Genetic link between obesity and MMP14-dependent adipogenic collagen turnover

Tae Hwa Chun, Mayumi Inoue, Hiroko Morisaki, Itaru Yamanaka, Yoshihiro Miyamoto, Tomonori Okamura, Kaori Sato-Kusubata, Stephen J. Weiss

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)2484-2494
Number of pages11
JournalDiabetes
Volume59
Issue number10
DOIs
Publication statusPublished - 2010 Oct
Externally publishedYes

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High Fat Diet
Collagen Type I
Collagen
Obesity
Adipocytes
Adipose Tissue
Matrix Metalloproteinase 14
Dominant Genes
Adipogenesis
White Adipose Tissue
Lipogenesis
Gene Expression Profiling
Collagenases
Oligonucleotide Array Sequence Analysis
Electron Scanning Microscopy
Genes
Weight Gain
Catalytic Domain
Hydrolysis
Research Design

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Chun, T. H., Inoue, M., Morisaki, H., Yamanaka, I., Miyamoto, Y., Okamura, T., ... Weiss, S. J. (2010). Genetic link between obesity and MMP14-dependent adipogenic collagen turnover. Diabetes, 59(10), 2484-2494. https://doi.org/10.2337/db10-0073

Genetic link between obesity and MMP14-dependent adipogenic collagen turnover. / Chun, Tae Hwa; Inoue, Mayumi; Morisaki, Hiroko; Yamanaka, Itaru; Miyamoto, Yoshihiro; Okamura, Tomonori; Sato-Kusubata, Kaori; Weiss, Stephen J.

In: Diabetes, Vol. 59, No. 10, 10.2010, p. 2484-2494.

Research output: Contribution to journalArticle

Chun, TH, Inoue, M, Morisaki, H, Yamanaka, I, Miyamoto, Y, Okamura, T, Sato-Kusubata, K & Weiss, SJ 2010, 'Genetic link between obesity and MMP14-dependent adipogenic collagen turnover', Diabetes, vol. 59, no. 10, pp. 2484-2494. https://doi.org/10.2337/db10-0073
Chun TH, Inoue M, Morisaki H, Yamanaka I, Miyamoto Y, Okamura T et al. Genetic link between obesity and MMP14-dependent adipogenic collagen turnover. Diabetes. 2010 Oct;59(10):2484-2494. https://doi.org/10.2337/db10-0073
Chun, Tae Hwa ; Inoue, Mayumi ; Morisaki, Hiroko ; Yamanaka, Itaru ; Miyamoto, Yoshihiro ; Okamura, Tomonori ; Sato-Kusubata, Kaori ; Weiss, Stephen J. / Genetic link between obesity and MMP14-dependent adipogenic collagen turnover. In: Diabetes. 2010 ; Vol. 59, No. 10. pp. 2484-2494.
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AU - Okamura, Tomonori

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