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.

人类肥胖是一个严重的全球性健康问题。肥胖的一个后果是代谢综合征的发展，以胰岛素抵抗和高血糖为特征，可导致β细胞功能障碍和2型糖尿病。因此，我们了解肥胖发展的生理学和病理生理学是很重要的，因为这些知识代表了设计潜在治疗干预的基础。最近的研究发现，脂肪组织产热引起的能量消耗增加是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促进脂肪组织产热。白色脂肪组织库中棕色样脂肪细胞的存在增加了这种反应的强度。与内脏脂肪组织相比，这些白色/米色脂肪细胞在皮下脂肪组织中更常见，它们的存在是由暴露于寒冷强烈诱导的。控制米色/白脂细胞——例如，使用药理学工具——代表了治疗肥胖的一种潜在的治疗选择。因此，重要的是，我们获得的分子机制，有助于脂肪组织产热的理解。这些知识对于确定可能用于治疗干预的分子靶点至关重要。在定义米色/白垩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。然而，我们在这方面的知识有很大的差距。我的实验室最近的研究发现了替代前mrna剪接在脂肪组织产热调节中的作用。我们已经确定了高脂肪饮食后白色脂肪细胞中选择性前mrna剪接的广泛变化。生物信息学分析在大部分受调节的脂肪细胞前mrna剪接事件中发现了NOVA结合位点。事实上，我们发现NOVA的表达在啮齿类动物和人类中都受到饮食引起的肥胖的调节。为了验证NOVA蛋白的作用，我们建立了Nova1LoxP/LoxP和Nova2LoxP/LoxP小鼠，研究了NOVA缺乏对脂肪细胞的影响。我们发现nova缺乏导致白色脂肪库“褐变”，增加脂肪组织产热，并防止饮食引起的肥胖和代谢综合征。这些研究确定前mrna剪接是肥胖诱导代谢综合征治疗干预的潜在靶点。重要的是，先前的研究已经建立了pre-mRNA剪接作为一种药理学上可处理的疾病治疗干预靶点。本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。这一目标的实现将增加对肥胖分子反应的理解。我们期待这项研究项目的成功完成将有助于确定肥胖反应的新机制。这一知识可能代表了设计治疗代谢综合征和2型糖尿病的新治疗策略的基础。