Post-translational control of adipose tissue remodeling and metabolic health

脂肪组织重塑，包括脂肪生成、脂肪生成、脂解、细胞外基质(EM)重塑和产热，在调节能量平衡方面起着核心作用。脂肪组织内一个显著的适应过程是白色脂肪组织(WAT)的“褐化”或“褐化”：棕色/米色脂肪功能增强的同时，代谢健康也得到显著改善，包括葡萄糖耐量和胰岛素敏感性的增加，以及脂肪组织炎症和纤维化的减少。反过来，这一过程中的失调与肥胖和2型糖尿病密切相关。因此，更好地了解棕色/米色脂肪的生物发生仍然是代谢紊乱领域的一个重要研究领域。棕色/米色脂肪生物发生最著名的刺激是寒冷和PPARγ：通过激活β肾上腺素受体(β-AR)的冷暴露或用合成的PPARγ配体(例如，噻唑烷二酮)长期处理激活棕色/米色脂肪选择遗传程序。然而，这些通路的慢性激活往往会导致多种副作用，如心血管疾病。因此，找到选择性地刺激棕色/米色脂肪生物生成的替代途径，同时避免传统途径的有害影响，可能会带来以最小副作用改善代谢健康的新方法。在这方面，我们最近的发现可能提供了一个新的机会：我们发现了一种以前未知的细胞固有的翻译后途径，它激活了棕色/米色脂肪的生物发生-例如，增强线粒体生物发生、脂肪酸氧化、产热以及减少脂肪组织的炎症和纤维化-而不激活典型的PPARγ转录途径。我们发现了第一个控制PRDM16蛋白质稳定性的泛素E3-连接酶复合体，PRDM16是棕色/米色脂肪基因的显性转录共激活因子 程序。值得注意的是，抑制泛素E3-连接酶复合体足以通过延长PRDM16蛋白的半衰期来激活棕色/米色脂肪计划。因此，本建议旨在确定新发现的PRDM16的E3-连接酶复合体调节全身能量代谢的翻译后机制。

Adipose tissue remodeling, involving adipogenesis, lipogenesis, lipolysis, extracellular matrix (EM) remodeling, and thermogenesis, plays a central role in regulating energy homeostasis. A notable adaptive process within adipose tissues is the “browning” or “beiging” of white adipose tissue (WAT): enhanced brown/beige fat function is accompanied by a substantial improvement in metabolic health, including increased glucose tolerance and insulin sensitivity as well as reduced adipose tissue inflammation and fibrosis. Reciprocally, dysregulation in the processes is tightly associated with obesity and type 2 diabetes. As such, a better understanding of the brown/beige fat biogenesis continues to be a significant area of research in the field of metabolic disorders. The best-known stimuli of brown/beige fat biogenesis are cold and PPARγ: cold exposure via activation of β-adrenoceptor (β-AR) or chronic treatment with synthetic PPARγ ligands (e.g., thiazolidinediones) activate the brown/beige fat-selective genetic program. However, chronic activation of these pathways often causes multiple side effects, such as cardiovascular diseases. Thus, identifying alternative pathways that selectively stimulate brown/beige fat biogenesis, while avoiding the detrimental effects of the conventional pathways, may promise new approaches that improve metabolic health with minimal side effects. In this regard, our recent finding may offer a new opportunity: we identified a previously uncharacterized cell-intrinsic post-translational pathway that activates brown/beige fat biogenesis – e.g., enhanced mitochondrial biogenesis, fatty acid oxidation, thermogenesis, as well as reduced adipose tissue inflammation and fibrosis – without activating the canonical PPARγ transcription pathway. We found the first ubiquitin E3-ligase complex that controls the protein stability of PRDM16, a dominant transcriptional co-activator of the brown/beige fat gene program. Notably, inhibition of the ubiquitin E3-ligase complex is sufficient to activate the brown/beige fat program through extending the half-life of PRDM16 protein. Accordingly, this proposal aims to determine the post-translational mechanisms through which the newly identified E3-ligase complex for PRDM16 regulateswhole-body energy metabolism.