Role of Adipose Tissue TGF-b signaling on Adipose Dysfunction in Obesity

肥胖与脂肪功能障碍有关，脂肪功能障碍会导致胰岛素抵抗、糖尿病和心脏病 疾病。有人提出，脂肪功能障碍是由对缺氧的不适当反应引起的。 这会导致ECM表达增加，血管生成减少。我们的数据表明，脂肪细胞巨噬细胞 串扰导致多功能的凝血酶反应蛋白-1(TSP-1)表达增加 通过激活转化生长因子-β信号促进纤维化的蛋白质。转化生长因子-β对肥胖有多种影响 除诱导纤维化外，还包括抑制脂肪生成和复杂的血管生成作用。 最近，全身敲除Smad3以阻断转化生长因子-β信号导致小鼠患上了改善的 代谢功能和白色脂肪的褐化；这部分是由于逆转了对 转化生长因子-β对PGC-1α表达的影响。我们的总体假设是TSP-1表达增加和 肥胖白色脂肪中的转化生长因子-β信号导致纤维化增加，毛细血管密度降低， 减少了PGC-1α和UCP-1的表达，从而减少了“褐变”，并损害了WAT功能。 因此，抑制人体内的转化生长因子-β途径可能会改善脂肪功能，逆转 肥胖与胰岛素抵抗有关。第一个目标将表征白色脂肪细胞外基质和毛细血管密度。 TSP-1基因敲除小鼠和它们的产仔对照受到高脂肪饮食的挑战。第二个目标是 用cre/lox技术敲除脂肪中的转化生长因子-β，以阐明转化生长因子-β信号转导在 脂肪功能是对高脂饮食的反应。第三个目标将决定大幅削减 在脂肪细胞中，巨噬细胞共培养的PGC-1α依赖于转化生长因子-β。第四个目标将决定 Toll样受体(TLR)信号是否参与诱导脂肪细胞-巨噬细胞串扰 巨噬细胞中的TSP-1和转化生长因子-β信号转导。因此，这两个鼠标模型将指示贡献 TSP-1和转化生长因子-β对肥胖患者脂肪功能紊乱的影响共同文化研究将开始定义 脂肪细胞和巨噬细胞相互沟通诱导TSP-1的机制 两种细胞均可表达PGC-1α，并降低脂肪细胞PGC-1α的表达。

Obesity is associated with adipose dysfunction, which contributes to insulin resistance, diabetes, and heart disease. It has been proposed that adipose dysfunction is caused by an inappropriate response to hypoxia that results in increased ECM expression and reduced angiogenesis. Our data indicate that adipocytemacrophage crosstalk results in increased expression of thrombospondin-1 (TSP-1), a multifunctional protein that promotes fibrosis by activating TGF-beta signaling. TGF-beta has multiple effects on adipose in addition to inducing fibrosis including inhibiting adipogenesis and complicated effects on angiogenesis. Recently, a whole-body knockout of SMAD3 to block TGF-beta signaling resulted in mice with improved metabolic function and browning of their white adipose; this was due in part to reversing the inhibition of TGF-beta on the expression of PGC-1 alpha. Our overall hypothesis is that increased TSP-1 expression and TGF-beta signaling in white adipose with obesity cause increased fibrosis, reduced capillary density, reduced PGC-1 alpha and reduced UCP-1 expression hence less "browning", and impaired WAT function. Thus, inhibiting the TGF-beta pathway in humans may improve adipose function and reverse the effects of obesity on insulin resistance. The first aim will characterize the white adipose ECM and capillary density of TSP-1 knockout mice and their littermate controls challenged with a high fat diet. The second aim will knockout TGF-beta in adipose using cre/lox technology to elucidate the role of TGF-beta signaling on adipose function is response to high fat feeding. The third aim will determine whether the dramatic reduction in adipocyte PGC-1 alpha by macrophage coculture is TGF-beta dependent. The fourth aim will determine whether toll-like receptor (TLR) signaling is involved in the adipocyte-macrophage crosstalk that induces TSP-1 and TGF-beta signaling in macrophages. Thus, the two mouse models will indicate the contribution of TSP-1 and TGF- beta to adipose dysfunction with obesity. The coculture studies will begin to define the mechanisms by which adipocytes and macrophages communicate with each other to induce TSP-1 expression by both cells types and to decrease PGC-1 alpha expression in adipocytes.