zuberi, A., Chagnon, Y. C., Weisnagel, S. J., Argyropoulos, G., Walts, B., Pérusse, L., & Bouchard, C. (2006) · Obesity · doi:10.1038/oby.2006.71 · Cited by 1,119 · see citing works
Brown, B. N., Ratner, B. D., Goodman, S. B., Amar, S., & Badylak, S. F. (2012) · Biomaterials · doi:10.1016/j.biomaterials.2012.02.034 · Cited by 926 · see citing works
Feige, J. N., Gelman, L., Michalik, L., Desvergne, B., & Wahli, W. (2006) · Progress in Lipid Research · doi:10.1016/j.plipres.2005.12.002 · Cited by 786 · see citing works
Mauer, J., Chaurasia, B., Goldau, J., Vogt, M. C., Ruud, J., Nguyen, K. D., Theurich, S., Hausen, A. C., Schmitz, J., Brönneke, H. S., et al. (2014) · Nature Immunology · doi:10.1038/ni.2865 · Cited by 727 · see citing works
Perry, C. G. R., Lally, J., Holloway, G. P., Heigenhauser, G. J. F., Bonen, A., & Spriet, L. L. (2010) · The Journal of Physiology · doi:10.1113/jphysiol.2010.199448 · Cited by 559 · see citing works
Hevener, A. L., Olefsky, J. M., Reichart, D., Nguyen, M. T. A., Bandyopadyhay, G., Leung, H.-Y., Watt, M. J., Benner, C., Febbraio, M. A., Nguyen, A.-K., et al. (2007) · Journal of Clinical Investigation · doi:10.1172/jci31561 · Cited by 459 · see citing works
Self-citationPPAR- and LXR-dependent pathways controlling lipid metabolism and the development of atherosclerosis
Li, A. C., & Glass, C. K. (2004) · Journal of Lipid Research · doi:10.1194/jlr.r400010-jlr200 · Cited by 357 · see citing works
Obesity-related derangements in metabolic regulation
Muoio, D. M., & Newgard, C. B. (2006) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.75.103004.142512 · Cited by 345 · see citing works
Muscle as a “Mediator” of Systemic Metabolism
Baskin, K. K., Winders, B. R., & Olson, E. N. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2014.12.021 · Cited by 333 · see citing works
Thiazolidinediones are acute, specific inhibitors of the mitochondrial pyruvate carrier
Divakaruni, A. S., Wiley, S. E., Rogers, G. W., Andreyev, A. Y., Petrosyan, S., Loviscach, M., Wall, E. A., Yadava, N., Heuck, A. P., Ferrick, D. A., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1303360110 · Cited by 308 · see citing works
PPARγ activation in adipocytes is sufficient for systemic insulin sensitization
Sugii, S., Olson, P., Sears, D. D., Saberi, M., Atkins, A. R., Barish, G. D., Hong, S.-H., Castro, G. L., Yin, Y.-Q., Nelson, M. C., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0912487106 · Cited by 255 · see citing works
MICU1 regulation of mitochondrial Ca2+ uptake dictates survival and tissue regeneration
Antony, A. N., Paillard, M., Moffat, C., Juskeviciute, E., Correnti, J., Bolon, B., Rubin, E., Csordás, G., Seifert, E. L., Hoek, J. B., et al. (2016) · Nature Communications · doi:10.1038/ncomms10955 · Cited by 206 · see citing works
Koh, H.-J., Arnolds, D. E., Fujii, N., Tran, T. T., Rogers, M. J., Jessen, N., Li, Y., Liew, C. W., Ho, R. C., Hirshman, M. F., et al. (2006) · Molecular and Cellular Biology · doi:10.1128/mcb.00979-06 · Cited by 202 · see citing works
Self-citationThiazolidinediones improve β-cell function in type 2 diabetic patients
Gastaldelli, A., Ferrannini, E., Miyazaki, Y., Matsuda, M., Mari, A., & DeFronzo, R. A. (2007) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00551.2006 · Cited by 200 · see citing works
Musclin, a novel skeletal muscle-derived secretory factor
