Genetic link between obesity and MMP14-dependent adipogenic collagen turnover.
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.
Chun
Tae-Hwa
TH
Division of Metabolism, Endocrinology and Diabetes, the Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA. taehwa@umich.edu
Inoue
Mayumi
M
Morisaki
Hiroko
H
Yamanaka
Itaru
I
Miyamoto
Yoshihiro
Y
Okamura
Tomonori
T
Sato-Kusubata
Kaori
K
Weiss
Stephen J
SJ
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
D004041:Dietary Fats; C507096:Mmp14 protein, mouse; D003094:Collagen; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14