The Regulation and Metabolic Effects of gp130 Cytokines in Human White Adipose Ti

描述（由申请人提供）：肥胖，以过度肥胖为特征，是许多代谢病理的危险因素，如2型糖尿病（T2DM）。大量研究表明，脂肪组织分布可能是代谢健康的一个更大的预测指标。上半身脂肪通常与肥胖并发症有关，而下半身脂肪可能具有保护作用。然而，控制白色脂肪组织（AT）储存扩张的因素和机制尚未阐明。已发表的研究强调了gp130细胞因子，特别是心营养因子-1 （CT-1）和抑癌素M （OSM）对小鼠体外脂肪细胞和啮齿动物体内WAT功能的影响。我们新的初步数据显示，CT-1和OSM在人类AT库中表达差异，AT衍生的gp130细胞因子的产生在肥胖中发生改变。我们的初步数据也强烈表明，人类AT中OSM表达的升高与整体胰岛素抵抗相关。拟定项目的研究目标是收集和分析3项已完成和正在进行的临床研究的人体样本和生理数据[“脂肪分布的细胞动力学”（R01-DK090607）；“脂肪细胞大小与过度喂养”（R01-DK060412）；和“减肥手术和减肥对能量代谢和胰岛素敏感性的影响”（Ethicon endosurgery, Inc.）。研究肥胖和代谢健康状况如何调节不同人类AT库的gp130细胞因子的产生，并评估这些细胞因子对胰岛素敏感性的影响。我们假设CT-1和OSM的产生和分泌受脂肪和肥胖的调节，并与全身胰岛素抵抗高度相关。此外，我们提出CT-1和OSM可以直接影响胰岛素在人脂肪细胞中的作用。这些研究将通过评估gp130家族在人类AT中的新作用来填补文献中的一个关键空白。重要的是，怀特博士将学习和实施临床研究的新方法，这是成为一名转化研究者所必需的。彭宁顿生物医学研究中心拥有大量的研究设施，将为候选人提供一个良好的学习环境，以成功完成申请的目的和目标。本研究项目的训练也将为未来的分析奠定基础，以研究控制区域脂肪组织生长和分布的机制，这可能是体重调节的重要药理靶点，这是候选人的长期研究目标。NIDDK K01奖项的目标是通过经验丰富的导师的培训和拟议研究项目的实施，促进候选人的职业发展。PI组建了一支由经验丰富的调查人员组成的优秀指导团队，他们将为她的研究兴趣提供指导和专业知识，并为她的独立之路做出贡献。总的来说，这项申请将促进怀特博士成为一名独立的、资金充足的脂肪组织生物学转化研究者的长期目标。

DESCRIPTION (provided by applicant): Obesity, characterized by excessive adiposity, is a risk factor for many metabolic pathologies, such as Type 2 Diabetes mellitus (T2DM). Numerous studies have shown that adipose tissue distribution may be a greater predictor of metabolic health. Upper-body fat is commonly associated with complications of obesity, while lower-body fat may be protective. However, the factors and mechanisms that govern white adipose tissue (AT) depot expansion have not been elucidated. Published studies have highlighted the effects of gp130 cytokines, specifically cardiotrophin-1 (CT-1) and oncostatin M (OSM), on the function of murine adipocytes in vitro and rodent WAT in vivo. Our novel preliminary data reveal that CT-1 and OSM are differentially expressed in human AT depots and that AT-derived gp130 cytokine production is altered in obesity. Our preliminary data also strongly suggest that elevated OSM expression in human AT correlates with global insulin resistance. The research objective for the proposed project is to collect and analyze human samples and physiological data from 3 completed and on-going clinical studies ["Cellular Dynamics of Fat Distribution" (R01-DK090607); "Fat Cell Size and Overfeeding"(R01-DK060412); and "Effect of Bariatric Surgery and Weights Loss on Energy Metabolism and Insulin Sensitivity" (Ethicon Endo-Surgery, Inc. Grant #25404)- all PI: Ravussin, E)] to investigate how the production of gp130 cytokines from divergent human AT depots is modulated by obesity and metabolic health status and to assess the influence of these cytokines on insulin sensitivity. We hypothesize that CT-1 and OSM production and secretion are modulated by depot and adiposity and highly correlate with systemic insulin resistance. In addition, we propose that CT-1 and OSM can directly affect insulin action in human adipocytes. These studies will fill a critical void in the literature by assessing the novel actions of the gp130 family in human AT. Importantly, Dr. White will learn and implement new methods in clinical research that are necessary to become a translational investigator. Pennington Biomedical Research Center, with its vast array of research facilities, will provide a nurturing learning environment for the candidate to successfully complete the aims and objectives of the application. The training in this research project will also set the stage fo future analyses to investigate mechanisms that control regional adipose tissue growth and distribution that may be important as pharmacological targets for body weight regulation- which is the candidate's long-term research goal. The objective of the NIDDK K01 award is to facilitate the career development of the candidate through training from experienced mentors and implementation of the proposed research project. The PI has assembled an outstanding mentoring team comprised of experienced investigators that will all provide instruction and expertise to her research interests and contribute to her path to independence. Overall, this application will promote Dr. White's long-term goal of becoming an independent, well-funded translational investigator of adipose tissue biology.