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: 8828181
• 负责人: STEPHEN ROBERT FARMER
• 金额: $ 49.78万
• 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 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8828181
• 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; 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; Health; 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; 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）： 肥胖已达到流行的程度，导致 2 型糖尿病和心血管疾病的发病率急剧增加。由于白色脂肪中甘油三酯 (TG) 的过度积累，肥胖个体的脂肪组织扩张是这些疾病的直接原因。 (WAT) 脂肪细胞主要有两种类型：储存 TG 的白色脂肪细胞和氧化它们产生热量的棕色脂肪细胞 (BAT)。直到最近，人们还认为 BAT 只存在于体内。新生儿的肩胛间区域，但最近的几项研究发现，颈椎、锁骨上、腋窝中存在 BAT 库。 BAT 对动物静息代谢率和健康体重稳态的贡献现已得到充分证实。事实上，BAT 是一种灵活的组织，可以通过刺激而募集。研究表明，棕色脂肪细胞会被招募到 WAT 中，以解释不同效应物引起的能量平衡变化。我们最近发现，MRTF-A（血清反应因子的转录辅激活因子，SRF）的缺乏，在小鼠体内，棕色（米色）脂肪细胞会被招募到 WAT。在一系列体外研究中，我们已经证明 TGF 的两个成员。超家族，TGF¿ BMP7 和 BMP7 对 MRTF-A 活性以及这些效应器将间充质干细胞定向为棕色/米色脂肪形成与血管谱系的能力具有相反的作用。具体来说，BMP7 通过抑制 Rho 激酶 (ROCK) 活性导致 F 解聚来诱导棕色脂肪形成。 -肌动蛋白和细胞质 G-肌动蛋白的积累，这通过防止 MRTF-A 易位到细胞核中来减弱 SRF 靶基因的表达。 CCG1423 通过小分子抑制剂抑制 SRF 活性，促进 MSC 不依赖于 BMP7 向脂肪细胞谱系定向。另一方面，通过促进 MRTF-A 运动到细胞核中来激活 SRF 活性，从而抑制脂肪细胞基因并激活血管基因，包括平滑肌 (SM) 肌动蛋白、SM 重链肌球蛋白 (SM-MHC) 和 SM22。根据这些令人兴奋的数据，我们发现 WAT 的褐变是通过抑制 SRF 靶基因表达的机制来调节的，我们提出了三个目标来检验这一假设。调节 BMP7 和 TGF 的相反作用的机制¿在目标 2 中，我们将确定 MRTF-A/SRF 调节祖细胞向脂肪形成与血管谱系的命运的机制。在目标 3 中，我们将确定 MRTF 的作用。 -小鼠白色脂肪组织褐变和能量平衡的缺陷了解生理效应器调节 WAT“褐变”的分子机制并识别促进这一过程的化合物。为肥胖相关疾病的治疗方法的开发做出了重大贡献。