Obesity is the central component of metabolic syndrome that represents the aggregated risk for cardiovascular disease, diabetes mellitus, and cancer. Visceral fat pads accumulated inside the abdomen are known to behave differently from subcutaneous fat pads. Expanded visceral fat pads become pro-inflammatory with high-fat diet-induced chemokine production followed by the infiltration of pro-inflammatory mononuclear cells. Our preliminary data suggest that the matrix metalloproteinase 14 (MMP14)-dependent collagen degradation is one of the earliest biological processes underlying extracellular matrix (ECM) remodeling in response to high- fat diet challenge. While the reduced gene dose of MMP14 suppresses high-fat diet-induced obesity progression, more detailed gene expression profiling of visceral fat pads displays aggravated pro-inflammatory response relative to controls. These findings suggest that undigested collagens in visceral fat pads may accelerate the pro-inflammatory response in MMP14 haploinsufficient mice. Consistent with the observation, MMP14 gene dose reduction leads to an accelerated atherosclerosis formation in ApoE knockout mice. Based on these unexpected results obtained from K08DK078801-01A1 "3-Dimensional Proteolytic Regulation of Adipose Tissue Development and Function", this research aims to define the potentially inflammatory consequence of undigested collagen fibers in visceral fat pads. This study is expected to shed new light on MMP- and ECM-dependent mechanism that regulates the intricate balance between adiposity and tissue inflammation.
The proposed research will identify the role of extracellular matrix remodeling in the inflammation of visceral fat pads. The identification of the molecular mechanism that underlies the obesity-dependent progression of inflammation allows us better understand the pathogenesis of cardiovascular diseases, diabetes mellitus, and cancer.
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