Genetic Link Between Obesity and MMP14-Dependent Adipogenic Collagen Turnover
Open accessAbstract
OBJECTIVE: In white adipose tissue, adipocytes and adipocyte precursor cells are enmeshed in a dense network of type I collagen fibrils. The fate of this pericellular collagenous web in diet-induced obesity, however, is unknown. This study seeks to identify the genetic underpinnings of proteolytic collagen turnover and their association with obesity progression in mice and humans. RESEARCH DESIGN AND METHODS: The hydrolysis and degradation of type I collagen at early stages of high-fat diet feeding was assessed in wild-type or MMP14 (MT1-MMP)-haploinsufficient mice using immunofluorescent staining and scanning electron microscopy. The impact of MMP14-dependent collagenolysis on adipose tissue function was interrogated by transcriptome profiling with cDNA microarrays. Genetic associations between MMP14 gene common variants and obesity or diabetes traits were examined in a Japanese cohort (n = 3,653). RESULTS: In adult mice, type I collagen fibers were cleaved rapidly in situ during a high-fat diet challenge. By contrast, in MMP14 haploinsufficient mice, animals placed on a high-fat diet were unable to remodel fat pad collagen architecture and display blunted weight gain. Moreover, transcriptional programs linking type I collagen turnover with adipogenesis or lipogenesis were disrupted by the associated decrease in collagen turnover. Consistent with a key role played by MMP14 in regulating high-fat diet–induced metabolic programs, human MMP14 gene polymorphisms located in proximity to the enzyme's catalytic domain were closely associated with human obesity and diabetes traits. CONCLUSIONS: Together, these findings demonstrate that the MMP14 gene, encoding the dominant pericellular collagenase operative in vivo, directs obesogenic collagen turnover and is linked to human obesity traits.
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?
Genes involved in collagen breakdown, particularly MMP14, are significantly upregulated in mice fed a high-fat diet for one week.
“Genes involved in collagen breakdown, particularly MMP14, are significantly upregulated in mice fed a HFD for one week (48).”
From The ominous triad of adipose tissue dysfunction: inflammation, fibrosis, and impaired angiogenesis. (2017) · cites this paper as [48]
Mice with heterozygous deletion of MMP-14 cannot appropriately remodel the ECM, resulting in reduced capacity for adipose expansion.
“Mice with heterozygous deletion of MMP-14 are not able to appropriately re-model the ECM, resulting in reduced capacity for adipose expansion (48).”
From The ominous triad of adipose tissue dysfunction: inflammation, fibrosis, and impaired angiogenesis. (2017) · cites this paper as [48]
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
Exploration, normalization, and summaries of high density oligonucleotide array probe level data
Irizarry, R. A. (2003) · Biostatistics · doi:10.1093/biostatistics/4.2.249 · Cited by 10,603 · see citing works
Hynes (2002) · doi:10.1016/s0092-8674(02)00971-6 · Cited by 8,606 · see citing works
Insulin signalling and the regulation of glucose and lipid metabolism
Saltiel, A. R., & Kahn, C. R. (2001) · Nature · doi:10.1038/414799a · Cited by 5,326 · see citing works
Frayling, T. M., Timpson, N. J., Weedon, M. N., Zeggini, E., Freathy, R. M., Lindgren, C. M., Perry, J. R. B., Elliott, K. S., Lango, H., Rayner, N. W., et al. (2007) · Science · doi:10.1126/science.1141634 · Cited by 4,531 · see citing works
Matrix metalloproteinases and the regulation of tissue remodelling
Page, A. W., Ewald, A. J., & Werb, Z. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2125 · Cited by 3,011 · see citing works
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
A matrix metalloproteinase expressed on the surface of invasive tumour cells
Sato, H., Takino, T., Okada, Y., Cao, J. P., Shinagawa, A., Yamamoto, E., & Seiki, M. (1994) · Nature · doi:10.1038/370061a0 · Cited by 2,534 · see citing works
Mechanotransduction at a distance: mechanically coupling the extracellular matrix with the nucleus
Wang, N., Tytell, J. D., & Ingber, D. E. (2008) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2594 · Cited by 1,768 · see citing works
COLLAGENS: Molecular Biology, Diseases, and Potentials for Therapy
Prockop, D. J., & Kivirikko, K. I. (1995) · Annual Review of Biochemistry · doi:10.1146/annurev.bi.64.070195.002155 · Cited by 1,625 · 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
