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

脂肪组织 TGF-b 信号传导在肥胖症脂肪功能障碍中的作用

• 批准号: 8602579
• 负责人: Brian S Finlin
• 金额: $ 25.5万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8602579
• 关键词: Adipocytes; Adipose tissue; Blood capillaries; Brown Fat; Cardiovascular Diseases; Coculture Techniques; Complex; Data; Diabetes Mellitus; Diet; Docosahexaenoic Acids; Euglycemic Clamping; Extracellular Matrix; Fatty acid glycerol esters; Fibrosis; Fish Oils; Functional disorder; Gene Expression; Glucose Clamp; Heart Diseases; Human; Hypoxia; Immune; Insulin Resistance; Interleukin-10; Knock-out; Knockout Mice; MADH3 gene; Measures; Mediating; Metabolic; Methods; Mus; Obesity; Pathway interactions; Process; Proteins; Receptor Signaling; Research; Role; Signal Transduction; Small Interfering RNA; TLR2 gene; TLR4 gene; Technology; Testing; Thrombospondin 1; Toll-like receptors; Transforming Growth Factor beta; angiogenesis; capillary; cell type; combat; density; feeding; glucose tolerance; improved; inhibitor/antagonist; insulin tolerance; lipid biosynthesis; macrophage; mouse model; receptor; response

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.

肥胖与脂肪功能障碍有关，这有助于胰岛素抵抗、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 导致ECM表达增加和血管生成减少。我们的数据表明脂肪巨噬细胞 串扰导致血小板反应蛋白-1（TSP-1）表达增加， 通过激活TGF-β信号促进纤维化的蛋白质。TGF-β对脂肪有多种作用， 此外还诱导纤维化，包括抑制脂肪生成和对血管生成的复杂作用。 最近，SMAD 3的全身敲除阻断TGF-β信号传导导致小鼠的 代谢功能和白色脂肪的布朗宁;这部分是由于逆转了 TGF-β对PGC-1 α表达的影响。我们的总体假设是，增加TSP-1表达和 肥胖患者白色脂肪中的TGF-β信号传导导致纤维化增加，毛细血管密度降低， PGC-1 α减少和UCP-1表达减少，因此“布朗宁”减少，WAT功能受损。 因此，抑制人的TGF-β途径可以改善脂肪功能并逆转TGF-β的作用。 肥胖对胰岛素抵抗的影响第一个目标是表征白色脂肪ECM和毛细血管密度， TSP-1敲除小鼠及其同窝对照用高脂肪饮食攻击。第二个目标将 使用cre/lox技术敲除脂肪中的TGF-β，以阐明TGF-β信号传导在 脂肪功能是对高脂喂养的反应。第三个目标将决定是否大幅减少 在脂肪细胞中，PGC-1 α通过巨噬细胞共培养是TGF-β依赖性的。第四个目标将决定 Toll样受体（TLR）信号传导是否参与了诱导巨噬细胞凋亡的脂肪细胞-巨噬细胞串扰， 巨噬细胞中的TSP-1和TGF-β信号传导。因此，这两种小鼠模型将表明 TSP-1和TGF-β与肥胖症脂肪功能障碍的关系。共培养研究将开始确定 脂肪细胞和巨噬细胞相互沟通以诱导TSP-1的机制 通过两种细胞类型的表达和减少脂肪细胞中PGC-1 α的表达。