In rapidly expanding adipose tissue (AT), pervasive hypoxia stimulates massive induction of Hypoxia Induced Factor 1 ? (HIF1?), which in turn initiates fibrosis and local inflammation ultimately leading to insulin resistance. AT responds to the fibrosis by up-regulating MMPs, a family of endopeptidases that cleave collagens. MT1-MMP (MMP14) is the major collagenase in AT that is up-regulated in obese fat pads. How MT1-MMP is up-regulated and what are the functional consequences of the activation of MT1-MMP remain largely unknown. Interestingly, we recently identified a novel collagen 6 digestion product (we refer to it as endotrophin) which stimulates fibrosis and inflammation locally in unhealthy AT. However, the participating MMPs and detailed digesting event still remain largely unknown. Based on the preliminary observations, it is hypothesized that MT1-MMP is responsible for the digestion event to produce endotrophin. MT1-MMP might have dichotomous effects based on different metabolic contexts in obese AT: On the one hand, at early-stage of AT expansion, MT1-MMP cleaves ECM proteins to release the high pressure on fat cells, thus attempting to maintain healthy conditions; On the other hand, at the late-stage of obese AT remodeling, it digests abnormally accumulated collagen 6?3 and produces endotrophin which further enhances fibrosis and inflammation, ultimately leading a microenvironment highly unfavorable for metabolic flexibility. To test the hypothesis, the current study has three specific Aims: 1). To investigate the role of HIF1? in upregulation of MT1-MMP in obese AT; 2). To determine whether MT1-MMP exerts anti-fibrotic and pro-angiogenic activity at early-stage of obesity development; and 3).To determine whether MT1-MMP produces endotrophin by digesting abnormal accumulating collagen 6?3 to shape unhealthy fat pads in late-stage of obesity development. Both gain-of-function and loss-of-function of HIF1? models will be applied to achieve Aim 1. Diet-induced obese and doxycycline (Dox)-inducible AT specific MT1-MMP transgenic mouse models will be used for Aim 2 and 3. Specifically, the overexpression of MT1-MMP will be induced in AT during both ?early-stage? and ?late-stage? of obesity development. Endotrophin production, fibrosis and inflammation in AT will be detected and metabolic phenotypes in the transgenic mice will be characterized under different metabolic contexts. To further study the role of endotrophin in shaping unhealthy microenvironment, both AT specific endotrophin overexpression and anti-endotrophin neutralizing antibody treated mouse models will be utilized. The molecular mechanism by which endotrophin stimulates the local fibrosis and inflammation will be further investigated in the mice. Findings from the study will enhance the general understanding of the complexity of AT physiology and highlight the central role of MT1-MMP in the dynamics of AT remodeling during obesity development. Therefore, inhibition of MT1-MMP and endotrophin produced by MT1-MMP bears great promise from a therapeutic perspective for obesity and obesity related metabolic disorders.
Fibrosis and inflammation in fat tissue can exert a potent negative impact on systemic insulin sensitivity. A better understanding of the molecular details of the regulation of the extracellular matrix (ECM) formation during obese fat tissue expansion will help to define the pathogenesis of fat tissue fibrosis and inflammation, both of which are closely linked to diabetes and other metabolic related diseases. MT1-MMP is the predominant matrix metalloprotease (MMP) in fat tissue and will be used as a major tool for the manipulation of fibrosis in fat tissue. This will enable the development of more rational therapy for obesity and diabetes related metabolic disorders.
