Genetic Link Between Obesity and <i>MMP14</i>-Dependent Adipogenic Collagen Turnover

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

doi:10.2337/db10-0073

Cited by 97 publications

(90 citation statements)

References 49 publications

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“…These events are known to be inhibited by collagen and require remodeling of ECM (Sun et al, 2013). For instance, newborn mice deficient for Mmp14, a cell surface matrix metalloproteinase involved in collagen turnover, fail to undergo adipocyte hypertrophy and consequently are lipodystrophic (Chun et al, 2010). The Mmp14 −/− preadipocytes were shown to be functionally committed, but lacked the capacity to undergo morphological changes required for adipogenesis in a three-dimensional collagen matrix.…”

Section: Discussionmentioning

confidence: 99%

PDGFRα controls the balance of stromal and adipogenic cells during adipose tissue organogenesis

2017

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Adipose tissue is distributed in depots throughout the body with specialized roles in energy storage and thermogenesis. PDGFRα is a marker of adipocyte precursors, and increased PDGFRα activity causes adipose tissue fibrosis in adult mice. However, the function of PDGFRα during adipose tissue organogenesis is unknown. Here, by analyzing mice with juxtamembrane or kinase domain point mutations that increase PDGFRα activity (V561D or D842V), we found that PDGFRα activation inhibits embryonic white adipose tissue organogenesis in a tissue-autonomous manner. By lineage tracing analysis, we also found that collagen-expressing precursor fibroblasts differentiate into white adipocytes in the embryo. PDGFRα inhibited the formation of adipocytes from these precursors while favoring the formation of stromal fibroblasts. This imbalance between adipocytes and stromal cells was accompanied by overexpression of the cell fate regulator Zfp521. PDGFRα activation also inhibited the formation of juvenile beige adipocytes in the inguinal fat pad. Our data highlight the importance of balancing stromal versus adipogenic cell expansion during white adipose tissue development, with PDGFRα activity coordinating this crucial process in the embryo.

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Section: Discussionmentioning

confidence: 99%

PDGFRα controls the balance of stromal and adipogenic cells during adipose tissue organogenesis

2017

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“…The adiposity in TIMP-2 KO mice could result from feedback of elevated IGF-1 to the hypothalamus and pituitary gland to decrease growth hormone levels, leading to lipogenesis and triacylglycerol accumulation, which would require enhanced pericellular adipocyte ECM remodeling. MMP-14-mediated collagenolysis plays a critical role in the development of adipocytes (12) and an obesogenic phenotype (10). Furthermore, a HFD increases MMP-14-mediated collagen turnover, and human MMP-14 gene polymorphisms near the catalytic domain correlate with sexually dimorphic obese and diabetic phenotypes (10).…”

Section: Discussionmentioning

confidence: 99%

“…MMP-14-mediated collagenolysis plays a critical role in the development of adipocytes (12) and an obesogenic phenotype (10). Furthermore, a HFD increases MMP-14-mediated collagen turnover, and human MMP-14 gene polymorphisms near the catalytic domain correlate with sexually dimorphic obese and diabetic phenotypes (10). Interestingly, one MMP-14 haplotype was consistently associated with increased fasting blood glucose and insulin resistance in males, supporting a potential link between MMP-14 and diabetes in males.…”

Section: Discussionmentioning

confidence: 99%

Sexually Dimorphic Diet-Induced Insulin Resistance in Obese Tissue Inhibitor of Metalloproteinase-2 (TIMP-2)-Deficient Mice