Common variants near MC4R are associated with fat mass, weight and risk of obesity
The Prostate, L., Loos, R. J. F., KORA, Study, N. H., Initiative, D. G., Study, T. S., The Wellcome Trust Case Control Consortium, FUSION, Lindgren, C. M., Li, S., et al. (2008) · Nature Genetics · doi:10.1038/ng.140 · Cited by 1,325 · see citing works
Holmbeck, K., Bianco, P., Caterina, J., Yamada, S., Kromer, M., Kuznetsov, S. A., Mankani, M., Gehron Robey, P., Poole, A. R., Pidoux, I., et al. (1999) · Cell · doi:10.1016/s0092-8674(00)80064-1 · Cited by 1,298 · see citing works
White Fat Progenitor Cells Reside in the Adipose Vasculature
Tang, W., Zeve, D., Suh, J. M., Bosnakovski, D., Kyba, M., Hammer, R. E., Tallquist, M. D., & Graff, J. M. (2008) · Science · doi:10.1126/science.1156232 · Cited by 1,113 · see citing works
Human genetic variation and its contribution to complex traits
Frazer, K. A., Murray, S. S., Schork, N. J., & Topol, E. J. (2009) · Nature Reviews Genetics · doi:10.1038/nrg2554 · Cited by 1,073 · see citing works
Metabolic Dysregulation and Adipose Tissue Fibrosis: Role of Collagen VI
Khan, T., Muise, E. S., Iyengar, P., Wang, Z. V., Chandalia, M., Abate, N., Zhang, B. B., Bonaldo, P., Chua, S., & Scherer, P. E. (2009) · Molecular and Cellular Biology · doi:10.1128/mcb.01300-08 · Cited by 1,053 · see citing works
Identification of White Adipocyte Progenitor Cells In Vivo
Rodeheffer, M. S., Birsoy, K., & Friedman, J. M. (2008) · Cell · doi:10.1016/j.cell.2008.09.036 · Cited by 945 · see citing works
Acquired and Inherited Lipodystrophies
Garg, A. (2004) · New England Journal of Medicine · doi:10.1056/nejmra025261 · Cited by 939 · see citing works
Hypoxia-Inducible Factor 1α Induces Fibrosis and Insulin Resistance in White Adipose Tissue
Halberg, N., Khan, T., Trujillo, M. E., Wernstedt-Asterholm, I., Attie, A. D., Sherwani, S., Wang, Z. V., Landskroner-Eiger, S., Dineen, S., Magalang, U. J., et al. (2009) · Molecular and Cellular Biology · doi:10.1128/mcb.00192-09 · Cited by 896 · see citing works
Cellular Mechanisms for Human Procollagenase-3 (MMP-13) Activation
Knäuper, V., Will, H., López-Otı́n, C., Smith, B., Atkinson, S. J., Stanton, H., Hembry, R. M., & Murphy, G. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.29.17124 · Cited by 747 · see citing works
Sabeh, F., Shimizu‐Hirota, R., & Weiss, S. J. (2009) · The Journal of Cell Biology · doi:10.1083/jcb.200807195 · Cited by 658 · see citing works
Self-citationHotary, K. B., Allen, E. D., Punturieri, A., Yana, I., & Weiss, S. J. (2000) · The Journal of Cell Biology · doi:10.1083/jcb.149.6.1309 · Cited by 594 · see citing works
Self-citationDiet-induced adipocyte number increase in adult rats: a new model of obesity.
Faust, I. M., Johnson, P. R., Stern, J. S., & Hirsch, J. (1978) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1978.235.3.e279 · Cited by 514 · see citing works
Forecasting the effects of obesity and smoking on U.S. life expectancy
Stewart, S. T., Cutler, D. M., & Rosen, A. B. (2009) · New England Journal of Medicine · doi:10.1056/nejmsa0900459 · Cited by 478 · see citing works
THE DIFFERENTIATION OF WHITE ADIPOSE CELLS
Napolitano, L. (1963) · The Journal of Cell Biology · doi:10.1083/jcb.18.3.663 · Cited by 421 · see citing works
A Pericellular Collagenase Directs the 3-Dimensional Development of White Adipose Tissue
Chun, T.-H., Hotary, K. B., Sabeh, F., Saltiel, A. R., Allen, E. D., & Weiss, S. J. (2006) · Cell · doi:10.1016/j.cell.2006.02.050 · Cited by 378 · see citing works
Self-citationChun, T., Sabeh, F., Ota, I., Murphy, H. S., McDonagh, K. T., Holmbeck, K., Birkedal‐Hansen, H., Allen, E. D., & Weiss, S. J. (2004) · The Journal of Cell Biology · doi:10.1083/jcb.200405001 · Cited by 348 · see citing works
Self-citationChanges in Gene Expression Foreshadow Diet-Induced Obesity in Genetically Identical Mice
Koza, R. A., Nikonova, L. V., Hogan, J. C., Rim, J., Mendoza, T. M., Faulk, C. D., Skaf, J. S., & Kozak, L. P. (2006) · PLoS Genetics · doi:10.1371/journal.pgen.0020081 · Cited by 344 · see citing works
Sakurai‐Yageta, M., Recchi, C., Dez, G. L., Sibarita, J., Daviet, L., Camonis, J., D’Souza‐Schorey, C., & Chavrier, P. (2008) · The Journal of Cell Biology · doi:10.1083/jcb.200709076 · Cited by 307 · see citing works
Validation of candidate causal genes for obesity that affect shared metabolic pathways and networks
Yang, X., Deignan, J. L., Qi, H., Zhu, J., Qian, S., Zhong, J., Torosyan, G., Majid, S., Falkard, B., Kleinhanz, R. R., et al. (2009) · Nature Genetics · doi:10.1038/ng.325 · Cited by 288 · see citing works
