Excess accumulation of collagen fibers next to fat cells (peri-adipocyte fibrosis) is observed in insulin-resistant individuals with inappropriate fat mass (obesity and lipodystrophy). The molecular mechanism underlying the formation of peri-adipocyte fibrosis, however, is poorly understood. MMP14 encodes a pericellular collagenase that plays a critical role in type I collagen turnover. Moreover, MMP14 has been shown to maintain pro- transcriptional histone acetylation (H3K9ac) by cleaving juxtaposed type I collagen fibers. The central hypothesis of this research is that MMP14-dependent peri-adipocyte collagen turnover promotes healthy adipocyte function via epigenetic gene regulation. My central hypothesis here is that MMP14 expressed by adipocytes directs peri-adipocyte collagen turnover and maintains healthy adipocyte function.
I aim to pursue the following three aims to test my hypothesis.
Aim 1. Characterize the role of adipocyte MMP14 in preventing peri-adipocyte fibrosis and adipocyte dysfunction in vivo: I hypothesize that MMP14 tethered to adipocytes maintains the anti-fibrotic and anti- inflammatory state of adipose tissues. Using a peri-adipocyte fibrosis model, i.e., tamoxifen-inducible adipocyte-selective MMP14 gene deletion, I will characterize the link between peri-adipocyte fibrosis, inflammatory tissue damage, and the induction of insulin resistance.
Aim 2. Define type I collagen-dependent and -independent regulation of adipocyte function in vitro and in vivo: I hypothesize that MMP14-dependent type I collagen cleavage is the primary event that leads to epigenetic histone modification necessary for adipocyte gene regulation. By using MMP-resistant mutant type I collagen mice and non-collagenous 3-D nanomaterial, I will determine the type I collagen-dependent and - independent mechanisms underlying adipocyte gene regulation.
Aim 3. Define the epigenetic histone modification regulated by MMP14 in vitro and in vivo: I propose that MMP14-dependent peri-adipocyte collagenolysis regulates pro-transcriptional histone modification (H3K9ac) that intersects with PPARg-dependent adipocyte gene regulation. By using peri-adipocyte fibrosis model, I will define the role of MMP14 in regulating the interaction between H3K9ac and PPARg in regulating adipocyte gene expression. This study is expected to demonstrate that MMP14-dependent peri-adipocyte collagen turnover enhances PPARg-dependent gene regulation via histone acetylation. Together, expected outcomes will define the role of MMP14 in preventing peri-adipocyte fibrosis and adipocyte dysfunction. The knowledge will help us understand the pathogenesis of insulin resistance and obesity-related metabolic diseases from the perspective of peri-adipocyte collagen turnover.

Public Health Relevance

The proposed research is relevant to public health because identifying the molecular mechanism underlying dysfunctional fat tissue is expected to advance the understanding of the link between obesity and diabetes. The expected outcomes will promote the development of diagnostic markers and pharmacological therapies for obesity and diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK095137-02
Application #
8445233
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Haft, Carol R
Project Start
2012-09-01
Project End
2017-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2013
Total Cost
$326,376
Indirect Cost
$116,488
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Moraes, Christopher; Labuz, Joseph M; Leung, Brendan M et al. (2013) On being the right size: scaling effects in designing a human-on-a-chip. Integr Biol (Camb) 5:1149-61