Novel Posttranslational Modifications in Adipose Biology

项目摘要 代谢健康依赖于脂肪组织(AT)的正常质量和功能的维持。 体内过多脂肪堆积或AT病理性丧失与胰岛素抵抗和 心脏代谢疾病。白色AT(Wat)和棕色AT(BAT)一起起作用，以维持脂肪之间的平衡 积累和能量消耗。监管WAT和BAT维护的上游球员仍然较少 特色化的。泛素(Ub)和类Ub蛋白修饰不同的蛋白质底物，扩展其功能 蛋白质组的多样性。然而，NEDD8，一个新的Ub样蛋白，具有最高的功能作用 与Ub的同源性在脂肪组织中仍然知之甚少。Neddyling将NEDD8共价连接到 靶蛋白通过NEDD8特异性的E1-E2-E3酶。NAE1(一种调节亚基)的诱导脂肪缺失 NEDD8 E1酶)可能通过线粒体功能障碍导致脂肪组织的丢失 和炎症。药物抑制去甲肾上腺素促进线粒体ROS的产生和 成熟脂肪细胞线粒体功能受损。有趣的是，AT特有的CUL3丢失(一种真正的 肾病靶)主要表现为肾病缺乏所致的AT丢失，且以肾病为主 靶向CUL3来调节线粒体功能和脂肪细胞的周转。在蝙蝠中，糖尿病缺乏导致 BAT萎缩和非典范的NF-κB信号的激活。这些令人信服的初步数据构成了 我们的中心假设是成熟的白色和棕色脂肪组织需要变性 通过调节Cl3介导的线粒体功能和/或非规范的NF-κB来维持 促炎信号。目的1确定糖尿病肾病的意义并鉴定其蛋白质组。 调节线粒体功能障碍，脂肪组织重塑，从而实现能量平衡和适应性 生热作用。《目标2》将剖析一种新型线粒体的脱氧核糖核酸的分子基础 靶向CUL3E3Ub连接酶介导脂肪细胞线粒体活性和周转，从而实现能量平衡。目标 3将阐明一个新发现的核代谢靶点，该靶点介导非规范的NF-κB信号加速 棕色脂肪细胞炎症和周转。我们建议的研究将提供最深入的分析 作为迄今为止对成熟白色和棕色脂肪都必不可少的一种新的翻译后修饰 组织保养。我们期待这项提案的新发现将为我们的 了解脂肪组织的病理生理学及其与肥胖/脂营养不良的关系 相关的代谢紊乱。

Project Summary Metabolic health depends on the maintenance of normal mass and function of adipose tissue (AT). Accumulation of excess body fat or pathological loss of AT is associated with insulin resistance and cardiometabolic diseases. White AT (WAT) and brown AT (BAT) act together to maintain a balance between fat accumulation and energy expenditure. Upstream players that regulate WAT and BAT maintenance remain less characterized. Ubiquitin (Ub) and Ub-like proteins modify diverse protein substrates and expand the functional diversity of the proteome. However, the functional role of NEDD8, a novel Ub-like protein that has the highest homology with Ub, remains poorly understood in the adipose tissue. Neddylation covalently attaches NEDD8 to target proteins via NEDD8-specific E1-E2-E3 enzymes. Induced adipose deletion of NAE1 (a regulatory subunit of the NEDD8 E1 enzyme) in mice resulted in loss of adipose tissue potentially through mitochondrial dysfunction and inflammation. Pharmacological inhibition of neddylation promoted mitochondrial ROS production and impaired mitochondrial function in mature adipocytes. Interestingly, AT-specific loss of CUL3 (a bona fide neddylation target) largely phenocopied neddylation deficiency-induced AT loss, and neddylation dominantly targets CUL3 to modulate mitochondrial function and adipocyte turnover. In BAT, neddylation deficiency causes BAT atrophy and activation of non-canonical NF-κB signaling. These compelling preliminary data form the basis of our central hypothesis that neddylation is required for mature white and brown adipose tissue maintenance through regulation of CUL3-mediated mitochondrial function and/or non-canonical NF-κB pro-inflammatory signaling. Aim 1 will establish the significance and identify the proteome of neddylation in regulating mitochondrial dysfunction, adipose tissue remodeling and thus energy balance and adaptive thermogenesis. Aim 2 will dissect the molecular basis by which neddylation targets a novel mitochondrial targeted CUL3 E3 Ub ligase to mediate adipocyte mitochondrial activity and turnover thus energy balance. Aim 3 will elucidate a newly identified neddylation target in mediating non-canonical NF-κB signaling to accelerate brown adipocyte inflammation and turnover. Our proposed study will provide the most in-depth analysis of neddylation as a hitherto novel post-translational modification essential for both mature white and brown adipose tissue maintenance. We expect that new findings from this proposal will provide novel insights into our understanding of the pathophysiology of adipose tissue and its implications on obesity/ lipodystrophy and its associated metabolic disorders.