Enhancing Energy Expending Adipocytes in White Adipose Tissue

增强白色脂肪组织中的能量消耗脂肪细胞

• 批准号: 8629741
• 负责人: STEPHEN ROBERT FARMER
• 金额: $ 43.49万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8629741
• 关键词: Actins; Adipocytes; Adipose tissue; Adult; Animals; Atrophic; Attenuated; Axilla; Basal metabolic rate; Binding; Blood Vessels; Body Weight; Brown Fat; Cardiovascular Diseases; Catabolism; Cell Nucleus; Cervical; Commit; Complex; Consumption; Data; Development; Dietary Fats; Disease; Ectopic Expression; Electron Transport; Energy Metabolism; Event; Expenditure; F-Actin; Fibrosis; G Actin; Gene Activation; Gene Expression; Gene Targeting; Genes; Goals; Healthcare; Heating; Homeostasis; In Vitro; Incidence; Individual; Inflammation; Insulin Resistance; Investigation; Knowledge; Lipids; Mammals; Mesenchymal Stem Cells; Metabolism; Microfilaments; Molecular; Morphology; Movement; Mus; Myosin Heavy Chains; Newborn Infant; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Pathway interactions; Physiological; Process; Production; Proteins; Recruitment Activity; Regulatory Pathway; Research Design; Rho-associated kinase; Role; Series; Serum Response Factor; Signal Pathway; Smooth Muscle; Smooth Muscle Actin Staining Method; Smooth Muscle Myosins; Stimulus; Stress; Suggestion; Supraclavicular; Technology; Testing; Therapeutic; Tissues; Transactivation; Transcription Coactivator; Transforming Growth Factors; Triglycerides; United States; Work; attenuation; base; bone morphogenetic protein 7; combat; depolymerization; energy balance; factor A; flexibility; inhibitor/antagonist; lipid biosynthesis; member; myocardin; novel; pandemic disease; prevent; progenitor; public health relevance; response; small molecule; subcutaneous; therapeutic development; therapeutic target; transcription factor; vascular factor

DESCRIPTION (provided by applicant): Obesity has reached pandemic proportions contributing to the dramatic increases in the incidence of type 2- diabetes and cardiovascular disease. The expansion of adipose tissue in obese individuals is a direct cause of these diseases due to an excessive accumulation of triglycerides (TGs) within white adipose (WAT) adipocytes. There are two major types of adipose, white that stores TGs and brown (BAT) that oxidizes them to produce heat. Until recently, it was thought that BAT only existed within the interscapular regions of newborns, but several recent investigations have identified BAT depots in the cervical, supraclavicular, axillary and paravertebral regions of adult humans. The contribution of BAT to resting metabolic rate and healthy body weight homeostasis in animals is now well established. BAT is a flexible tissue that can be recruited by stimuli and atrophies in the absence of a stimulus. In fact, studies have implicated the recruitment of brown adipocytes to WAT to explain changes in energy balance in response to different effectors. We have recently shown that lack of MRTF-A (the transcriptional coactivator of serum response factor, SRF), in mice leads to recruitment of brown-like (beige) adipocytes to WAT. In a series of in vitro studies, we have demonstrated that two members of the TGF¿ superfamily, TGF¿ and BMP7 have opposing effects on MRTF-A activity and the ability of these effectors to commit mesenchymal stem cells to an brown/beige adipogenic versus vascular lineage. Specifically, BMP7 induces brown adipogenesis by suppressing Rho kinase (ROCK) activity leading to depolymerization of F-actin and accumulation of cytoplasmic G-actin. This attenuates expression of SRF target genes by preventing translocation of MRTF- A into the nucleus. Inhibition of SRF activity with a small molecule inhibitor, CCG1423 promotes commitment of MSCs to the adipocyte lineage independent of BMP7. TGF¿ on the other hand activates SRF activity by promoting MRTF-A movement into the nucleus, which leads to suppression of adipocyte genes and activation of vascular genes including smooth muscle (SM) actin, SM heavy chain myosin (SM- MHC) and SM22. Based on these exciting data, we hypothesize that the browning of WAT is regulated by recruitment of progenitors through mechanisms involving suppression of SRF target gene expression. We propose three aims to test this hypothesis. In Aim 1, we will identify the mechanisms regulating the opposing effects of BMP7 and TGF¿ on ROCK activity and the morphology of mesenchymal stem cells. In Aim 2, we will identify the mechanisms by which MRTF-A/SRF regulates the fate of progenitors to an adipogenic versus vascular lineage. In Aim 3, we will determine the effect of MRTF-A deficiency on browning of white adipose tissue and energy balance in mice. Understanding the molecular mechanisms by which physiological effectors regulate the "browning" of WAT and identifying compounds that promote this process will significantly contribute to the development of therapeutics for obesity-associated disorders.

描述（由申请人提供）： 肥胖症已经达到了大流行比例，导致2型糖尿病和心血管疾病事件的急剧增加。肥胖个体中脂肪组织的扩张是这些疾病的直接原因，因为白色脂肪（WAT）脂肪细胞中甘油三酸酯（TGS）的过量积累。有两种主要类型的脂肪，白色，它们存储TGS和棕色（BAT），它们将它们氧化以产生热量。直到最近，人们认为蝙蝠仅存在于新生儿的界面区域内，但最近的一些调查已经确定了宫颈上的蝙蝠沉积物 和成年人类的副杂志区域。现在已经确定了蝙蝠对动物静息代谢率和健康体重稳态的贡献。蝙蝠是一种柔性组织，在没有刺激的情况下可以通过刺激和萎缩来招募。实际上，研究已经实施了棕色脂肪细胞的募集，以解释能够响应不同影响的能量平衡的变化。我们最近表明，在小鼠中缺乏MRTF-A（血清反应因子的转录共激活因子SRF）导致募集到WAT的棕色（米色）脂肪细胞。在一系列的体外研究中，我们证明了TGF¿超家族的两个成员，TGF¿和BMP7对MRTF-A活性具有相反的影响，以及这些作用使间充质干细胞对棕色/米色的脂肪型与血管谱系的能力。具体而言，BMP7通过抑制Rho激酶（岩石）活性来影响棕色的脂肪形成，从而导致F-肌动蛋白解聚和胞质G-肌动蛋白的积累。这种通过防止MRTF-A转移到细胞核中来减轻SRF靶基因的表达。用小分子抑制剂抑制SRF活性，CCG1423促进了MSC对脂肪细胞谱系的承诺，而与BMP7无关。另一方面，TGF促进了MRTF-A向细胞核的运动来激活SRF活性，从而导致抑制脂肪细胞基因并激活包括平滑肌（SM）肌动蛋白，SM重链肌球蛋白（SM-MHC）和SM22的血管基因的激活。基于这些令人兴奋的数据，我们假设WAT通过涉及抑制SRF靶基因表达的机制来调节WAT的褐变受到调节。我们提出了三个旨在检验这一假设的目标。在AIM 1中，我们将确定调查BMP7和TGF知识对岩石活性和间充质干细胞形态的相反作用的机制。在AIM 2中，我们将确定MRTF-A/SRF调节祖细胞对脂肪生成与血管谱系的命运的机制。在AIM 3中，我们将确定MRTF-A缺乏对小鼠白色脂肪组织和能量平衡的褐变的影响。了解物理效应调节WAT的“褐变”并识别促进该过程的化合物的分子机制将显着有助于肥胖相关疾病理论的发展。