Genetic link between obesity and MMP14-dependent adipogenic collagen turnover.
Genetic link between obesity and MMP14-dependent adipogenic collagen turnover.
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作者：
Chun TH;Inoue M;Morisaki H;Yamanaka I;Miyamoto Y;Okamura T;Sato-Kusubata K;Weiss SJ
在白色脂肪组织中，脂肪细胞和脂肪细胞前体细胞陷入I型胶原纤维的致密网络中。然而，这种细胞周围胶原网在饮食诱导的肥胖中的命运尚不清楚。本研究旨在确定蛋白水解胶原蛋白周转的遗传基础及其与小鼠和人类肥胖进展的相关性。使用免疫荧光染色和扫描电子显微镜在野生型或MMP 14（MT 1-MMP）-haploinsufficient小鼠中评估高脂饮食喂养早期阶段I型胶原的水解和降解。MMP 14依赖性胶原溶解对脂肪组织功能的影响通过cDNA微阵列的转录组分析来研究。在一个日本队列（n = 3，653）中检查了MMP 14基因常见变异与肥胖或糖尿病特征之间的遗传关联。在成年小鼠中，I型胶原纤维在高脂饮食挑战期间原位快速裂解。相比之下，在MMP 14单倍不足的小鼠中，高脂肪饮食的动物不能重塑脂肪垫胶原结构，并显示出迟钝的体重增加。此外，转录程序连接I型胶原蛋白营业额与脂肪形成或脂肪生成被破坏的胶原蛋白营业额的相关减少。与MMP 14在调节高脂饮食诱导的代谢程序中所起的关键作用一致，位于该酶催化结构域附近的人类MMP 14基因多态性与人类肥胖和糖尿病性状密切相关。总之，这些发现表明，MMP 14基因，编码在体内起作用的显性细胞周胶原酶，指导致肥胖胶原蛋白的周转，并与人类肥胖性状。
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. 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). 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. 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.
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影响因子：
--
作者：
FAUST, IM;JOHNSON, PR;HIRSCH, J
通讯作者：
HIRSCH, J
DOI：
10.1084/jem.20050607
发表时间：
2005-09-05
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Filippov S;Koenig GC;Chun TH;Hotary KB;Ota I;Bugge TH;Roberts JD;Fay WP;Birkedal-Hansen H;Holmbeck K;Sabeh F;Allen ED;Weiss SJ
通讯作者：
Weiss SJ
影响因子：
56.9
作者：
Frayling, Timothy M.;Timpson, Nicholas J.;McCarthy, Mark I.
通讯作者：
McCarthy, Mark I.
影响因子：
30.8
作者：
Loos, Ruth J. F.;Lindgren, Cecilia M.;Li, Shengxu;Wheeler, Eleanor;Zhao, Jing Hua;Prokopenko, Inga;Inouye, Michael;Freathy, Rachel M.;Attwood, Antony P.;Beckmann, Jacques S.;Berndt, Sonja I.;Bergmann, Sven;Bennett, Amanda J.;Bingham, Sheila A.;Bochud, Murielle;Brown, Morris;Cauchi, Stephane;Connell, John M.;Cooper, Cyrus;Smith, George Davey;Day, Ian;Dina, Christian;De, Subhajyoti;Dermitzakis, Emmanouil T.;Doney, Alex S. F.;Elliott, Katherine S.;Elliott, Paul;Evans, David M.;Farooqi, I. Sadaf;Froguel, Philippe;Ghori, Jilur;Groves, Christopher J.;Gwilliam, Rhian;Hadley, David;Hall, Alistair S.;Hattersley, Andrew T.;Hebebrand, Johannes;Heid, Iris M.;Herrera, Blanca;Hinney, Anke;Hunt, Sarah E.;Jarvelin, Marjo-Riitta;Johnson, Toby;Jolley, Jennifer D. M.;Karpe, Fredrik;Keniry, Andrew;Khaw, Kay-Tee;Luben, Robert N.;Mangino, Massimo;Marchini, Jonathan;McArdle, Wendy L.;McGinnis, Ralph;Meyre, David;Munroe, Patricia B.;Morris, Andrew D.;Ness, Andrew R.;Neville, Matthew J.;Nica, Alexandra C.;Ong, Ken K.;O'Rahilly, Stephen;Owen, Katharine R.;Palmer, Colin N. A.;Papadakis, Konstantinos;Potter, Simon;Pouta, Anneli;Qi, Lu;Randall, Joshua C.;Rayner, Nigel W.;Ring, Susan M.;Sandhu, Manjinder S.;Scherag, Andre;Sims, Matthew A.;Song, Kijoung;Soranzo, Nicole;Speliotes, Elizabeth K.;Syddall, Holly E.;Teichmann, Sarah A.;Timpson, Nicholas J.;Tobias, Jonathan H.;Uda, Manuela;Vogel, Carla I. Ganz;Wallace, Chris;Waterworth, Dawn M.;Weedon, Michael N.;Willer, Cristen J.;Wraight, Vicki L.;Yuan, Xin;Zeggini, Eleftheria;Hirschhorn, Joel N.;Strachan, David P.;Ouwehand, Willem H.;Caulfield, Mark J.;Samani, Nilesh J.;Frayling, Timothy M.;Vollenweider, Peter;Waeber, Gerard;Mooser, Vincent;Deloukas, Panos;McCarthy, Mark I.;Wareham, Nicholas J.;Barroso, Ines
通讯作者：
Barroso, Ines
影响因子：
--
作者：
Mannami, T;Baba, S;Ogata, J
通讯作者：
Ogata, J