Nishizawa, H., Matsuda, M., Yamada, Y., Kawai, K., Suzuki, E., Makishima, M., Kitamura, T., & Shimomura, I. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.c400066200 · Cited by 182 · see citing works
Obesity, Peroxisome Proliferator-Activated Receptor, and Atherosclerosis in Type 2 Diabetes
Blaschke, F., Takata, Y., Caglayan, E., Law, R. E., & Hsueh, W. A. (2006) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.0000191663.12164.77 · Cited by 176 · see citing works
Huh, M. S., Parker, M. H., Scimè, A., Parks, R., & Rudnicki, M. A. (2004) · The Journal of Cell Biology · doi:10.1083/jcb.200403004 · Cited by 156 · 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-citationMitochondrial dynamics in cancer-induced cachexia
van der Ende, M., Grefte, S., Plas, R., Meijerink, J., Witkamp, R. F., Keijer, J., & van Norren, K. (2018) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2018.07.008 · Cited by 87 · see citing works
Phua, W. W. T., Wong, M. X. Y., Liao, Z., & Tan, N. S. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19051425 · Cited by 72 · see citing works
Endothelium as a gatekeeper of fatty acid transport
Mehrotra, D., Wu, J., Papangeli, I., & Chun, H. J. (2014) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2013.11.001 · Cited by 60 · see citing works
Hepatic Glucose Intolerance Precedes Hepatic Steatosis in the Male Aromatase Knockout (ArKO) Mouse
Van Sinderen, M. L., Steinberg, G. R., Jørgensen, S. B., To, S. Q., Knower, K. C., Clyne, C. D., Honeyman, J., Chow, J. D., Herridge, K. A., Jones, M. E. E., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0087230 · Cited by 26 · see citing works
- Authors
- Norris, A. W., Chen, L., Fisher, S. J., Szanto, I., Ristow, M., Jozsi, A. C., Hirshman, M. F., Rosen, E. D., Goodyear, L. J., Gonzalez, F. J., Spiegelman, B. M., & Kahn, C. R.
- Affiliations
- Joslin Diabetes Center (US)
- Beth Israel Deaconess Medical Center (US)
- Harvard University (US)
- Corresponding author
- Kahn, C. Ronald
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2003-08-15
- Volume
- 112
- Issue
- 4
- Pages
- 608-618
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC171387
- OpenAlex
- W2124246813
- Cited by
- 417
- References
- 10
- Citations by year
- 2026: 1 · 2025: 8 · 2024: 5 · 2023: 9 · 2022: 9 · 2021: 12 · 2020: 9 · 2019: 15 · 2018: 21 · 2017: 15 · 2016: 19 · 2015: 24 · 2014: 17 · 2013: 17 · 2012: 18
- FWCI
- 12.90
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Joslin Diabetes Center
- National Institutes of Health (DK31036, DK 36836)
- National Institute of Diabetes and Digestive and Kidney Diseases (R37DK031036, R01DK031036, DK45935, DK31036, T32DK063702, T32-DK63702-01, R01DK045935, P30DK036836)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- PPARγ, thiazolidinediones, muscle-specific knockout, adiposity, insulin resistance, hepatic insulin action, glucose homeostasis, high-fat diet, lipid metabolism genes, skeletal muscle, tissue crosstalk, hyperinsulinemia
- MeSH terms
- Adipose Tissue, Alleles, Animals, Deoxyglucose, Fatty Acids, Genotype, Glucose, Glucose Tolerance Test, Insulin, Insulin Resistance, Male, Mice, Inbred C57BL, Mice, Inbred DBA, Mice, Transgenic, Models, Genetic, Muscles, Recombination, Genetic, Thiazoles, Time Factors, Transcription Factors, Triglycerides, Receptors, Cytoplasmic and Nuclear, Mice, Knockout, Muscle, Skeletal, Oligonucleotide Array Sequence Analysis, Thiazolidinediones, Lipid Metabolism, Mice
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