Investigation of CTRP-3 (C1q/TNF-related protein-3) functions in adipose tissue via characterization of a murine adipocyte-specific knockout model

通过鼠脂肪细胞特异性敲除模型的表征研究 CTRP-3（C1q/TNF 相关蛋白 3）在脂肪组织中的功能

• 批准号: 373807666
• 负责人: Dr. Andreas Schmid
• 金额: --
• 依托单位: Medizinische Klinik und Poliklinik III: Endokrinologie, Diabetologie, Stoffwechsel und Ernährungsmedizin
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/373807666?language=en
• 关键词: Investigation; CTRP; C1q; TNF; related

Background: The 15 identified members of the family of C1q/TNF-related proteins (CTRPs) represent a group of adiponectin paralogs. CTRP-3, a secretory protein mainly expressed in adipose tissue, affects processes in both immunology and metabolism and has been characterized as an endogenous antagonist of lipopolysaccharide (LPS) with anti-inflammatory properties and as an important regulatory factor in adipocyte biology and metabolism.Aims of the study: The anti-inflammatory properties of the adipokine CTRP-3 have been well described in monocytes and in adipocytes in vitro and also recently in LPS-induced inflammation in vivo. The introduced study will comprise the characterization of a recently established Cre/loxP-based mouse model (genetic background: C57BL/6NTac) of an adipocyte-specific CTRP-3 knockout in order to investigate systemic and local tissue functions of CTRP-3. A further aim of the present study is to investigate CTRP-3 regulation in obesity and during adipose tissue reduction due to weight loss. To address these issues, both local adipose tissue and systemic CTRP-3 expression will be analyzed in obese individuals either undergoing bariatric surgery (receiving a gastric bypass or a gastric sleeve, respectively) or participating in a diet-based weight-loss program.Methods: In addition to a phenotypical characterization of the new transgenic mouse model focusing on adipose tissue development, morphology, and metabolism, the impact of dysfunctional adipocyte CTRP-3 expression on LPS-induced inflammation as well as on metabolic status and processes in mice on standard or special diets (defined high-fat and high-sugar diets) will be analyzed. Experimental settings will comprise histological, biochemical, and molecular analysis of different adipose tissue depots and characterization of resident immune system cells in adipose tissue. Glucose tolerance tests as well as lipid analysis will be applied to clarify the role of adipocyte-derived CTRP-3 in whole body metabolism. In the human obesity cohort, CTRP-3 levels will be analyzed with regard to systemic concentrations and to local expression in subcutaneous and in visceral adipose tissue.Perspectives: Molecular characterization of an adipocyte-specific CTRP-3 knockout as well as investigation of CTRP 3 regulation under the conditions of obesity and of diverse approaches aiming on weight-loss will substantially improve our understanding of the role of this protein in metabolism and in adipose tissue inflammation and will help to develop a potential future drug target in obesity and in the Metabolic Syndrome.

背景：C1 q/TNF相关蛋白（CTRPs）家族的15个成员代表了一组脂联素旁系同源物。CTRP-3是一种主要在脂肪组织中表达的分泌性蛋白质，影响免疫学和代谢过程，被认为是脂多糖（LPS）的内源性拮抗剂，具有抗炎特性，是脂肪细胞生物学和代谢的重要调节因子。脂肪因子CTRP-3的抗炎特性已在体外单核细胞和脂肪细胞中以及最近在体内LPS诱导的炎症中得到充分描述。引入的研究将包括对最近建立的脂肪细胞特异性CTRP-3敲除的基于Cre/loxP的小鼠模型（遗传背景：C57 BL/6 NTac）进行表征，以研究CTRP-3的全身和局部组织功能。本研究的另一个目的是研究CTRP-3在肥胖症和由于体重减轻导致的脂肪组织减少期间的调节。为了解决这些问题，将在接受减肥手术的肥胖个体中分析局部脂肪组织和全身CTRP-3表达，（分别接受胃旁路术或胃袖）或参加基于饮食的减肥计划。方法：除了关注脂肪组织发育、形态和代谢的新转基因小鼠模型的表型表征外，将分析功能失调的脂肪细胞CTRP-3表达对LPS诱导的炎症以及对标准或特殊饮食（限定的高脂肪和高糖饮食）小鼠的代谢状态和过程的影响。实验设置将包括不同脂肪组织库的组织学、生物化学和分子分析以及脂肪组织中常驻免疫系统细胞的表征。将应用葡萄糖耐量试验以及脂质分析来阐明脂肪细胞衍生的CTRP-3在全身代谢中的作用。在人类肥胖队列中，将针对全身浓度以及皮下和内脏脂肪组织中的局部表达来分析CTRP-3水平。脂肪细胞特异性CTRP-3敲除的分子表征以及肥胖条件下CTRP 3调节和针对体重的不同方法的研究这种蛋白质的丢失将大大提高我们对这种蛋白质在代谢和脂肪组织炎症中的作用的理解，并将有助于开发肥胖症和代谢综合征中潜在的未来药物靶点。