3-Dimensional Proteolytic Regulation of Adipose Tissue Development and Function

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

DESCRIPTION (provided by applicant): A membrane-type matrix metalloproteinase, termed MT1-MMP, acts as the dominant pericellular collagenase during adipose tissue development (Chun et al., Cell 2006). MT1-MMP-null mice harbor a heretofore unrecognized, and major, defect in the development of adipose tissue and succumb to premature death. Despite the ability of MT1-MMP-null adipocyte precursor cells to fully differentiate into functional adipocytes under a 2-D in vitro condition, they are unable to engage adipogenic program in a 3-D collagenous microenvironment, which recapitulates an in vivo setting. High-calorie diet and hyperinsulinemia together increase adipose tissue mass. Both the expansion of adipocyte size and de novo adipogenesis contribute to the expansion of adult adipose tissue mass. Given the role of MT1-MMP in development, we ask a question whether the collagenolytic tissue remodeling contributes to obesity progression in the adult. As such, the applicant initiated a series of experiments to investigate the role of MT1-MMP-dependent collagenolysis in high fat-induced obesity and its molecular link to insulin signaling. Preliminary data suggest that the haploinsufficiency of MT1-MP substantially decreases high-fat induced weight gain (?50%). Further, human MT1-MMP gene polymorphisms are found to modify collagenolytic activity and human obesity. Thus, MT1-MMP-dependent proteolytic tissue remodeling is considered as a process critical for the regulation of obesity and metabolism in the adult. This research project will focus on identifying the role of MT1-MMP in regulation of collagenolysis, adipose tissue mass, and glucose metabolism in obesity progression. Moreover, the molecular mechanisms of 3-D adipocyte differentiation will be dissected and characterized by examining the spatial, temporal link of MT1-MMP-dependent collagenolysis to insulin signaling and adipocyte function. This should provide a unique perspective for understanding the molecular mechanisms of the tissue remodeling that regulates the progression of obesity and the consequent deterioration of cardiovascular system.