Dissecting the molecular mechanisms by which Bmp8b increases thermogenesis in brown adipose tissue.

剖析 Bmp8b 增加棕色脂肪组织生热作用的分子机制。

• 批准号: BB/J009865/1
• 负责人: Antonio Vidal-Puig
• 金额: $ 73.79万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FJ009865%2F1
• 关键词: Dissecting; molecular; mechanisms; Bmp8b; increases

Brown adipose tissue (BAT) is a unique tissue in that whilst it resembles traditional white adipose tissue in some ways it exists to burn fat rather than store it. Evolutionarily, BAT emerged as a way of generating heat to defend body temperature in cold conditions and order to perform this role it developed a number of specialized characteristics. BAT is heavily under the control of the sympathetic nervous system (SNS), to the degree that every single brown adipocyte receives neuronal input. This is so that the tissue can respond quickly to environmental demand, increasing mitochondrial content, mobilizing stored fat and oxidising large amounts of it to generate heat. To meet the demand placed on it BAT can expand in mass incredibly quickly, doubling in size and generating new nerves and blood vessels to supply it with the nutrients and control it requires. How all of these processes are activated, regulated and maintained is not understood but the mechanisms may be relevant to the regeneration of a range of tissues, for example veins, nerves and even liver. We have discovered a molecule that is secreted into and around active BAT, which believe plays a crucial role in a number of processes. Our preliminary evidence suggests that bone morphogenetic protein 8b (BMP8b) is able to increase BAT sensitivity to activation by the SNS whilst directly regulating the growth of neurons and vascular cells. In addition, we have reason to believe that BMP8b also acts at a central level, regulating pathways in the brain that respond to environmental and dietary changes in order to increase SNS activation of BAT at the periphery. Understanding how a secreted molecule can elicit such specific effects in diverse cell types is likely to uncover new molecular pathways that co-ordinate the remodeling of mature tissues and their metabolic activity. It is also likely to lead to the generation of new targets for drug development in a range of diseases, even those mediated by aberrant sympathetic nervous system activity.The potential benefits that may come from understanding the functions of BMP8b are not just extremely interesting from a molecular biology perspective. Recent studies have shown unequivocally that adult humans possess substantial quantities of brown fat. It may be that endogenous mechanisms such as Bmp8b exist in humans for activating BAT and increasing energy expenditure. In the face of a widening obesity epidemic, the ability to redress the positive energy balance that causes the disease would be extremely desirable.

棕色脂肪组织（BAT）是一种独特的组织，虽然它在某些方面类似于传统的白色脂肪组织，但它的存在是为了燃烧脂肪而不是储存脂肪。经过进化，BAT 成为一种在寒冷条件下产生热量以维持体温的方式，为了发挥这一作用，它开发了许多专门的特性。 BAT 很大程度上受到交感神经系统 (SNS) 的控制，以至于每个棕色脂肪细胞都接收神经元输入。这样组织就可以快速响应环境需求，增加线粒体含量，动员储存的脂肪并氧化大量脂肪以产生热量。为了满足对其的需求，BAT 可以以令人难以置信的速度膨胀，体积增加一倍，并产生新的神经和血管来为其提供营养和控制所需的物质。所有这些过程如何被激活、调节和维持尚不清楚，但其机制可能与一系列组织的再生有关，例如静脉、神经甚至肝脏。我们发现了一种分泌到活性 BAT 中及其周围的分子，该分子被认为在许多过程中发挥着至关重要的作用。我们的初步证据表明，骨形态发生蛋白 8b (BMP8b) 能够提高 BAT 对 SNS 激活的敏感性，同时直接调节神经元和血管细胞的生长。此外，我们有理由相信，BMP8b 也在中枢水平发挥作用，调节大脑中响应环境和饮食变化的通路，以增加外周 BAT 的 SNS 激活。了解分泌分子如何在不同细胞类型中引发此类特定效应可能会发现协调成熟组织重塑及其代谢活动的新分子途径。它还可能导致在一系列疾病中产生新的药物开发靶点，甚至是那些由异常交感神经系统活动介导的疾病。了解 BMP8b 功能可能带来的潜在好处不仅来自于以下方面：分子生物学视角。最近的研究明确表明，成年人拥有大量的棕色脂肪。人体中可能存在诸如 Bmp8b 之类的内源机制来激活 BAT 并增加能量消耗。面对日益扩大的肥胖流行病，纠正导致该疾病的正能量平衡的能力将是非常可取的。

项目成果

mTORC1 in AGRP neurons integrates exteroceptive and interoceptive food-related cues in the modulation of adaptive energy expenditure in mice

• DOI: 10.1101/110544
• 发表时间: 2017-02
• 期刊: eLife
• 影响因子: 7.7
• 作者: L. K. Burke;Tamana Darwish;Althea R. Cavanaugh;S. Virtue;Emma Roth;Joanna Morro;Shun-Mei Liu;Jing Xia;J. Dalley;K. Burling;S. Chua;Toni Vidal-Puig;G. Schwartz;C. Blouet

'Basic and Applied Thermogenesis Research' Bridging the Gap.

“基础和应用产热研究”弥合差距。

• DOI: 10.1016/j.tem.2017.10.002
• 发表时间: 2018
• 期刊: TEM
• 作者: Carobbio S