MMP14-dependent regulation of adipose tissue remodeling and function (R01)

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

DESCRIPTION (provided by applicant): 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.