et al. 2011

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Circulating levels of matrix metalloproteinases (MMPs) and their endogenous inhibitors, tissue inhibitor of metalloproteinases (TIMPs), are altered in human obesity and may contribute to its pathology. TIMP-2 exerts MMP-dependent (MMP inhibition and pro-MMP-2 activation) and MMP-independent functions. To assess the role of TIMP-2 in a murine model of nutritionally induced obesity, weight gain in wild-type and TIMP-2 deficient [knockout (KO)] mice fed a chow or high-fat diet (HFD) was determined. The effects of diet on glucose tolerance and insulin sensitivity, as well as pancreatic β-cell and adipocyte physiology, were assessed. Chow-fed TIMP-2 KO mice of both sexes became obese but maintained relatively normal glucose tolerance and insulin sensitivity. Obesity was exacerbated on the HFD. However, HFD-fed male, but not female, TIMP-2 KO mice developed insulin resistance with reduced glucose transporter 2 and pancreatic and duodenal homeobox 1 levels, despite increased β-cell mass and hyperplasia. Thus, although β-cell mass was increased, HFD-fed male TIMP-2 KO mice develop diabetes likely due to β-cell exhaustion and failure. TIMP-2 mRNA, whose expression was greatest in sc adipose tissue, was down-regulated in HFD-fed wild-type males, but not females. Furthermore, HFD increased membrane type 1-MMP (MMP-14) expression and activity in male, but not female, sc adipose tissue. Strikingly, MMP-14 expression increased to a greater extent in TIMP-2 KO males and was associated with decreased adipocyte collagen. Taken together, these findings demonstrate a role for TIMP-2 in maintaining extracellular matrix integrity necessary for normal β-cell and adipocyte physiology and that loss of extracellular matrix integrity may underlie diabetic and obesogenic phenotypes.

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“…3E). Finally, while the debilitated status of Mmp14 À/À mice precludes attempts to monitor cytokine responses to LPS challenge in the in vivo setting (i.e., even saline-injected mice succumb to this mild stress) (data not shown), MT1-MMP hemizygous (Mmp14 +/À ) mice are viable, fertile, and phenotypically indistinguishable from wild-type animals (Filippov et al 2005;Chun et al 2010). Hence, Mmp14 +/+ or Mmp14 +/À mice were administered a single dose of LPS, and 6 h later, blood cytokine levels were determined.…”

Section: An Unexpected Role For Mt1-mmp In Regulating Macrophage Proimentioning

confidence: 99%

MT1-MMP regulates the PI3Kδ·Mi-2/NuRD-dependent control of macrophage immune function

Shimizu–Hirota¹,

Xiong²,

Baxter³

et al. 2012

Genes Dev.

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Macrophages play critical roles in events ranging from host defense to obesity and cancer, where they infiltrate affected tissues and orchestrate immune responses in tandem with the remodeling of the extracellular matrix (ECM). Despite the dual roles played by macrophages in inflammation, the functions of macrophage-derived proteinases are typically relegated to tissue-invasive or -degradative events. Here we report that the membrane-tethered matrix metalloenzyme MT1-MMP not only serves as an ECM-directed proteinase, but unexpectedly controls inflammatory gene responses wherein MT1-MMP−/− macrophages mount exaggerated chemokine and cytokine responses to immune stimuli both in vitro and in vivo. MT1-MMP modulates inflammatory responses in a protease-independent fashion in tandem with its trafficking to the nuclear compartment, where it triggers the expression and activation of a phosphoinositide 3-kinase δ (PI3Kδ)/Akt/GSK3β signaling cascade. In turn, MT1-MMP-dependent PI3Kδ activation regulates the immunoregulatory Mi-2/NuRD nucleosome remodeling complex that is responsible for controlling macrophage immune response. These findings identify a novel role for nuclear MT1-MMP as a previously unsuspected transactivator of signaling networks central to macrophage immune responses.

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Genetic Link Between Obesity and MMP14-Dependent Adipogenic Collagen Turnover

Cited by 97 publications

References 49 publications

PDGFRα controls the balance of stromal and adipogenic cells during adipose tissue organogenesis

PDGFRα controls the balance of stromal and adipogenic cells during adipose tissue organogenesis

Sexually Dimorphic Diet-Induced Insulin Resistance in Obese Tissue Inhibitor of Metalloproteinase-2 (TIMP-2)-Deficient Mice

MT1-MMP regulates the PI3Kδ·Mi-2/NuRD-dependent control of macrophage immune function

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