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世界性健康问题，其后果之一是产生以胰岛素抵抗和高血糖为特征的代谢综合征，这可能导致 β 细胞功能障碍和 2 型糖尿病。肥胖发展的生理学和病理生理学，因为这些知识代表了潜在治疗干预措施设计的基础，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系统发展的重要因素。通过激活棕色脂肪组织来促进脂肪组织产热 与内脏脂肪组织相比，这些棕色/米色脂肪细胞在皮下脂肪组织中更常见。 ，并且它们的存在是通过暴露于寒冷而强烈诱导的——例如，使用药理学工具——代表了治疗肥胖的潜在治疗选择，重要的是，我们了解有助于脂肪组织生热的分子机制，这对于确定可用于治疗干预的可能分子靶标至关重要，在定义米色/布里特细胞发育和功能方面已取得了重大进展，然而，我们的实验室最近的研究发现了替代性前体 mRNA 剪接在脂肪组织生热调节中的作用，我们已经发现了替代性的广泛变化。前mRNA生物信息学分析发现，在大部分受调节的脂肪细胞前体 mRNA 剪接事件中，NOVA 的表达均受到饮食诱导的肥胖的调节。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 缺陷对脂肪细胞的影响。 NOVA 缺乏会导致白色脂肪库“褐变”，增加脂肪组织生热作用，并预防饮食引起的肥胖和代谢综合征。这些研究将前 mRNA 剪接确定为治疗肥胖引起的代谢综合征的潜在目标。 , 先前的研究已将 pre-mRNA 剪接确立为疾病治疗干预的药理上易于处理的靶标。该研究计划的总体目标是确定解释 NOVA pre-mRNA 功能的分子机制。脂肪细胞中剪接因子的实现将增加对肥胖分子反应的了解，我们预计该研究计划的成功完成将有助于识别有助于肥胖反应的新机制。设计治疗代谢综合征和 2 型糖尿病的新治疗策略。