Yana, I., Sagara, H., Τακακι, S., Takatsu, K., Nakamura, K., Nakao, K., Katsuki, M., Taniguchi, S.-I., Aoki, T., Sato, H., et al. (2007) · Journal of Cell Science · doi:10.1242/jcs.000679 · Cited by 185 · see citing works
Self-citationPatterns of Abdominal Fat Distribution
Pou, K. M., Massaro, J. M., Hoffmann, U., Lieb, K., Vasan, R. S., O’Donnell, C. J., & Fox, C. S. (2008) · Diabetes Care · doi:10.2337/dc08-1359 · Cited by 171 · see citing works
Secreted Versus Membrane-anchored Collagenases
Sabeh, F., Li, X.-Y., Saunders, T. L., Rowe, R. G., & Weiss, S. J. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.002808 · Cited by 150 · see citing works
Self-citationIncreased cellular proliferation in adipose tissue of adult rats fed a high-fat diet.
Klyde, B. J., & Hirsch, J. (1979) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)40024-0 · Cited by 144 · see citing works
Poole, A. R., Ionescu, M., Fitzcharles, M., & Billinghurst, R. C. (2004) · Journal of Immunological Methods · doi:10.1016/j.jim.2004.09.005 · Cited by 140 · see citing works
Recent progress in the genetics of common obesity
Loos, R. J. F. (2009) · British Journal of Clinical Pharmacology · doi:10.1111/j.1365-2125.2009.03523.x · Cited by 139 · see citing works
Filippov, S. I., Koenig, G. C., Chun, T., Hotary, K. B., Ota, I., Bugge, T. H., Roberts, J. D., Fay, W. P., Birkedal‐Hansen, H., Holmbeck, K., et al. (2005) · The Journal of Experimental Medicine · doi:10.1084/jem.20050607 · Cited by 130 · see citing works
Self-citationAn MT1-MMP-PDGF receptor-β axis regulates mural cell investment of the microvasculaturePreprint
Lehti, K., Allen, E. D., Birkedal‐Hansen, H., Holmbeck, K., Miyake, Y., Chun, T., & Weiss, S. J. (2005) · Genes & Development · doi:10.1101/gad.1294605 · Cited by 123 · see citing works
Self-citationChagnon, Y. C., Rice, T., Përusse, L., Borecki, I. B., Ho-Kim, M. A., Lacaille, M., Paré, C., Bouchard, L., Gagnon, J., Leon, A. S., et al. (2001) · Journal of Applied Physiology · doi:10.1152/jappl.2001.90.5.1777 · Cited by 113 · see citing works
MT1-MMP controls human mesenchymal stem cell trafficking and differentiation
Lu, C., Li, X.-Y., Hu, Y., Rowe, R. G., & Weiss, S. J. (2009) · Blood · doi:10.1182/blood-2009-06-228494 · Cited by 103 · see citing works
Self-citationMissing Heritability and GWAS Utility
Bogardus, C. (2009) · Obesity · doi:10.1038/oby.2008.613 · Cited by 93 · see citing works
Fine genetic mapping using haplotype analysis and the missing data problem
Chiano, M. N., & Clayton, D. G. (1998) · Annals of Human Genetics · doi:10.1046/j.1469-1809.1998.6210055.x · Cited by 93 · see citing works
Leptin Gene and Leptin Receptor Gene Polymorphisms Are Associated with Sweet Preference and Obesity
Mizuta, E., Kokubo, Y., Yamanaka, I., Miyamoto, Y., Okayama, A., Yoshimasa, Y., Tomoike, H., Morisaki, H., & Morisaki, T. (2008) · Hypertension Research · doi:10.1291/hypres.31.1069 · Cited by 88 · see citing works
Self-citationMannami, T., Baba, S., & Ogata, J. (2000) · Archives of Internal Medicine · doi:10.1001/archinte.160.15.2297 · Cited by 78 · see citing works
Kitamura, Y., Moriguchi, M., Kaneko, H., Morisaki, H., Morisaki, T., Toyama, K., & Kamatani, N. (2002) · PubMed · doi:10.1017/s0003480002001124 · Cited by 75 · see citing works
Self-citationItoh, Y., Ito, N., Nagase, H., & Seiki, M. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m709327200 · Cited by 73 · see citing works
KITAMURA, Y., Moriguchi, M., Kaneko, H., et al. (2002) · Annals of Human Genetics · doi:10.1046/j.1469-1809.2002.00112.x · Cited by 71 · see citing works
Yield of Opportunistic Targeted Screening for Type 2 Diabetes in Primary Care: The Diabscreen Study
Woolthuis, E. P. K., de Grauw, W. J. C., van Gerwen, W. H. E. M., et al. (2009) · The Annals of Family Medicine · doi:10.1370/afm.997 · Cited by 50 · see citing works
Traurig, M. T., Permana, P. A., Nair, S., Kobes, S., Bogardus, C., & Baier, L. J. (2006) · Diabetes · doi:10.2337/db06-0373 · Cited by 37 · see citing works
Simultaneous Estimation of Haplotype Frequencies and Quantitative Trait Parameters
Shibata, K., Ito, T., Kitamura, Y., et al. (2004) · Genetics · doi:10.1534/genetics.104.029751 · Cited by 16 · see citing works
Unoki‐Kubota, H., Bujo, H., Shibasaki, M., & Saitō, Y. (2006) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2006.09.054 · Cited by 12 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
The ominous triad of adipose tissue dysfunction: inflammation, fibrosis, and impaired angiogenesis.
