Adipose Tissue Metabolic Stress Responses

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，其特征在于胰岛素抵抗和高血糖症，其可导致β细胞功能障碍和2型糖尿病。因此，重要的是，我们获得的生理学和病理生理学的发展肥胖的理解，因为这方面的知识代表了潜在的治疗干预措施的设计基础。最近的研究表明，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。这种反应的幅度可以通过在白色脂肪组织库中存在棕色样脂肪细胞而增加。与内脏脂肪组织相比，这些浅褐色/米色脂肪细胞在皮下脂肪组织中更常见，并且它们的存在是由暴露于寒冷强烈诱导的。控制米色/棕色脂肪细胞-例如，使用药理学工具-代表了治疗肥胖症的潜在治疗选择。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。这一知识对于鉴定可用于治疗干预的可能分子靶点至关重要。在定义米色/棕色细胞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，我们的知识存在重大差距。最近在我的实验室的研究已经发现了一个作用的替代前mRNA剪接的调节脂肪组织产热。我们已经确定了广泛的变化，在白色脂肪细胞的选择性前mRNA剪接后，消费的高脂肪饮食。生物信息学分析鉴定了大部分调节的脂肪细胞前mRNA剪接事件中的NOVA结合位点。事实上，我们发现NOVA表达在啮齿动物和人类中都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Nova 1 LoxP/LoxP和Nova 2 LoxP/LoxP小鼠，并研究了NOVA缺乏对脂肪细胞的影响。我们发现，NOVA缺乏导致“布朗宁”的白色脂肪库，增加脂肪组织产热，并防止饮食诱导的肥胖和代谢综合征。这些研究将前体mRNA剪接确定为肥胖诱导的代谢综合征治疗干预的潜在靶点。重要的是，先前的研究已经将前体mRNA剪接确定为用于疾病治疗干预的易处理的靶标。这项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。我们预计，这项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。这些知识可能为设计治疗代谢综合征和2型糖尿病的新治疗策略奠定基础。

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.