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.

棕色的脂肪组织（BAT）是一种独特的组织，它在某些方面与传统的白色脂肪组织相似，以燃烧脂肪而不是储存脂肪。进化上，蝙蝠成为产生热量以在寒冷条件下捍卫体温的一种方式，并为了扮演此角色而产生了许多专业特征。蝙蝠在交感神经系统（SNS）的控制下严重，以至于每个棕色脂肪细胞都会接受神经元输入。这样一来，组织就可以迅速响应环境需求，增加线粒体含量，动员储存的脂肪并氧化大量其产生热量。为了满足其上的需求，蝙蝠可以迅速扩大质量，大小增加一倍，并产生新的神经和血管，以提供其所需的营养和控制。如何不理会如何激活，调节和维护所有这些过程，但是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。我们发现了一个分泌到活跃蝙蝠周围及其周围的分子，该分子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（BMP8B）能够通过SNS提高BAT对激活的敏感性，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也会在中央层面起作用，调节大脑中对环境和饮食变化的反应，以增加外围BAT的激活。了解分泌的分子如何在各种细胞类型中引起这种特定作用，可能会发现新的分子途径，以协调成熟组织的重塑及其代谢活性。它也可能导致在一系列疾病中产生新的药物开发目标，即使是由异常的交感神经系统活动介导的疾病。最近的研究明确表明，成年人类拥有大量的棕色脂肪。可能是人类中存在诸如BMP8B之类的内源性机制，用于激活蝙蝠和增加能量消耗。面对肥胖的流行，纠正导致疾病的正能量平衡的能力将是极为可取的。

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