Roles of GDF3 in the differentiation and function of the adipocyte

GDF3 在脂肪细胞分化和功能中的作用

• 批准号: 8297280
• 负责人: Chester W Brown
• 金额: $ 0.36万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8297280
• 关键词: 3T3-L1 Cells; Adipocytes; Adipose tissue; Affect; Anabolism; Apoptosis; BMP7 gene; Biochemical; Blood Vessels; Cell Line; Cell Proliferation; Cell Size; Cells; Clonal Expansion; Diet; Doxycycline; Drug Controls; Embryo; Energy Intake; Enzymes; Event; Fatty acid glycerol esters; Fibroblasts; GDF8 gene; Gene Expression; In Vitro; Leptin; Ligands; Link; Lipolysis; Measures; Mitotic; Molecular; Mus; Obesity; Phosphorylation; Play; Property; Proteins; Reporter; Research Personnel; Role; Signal Transduction; Testing; Tissues; Transforming Growth Factor beta; Transgenic Mice; Triglycerides; Weight Gain; adipocyte differentiation; bone morphogenetic protein 2; in vivo; lipid biosynthesis; member; myostatin; null mutation; precursor cell; programs; receptor; response

DESCRIPTION (provided by applicant): TGF-( superfamily signaling regulates pre-adipocyte determination and differentiation in vitro. These secreted ligands play roles in the stimulation and inhibition of adipogenesis. The determination and subsequent differentiation of precursor cell lines into adipocytes is stimulated by bone morphogenetic proteins (BMPs) 2, 4 and 7. BMP7-induced adipocyte differentiation can be inhibited by GDF8/myostatin, another TGF-( superfamily member. TGF-( is also antagonistic to adipogenesis in vitro and in vivo. We hypothesize that GDF3, another TGF-( superfamily member and the subject of this proposal, also plays an important role in regulating adipogenesis and/or in affecting the function of mature adipocytes. First, GDF3 is expressed in adipose tissues and is significantly up regulated in white adipose depots in response to high fat diets, with disproportionate increases in the adipocyte and stromal vascular fractions. Secondly, over expression of GDF3, in vivo, by adenoviral transduction results in a greater sensitivity to the adipogenic effects of high fat diets, reflected by greater weight gain, adipose tissue mass, higher leptin levels, and greater adipocyte cell size. Conversely, our studies of Gdf3-/- mice have revealed a protection from diet- induced obesity, including normal body and adipose tissue mass and adipocyte cell sizes, despite a greater caloric intake. Therefore, GDF3 may function in to regulate adipogenesis and/or mature adipocyte function. The aims of the application are as follows: Specific aim 1- Examine the effects of GDF3 on cell proliferation, survival, and differentiation. We will examine the effects of exogenous GDF3 protein on the proliferation, mitotic clonal expansion, apoptosis, and differentiation of two adipogenic cell lines. Specific aim 2- Assess GDF3's effects on mature adipocyte function. Fully differentiated 3T3-L1 cells will be analyzed to determine if exogenous GDF3 protein administration has effects on lipogenesis, lipolysis, and other mature adipocyte functions. Specific aim 3- Define the essential components of GDF3 signaling in adipocytes and determine if there is a link to brown/white adipocyte fate decisions. We will further define GDF3's interactions with its receptors and with other superfamily members that affect adipogenesis. Specific aim 4- Examine the consequences of GDF3 over expression in adipose tissues in vivo. We will generate transgenic mice which express GDF3 selectively in adipose tissues under the reversible control of the drug, doxycycline.

描述（申请人提供）：TGF-(超家族信号传导在体外调节前脂肪细胞的决定和分化。这些分泌的配体在刺激和抑制脂肪生成中发挥作用。前体细胞系的决定和随后分化为脂肪细胞受到骨的刺激形态发生蛋白 (BMP) 2、4 和 7。BMP7 诱导的脂肪细胞分化可被另一种 TGF-( 超家族成员) GDF8/肌生长抑制素抑制。 TGF-( 在体外和体内也拮抗脂肪生成。我们假设另一个 TGF-( 超家族成员和本提案的主题 GDF3 在调节脂肪生成和/或影响成熟脂肪细胞的功能中也发挥着重要作用首先，GDF3 在脂肪组织中表达，并且在高脂肪饮食下，白色脂肪库中的表达显着上调，脂肪细胞和基质中的增加不成比例。其次，通过腺病毒转导在体内过度表达 GDF3 导致对高脂肪饮食的脂肪形成作用更加敏感，这反映在体重增加、脂肪组织质量增加、瘦素水平升高和脂肪细胞尺寸增大。相反，我们对 Gdf3-/- 小鼠的研究表明，尽管摄入的热量较多，但 Gdf3-/- 小鼠可以防止饮食引起的肥胖，包括正常的身体和脂肪组织质量以及脂肪细胞大小。因此，GDF3可能起到调节脂肪生成和/或成熟脂肪细胞功能的作用。本申请的目的如下： 具体目的1-检查GDF3对细胞增殖、存活和分化的影响。我们将检查外源 GDF3 蛋白对两种脂肪细胞系的增殖、有丝分裂克隆扩增、凋亡和分化的影响。具体目标 2- 评估 GDF3 对成熟脂肪细胞功能的影响。将分析完全分化的 3T3-L1 细胞，以确定外源 GDF3 蛋白的施用是否对脂肪生成、脂肪分解和其他成熟脂肪细胞功能有影响。具体目标 3- 定义脂肪细胞中 GDF3 信号传导的基本组成部分，并确定是否与棕色/白色脂肪细胞的命运决定存在联系。我们将进一步定义 GDF3 与其受体以及影响脂肪生成的其他超家族成员的相互作用。具体目标 4 - 检查体内脂肪组织中 GDF3 过度表达的后果。我们将培育出在药物强力霉素可逆控制下在脂肪组织中选择性表达 GDF3 的转基因小鼠。