Adipose Tissue Metabolic Stress Responses

脂肪组织代谢应激反应

• 批准号: 9401372
• 负责人: Roger J Davis
• 金额: $ 52.12万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-17 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9401372
• 关键词: Achievement; Adipocytes; Adipose tissue; Beta Cell; Binding Sites; Bioinformatics; Brown Fat; Cells; Consumption; Data; Development; Diet; Disease; Energy Metabolism; Event; Exposure to; Functional disorder; Goals; Health; High Fat Diet; Human; Hyperglycemia; Insulin Resistance; Knowledge; Laboratories; Lead; Mediating; Metabolic stress; Metabolic syndrome; Molecular; Molecular Target; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nova antigen; Obesity; Pharmacology; Physiological; Physiology; RNA Splicing; Regulation; Research; Rodent; Role; Signal Pathway; Sympathetic Nervous System; Testing; Therapeutic; Therapeutic Intervention; Thermogenesis; Visceral; biological adaptation to stress; design; mRNA Precursor; novel; novel therapeutics; obesity treatment; programs; response; subcutaneous; targeted treatment; tool; transcription factor; treatment strategy

Human obesity represents a serious world-wide health problem. One consequence of obesity is the development of metabolic syndrome, characterized by insulin resistance and hyperglycemia, that can lead to β cell dysfunction and type 2 diabetes. It is therefore important that we gain an understanding of the physiology and pathophysiology of the development of obesity because this knowledge represents a basis for the design of potential therapeutic interventions. Recent studies have identified increased energy expenditure caused by adipose tissue thermogenesis as an important contributing factor that can limit obesity development. The sympathetic nervous system promotes adipose tissue thermogenesis by activating brown adipose tissue. The magnitude of this response can be increased by the presence of brown-like adipocytes in white adipose tissue depots. These brite/beige adipocytes are more common in sub-cutaneous adipose tissue compared with visceral adipose tissue, and their presence is strongly induced by exposure to cold. Control of beige/brite adipocytes – for example, using pharmacological tools – represents a potential therapeutic option for the treatment of obesity. Consequently, it is important that we gain an understanding of molecular mechanisms that contribute to adipose tissue thermogenesis. This knowledge is critical for identifying possible molecular targets that could be employed for therapeutic intervention. Significant progress has been achieved towards defining beige/brite cell development and function, including the role of signaling pathways and transcription factors. However, there are significant gaps in our knowledge. Recent studies in my laboratory have uncovered a role for alternative pre-mRNA splicing in the regulation of adipose tissue thermogenesis. We have identified widespread changes in alternative pre-mRNA splicing in white adipocytes following consumption of a high fat diet. Bioinformatic analysis identified NOVA binding sites in a large fraction of regulated adipocyte pre-mRNA splicing events. Indeed, we found that NOVA expression is regulated by diet-induced obesity in both rodents and humans. To test the role of NOVA proteins, we established Nova1LoxP/LoxP and Nova2LoxP/LoxP mice and studied the effect of NOVA-deficiency in adipocytes. We found that NOVA-deficiency caused “browning” of white adipose depots, increased adipose tissue thermogenesis, and protection against diet-induced obesity and metabolic syndrome. These studies identify pre-mRNA splicing as a potential target for therapeutic intervention in obesity-induced metabolic syndrome. Importantly, previous studies have established pre-mRNA splicing as a pharmacologically tractable target for therapeutic intervention in diseases. The overall goal of this research program is to identify molecular mechanisms that account for the function of NOVA pre-mRNA splicing factors in adipocytes. Achievement of this goal will increase understanding of the molecular response to obesity. We anticipate that the successful completion of this research program will lead to the identification of new mechanisms that contribute to the obesity response. This knowledge may represent a basis for the design of novel therapeutic strategies for the treatment of metabolic syndrome and type 2 diabetes.

人类对象是一个严重的全球健康问题。物体的结果之一是代谢综合征的发展，其特征是胰岛素抵抗和高血糖，可能导致β细胞功能障碍和2型糖尿病。因此，重要的是我们了解肥胖发展的生理学和病理生理学，因为这种知识代表了设计潜在治疗干预措施的基础。最近的研究已经确定，脂肪组织热发生引起的能量消耗增加是可能限制肥胖发展的重要因素。交感神经系统通过激活棕色脂肪组织来促进脂肪组织的热发生。通过白色脂肪组织沉积物中存在棕色的脂肪细胞，可以增加这种反应的大小。与内脏脂肪组织相比，这些Brite/米色脂肪细胞在下脂肪脂肪组织中更为常见，并且它们的存在是由于暴露于冷的强烈诱导的。控制米色/Brite脂肪细胞（例如，使用药品工具）代表了治疗肥胖症的潜在治疗选择。因此，重要的是要了解有助于脂肪组织热发生的分子机制。这些知识对于确定可以用于治疗干预的可能分子靶标至关重要。在定义米色/Brite细胞的发育和功能方面取得了重大进展，包括信号通路和转录因子的作用。但是，我们的知识存在很大的差距。我的实验室的最新研究发现了替代前MRNA剪接在调节脂肪组织热发生中的作用。在消耗高脂饮食后，我们已经确定了白色脂肪细胞中替代前MRNA剪接的宽度变化。生物信息学分析确定了大量受调节脂肪细胞前MRNA剪接事件的NOVA结合位点。确实，我们发现Nova表达受啮齿动物和人类饮食引起的肥胖症的调节。为了测试Nova蛋白的作用，我们建立了Nova1loxp/Loxp和Nova2loxp/Loxp小鼠，并研究了Nova缺乏症在脂肪细胞中的影响。我们发现，NOVA缺陷引起了白色脂肪沉积物的“褐变”，脂肪组织的热生成增加以及防止饮食引起的肥胖和代谢综合征的保护。这些研究确定了MRNA剪接是肥胖引起的代谢综合征治疗干预的潜在靶标。重要的是，先前的研究已经建立了MRNA剪接，作为用于疾病治疗干预的药物治疗靶标。该研究计划的总体目标是确定脂肪细胞中Nova前MRNA剪接因子功能的分子机制。实现这一目标将增加对分子对肥胖反应的理解。我们预计该研究计划的成功完成将导致识别有助于肥胖反应的新机制。这些知识可能代表了设计新型治疗策略的基础，用于治疗代谢综合征和2型糖尿病。