Crewe, C., An, Y. A., & Scherer, P. E. (2017) · Journal of Clinical Investigation · doi:10.1172/jci88883 · Cited by 732 · see citing works
The cell biology of fat expansion
Rutkowski, J. M., Stern, J. H., & Scherer, P. E. (2015) · Journal of Cell Biology · doi:10.1083/jcb.201409063 · Cited by 541 · see citing works
Macrophages and the Regulation of Adipose Tissue Remodeling
Martinez-Santibañez, G., & Nien-Kai Lumeng, C. (2014) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-071812-161113 · Cited by 111 · see citing works
Dankel, S. N., Svärd, J., Matthä, S., Claussnitzer, M., Klöting, N., Glunk, V., Fandalyuk, Z., Grytten, E., Solsvik, M. H., Nielsen, H., et al. (2014) · Obesity · doi:10.1002/oby.20758 · Cited by 95 · see citing works
Thrombospondin 1 Mediates High-Fat Diet-Induced Muscle Fibrosis and Insulin Resistance in Male Mice
Inoue, M., Jiang, Y., Barnes, R. H., Tokunaga, M., Martinez-Santibañez, G., Geletka, L., Lumeng, C. N., Buchner, D. A., & Chun, T.-H. (2013) · Endocrinology · doi:10.1210/en.2013-1587 · Cited by 85 · see citing works
Self-citation
- Authors
- Chun, T.-H., Inoue, M., Morisaki, H., Yamanaka, I., Miyamoto, Y., Okamura, T., Sato-Kusubata, K., & Weiss, S. J.
- Affiliations
- University of Michigan (US)
- Department of Bioscience, National Cardiovascular Center Research Institute, Suita, Japan;
- Department of Atherosclerosis and Diabetes, National Cardiovascular Center, Suita, Japan;
- National Cerebral and Cardiovascular Center (JP)
- The University of Tokyo (JP)
- Corresponding author
- Chun, Tae-Hwa
- ORCID
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2010-07-26
- Volume
- 59
- Issue
- 10
- Pages
- 2484-2494
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- PMC
- PMC3279534
- OpenAlex
- W2101706129
- Cited by
- 97
- References
- 50
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 8 · 2023: 7 · 2022: 13 · 2021: 5 · 2020: 6 · 2019: 7 · 2018: 3 · 2017: 7 · 2016: 6 · 2015: 2 · 2014: 7 · 2013: 9 · 2012: 7
- FWCI
- 5.12
- 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)
- Funders
- University of Michigan (DK020572)
- Ministry of Education, Culture, Sports, Science and Technology
- University of Tokyo
- National Institutes of Health (DK020572)
- National Cancer Institute (R01CA088308, R01CA071699, CA088308, CA071699)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK020572, P60DK020572, R03DK091433, K08DK078801, P30DK020572)
- Topics
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Disease and Adiposity
- Keywords
- MMP-14, MT1-MMP, collagen degradation, diet-induced obesity, white adipose tissue, adipogenesis, lipogenesis, collagen remodeling, high-fat diet, genetic association, obesity
- MeSH terms
- Adipose Tissue, Animals, Collagen, Dietary Fats, Haplotypes, Humans, Obesity, Weight Gain, Linkage Disequilibrium, Gene Expression Regulation, Enzymologic, Oligonucleotide Array Sequence Analysis, Polymorphism, Single Nucleotide, Mice, Matrix Metalloproteinase 14
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
