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，在调节能量稳态中起着核心作用。脂肪组织内值得注意的适应过程是白色脂肪组织（WAT）的“布朗宁”或“褐变”：增强的棕色/米色脂肪功能伴随着代谢健康的显著改善，包括增加的葡萄糖耐量和胰岛素敏感性以及减少的脂肪组织炎症和纤维化。反过来，该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/米色脂肪生物发生仍然是代谢紊乱领域的重要研究领域。棕色/米色脂肪生物发生的最著名的刺激是寒冷和PPARγ：通过激活β-肾上腺素受体（β-AR）或用合成的PPARγ配体（例如，噻唑烷二酮类）激活棕色/米色脂肪选择性遗传程序。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，确定选择性刺激棕色/米色脂肪生物合成的替代途径，同时避免传统途径的有害影响，可能会带来改善代谢健康的新方法，副作用最小。在这方面，我们最近的发现可能提供了一个新的机会：我们确定了一个以前未表征的细胞内在翻译后途径，该途径激活棕色/米色脂肪生物合成-例如，增强线粒体生物合成、脂肪酸氧化、产热以及减少脂肪组织炎症和纤维化-而不激活经典的PPARγ转录途径。我们发现了第一个控制PRDM 16蛋白稳定性的泛素E3-连接酶复合物，PRDM 16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，抑制遍在蛋白E3连接酶复合物足以通过延长PRDM 16蛋白的半衰期来激活棕色/米色脂肪程序。因此，本提案旨在确定新鉴定的PRDM 16的E3-连接酶复合物通过其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.