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。从进化的角度来看，BAT是作为一种在寒冷条件下产生热量以保护体温的方式出现的，为了发挥这一作用，它发展了一些专门的特征。BAT在很大程度上受到交感神经系统（SNS）的控制，以至于每一个棕色脂肪细胞都接受神经元的输入。这是为了使组织能够快速响应环境需求，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。为了满足对它的需求，BAT可以以令人难以置信的速度扩大质量，使其大小增加一倍，并产生新的神经和血管，以提供它所需的营养和控制。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中和周围的分子，这种分子被认为在许多过程中起着至关重要的作用。我们的初步证据表明，骨形态发生蛋白8b（BMP 8b）能够增加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也在中枢水平起作用，调节大脑中对环境和饮食变化做出反应的通路，以增加外周BAT的SNS激活。了解分泌的分子如何在不同的细胞类型中引起这种特定的作用，可能会发现新的分子途径，协调成熟组织的重塑及其代谢活性。它还可能导致在一系列疾病中产生药物开发的新靶点，即使是那些由异常交感神经系统活动介导的疾病。了解BMP 8b的功能可能带来的潜在好处不仅仅是非常有趣的从分子生物学的角度来看。最近的研究明确表明，成年人拥有大量的棕色脂肪。这可能是内源性机制，如Bmp8b存在于人类激活BAT和增加能量消耗。面对日益扩大的肥胖流行病，纠正导致这种疾病的正能量平衡的能力将是极其可取的。

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