Post-translational control of adipose tissue remodeling and metabolic health

脂肪组织重塑和代谢健康的翻译后控制

基本信息

批准号：
10453585
负责人：
Shingo Kajimura
金额：
$ 51.63万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-14 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10453585
关键词：
APPBP2 gene Adipose tissue Adrenergic Receptor Agonist Amyloid Proteins Animal Model Area Binding Proteins Biochemical Biogenesis Biological Branched-Chain Amino Acids Bypass Cardiovascular Diseases Catabolism Cells Chronic Code Complex Cues Data Dyslipidemias Energy Metabolism Extracellular Matrix FAT gene Fatty acid glycerol esters Fibrosis Genetic Genetic Transcription Glucose Intolerance Half-Life Health Homeostasis Hormonal Human Impairment Inflammation Insulin Resistance Knockout Mice Ligands Link Lipids Lipolysis Metabolic Metabolic Diseases Mitochondria Non-Insulin-Dependent Diabetes Mellitus Obesity Organ PPAR gamma Pathway interactions Physiological Play Post-Translational Regulation Process Proteins Regulation Research Role Stimulus Substrate Specificity Testing Thermogenesis Thiazolidinediones Transcription Coactivator Ubiquitination Variant Work blood glucose regulation fatty acid oxidation genetic variant glucose tolerance improved innovation insulin sensitivity lipid biosynthesis metabolic phenotype molecular phenotype mouse model novel novel strategies oxidation prevent programs receptor recruit response side effect ubiquitin-protein ligase uncoupling protein 1

项目摘要

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.

脂肪组织重塑，涉及脂肪生成，脂肪生成，脂解，细胞外基质（EM）重塑和热生成，在控制能量稳态中起着核心作用。脂肪时机内的一个显着的适应性过程是白色脂肪组织（WAT）的“褐变”或“存在”：增强的棕色/米色脂肪功能是通过代谢健康的实质性改善来实现的，包括葡萄糖耐受性和胰岛素敏感性的提高以及降低脂肪组织的敏感性以及脂肪组织注入和纤维化的降低。相度地，过程中的失调与肥胖和2型糖尿病密切相关。因此，对棕色/米色脂肪生物发生的更好理解仍然是代谢性疾病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冷和PPARγ：通过激活β-肾上腺素受体（β-AR）或通过合成PPARγ配体（例如thiazolidediones）激活的冷暴露，或激活棕色/米味的脂肪脂肪遗传遗传程序。但是，这些途径的慢性激活通常会引起多种副作用，例如心血管疾病。这是识别有选择地刺激棕色/米色脂肪生物发生的替代途径，同时避免了常规途径的有害影响，可能会有望提高新的方法，从而改善代谢健康，而副作用最少。在这方面，我们最近的发现可能提供了一个新的机会：我们确定了一种先前未经特色的细胞内部翻译后途径，该途径激活了棕色/米色脂肪生物发生，例如，增强的线粒体生物发生，脂肪酸氧化，热源，热源，热源，以及脂肪组织的注入和纤维纤维的降低，而无需激活能力允许的允许允许lane术的允许量。我们发现了第一个控制PRDM16的蛋白质稳定性的泛素E3 - 连接酶复合物，PRDM16是棕色/米色脂肪脂肪基因的主要转录共激活剂程序。值得注意的是，抑制泛素E3 - 连接酶复合物足以通过扩展PRDM16蛋白的半衰期来激活棕色/米色脂肪程序。根据该提案，旨在确定新鉴定的PRDM16的E3 - 连接酶复合物调节各种体能代谢的E3 - 连接酶复合物。