title: Genetic link between obesity and MMP14-dependent adipogenic collagen turnover.
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.
  
  
  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.
authors.affiliation: Division of Metabolism, Endocrinology and Diabetes, the Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA. taehwa@umich.edu
authors.forename: Tae-Hwa
authors.initials: TH
authors.lastname: Chun
authors.forename: Mayumi
authors.initials: M
authors.lastname: Inoue
authors.forename: Hiroko
authors.initials: H
authors.lastname: Morisaki
authors.forename: Itaru
authors.initials: I
authors.lastname: Yamanaka
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Miyamoto
authors.forename: Tomonori
authors.initials: T
authors.lastname: Okamura
authors.forename: Kaori
authors.initials: K
authors.lastname: Sato-Kusubata
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Weiss
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D003094:Collagen / Q000378:metabolism*; D004041:Dietary Fats / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D015810:Linkage Disequilibrium; D053511:Matrix Metalloproteinase 14 / Q000172:deficiency / Q000235:genetics*; D051379:Mice; D009765:Obesity / Q000201:enzymology / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D015430:Weight Gain
chemical_list: D004041:Dietary Fats; C507096:Mmp14 protein, mouse; D003094:Collagen; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14