Regulation of Brown Fat Development and Function by Cyclin C

细胞周期蛋白 C 对棕色脂肪发育和功能的调节

基本信息

批准号：
10164757
负责人：
JEFFREY E. PESSIN
金额：
$ 54.02万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10164757
关键词：
ATP Synthesis Pathway Adipocytes Adipose tissue American B-Lymphocytes Binding Proteins Brown Fat Carbohydrates Cell Respiration Cells Complex Cyclins Data Defect Development Diabetes Mellitus Diagnosis Diet Dietary Carbohydrates Elements Energy Metabolism Esterification Event Fatty Acids Fatty acid glycerol esters Gene Expression Gene Expression Profiling Generations Genes Genetic Transcription Health Care Costs Histologic Homeostasis Impairment Insulin Resistance Knock-out Ligands Lipids Lipoproteins Liver Maintenance Mediating Mediator of activation protein Metabolic Metabolic Diseases Molecular Mus Non-Insulin-Dependent Diabetes Mellitus Nutrient Obesity Epidemic Outcome PPARG gene Pathway interactions Physiology Prevalence Process Protein Complex Subunit RNA Polymerase II Regulation Residual state Rest Role Signal Transduction Temperature Testing Transcriptional Activation Transcriptional Regulation Triglycerides United States adipocyte differentiation adipokines base cell type cofactor cyclin C dietary in vivo lipid biosynthesis mature animal mitochondrial uncoupling protein mouse model novel novel strategies obesity prevention overexpression programs transcription factor uncoupling protein 1

项目摘要

The Mediator complex is a multi-subunit protein complex that acts as a transcriptional cofactor by connecting a number of transcription factors to the RNA polymerase II. Cyclin C (CycC) is a highly conserved subunit of the Mediator complex, but its role in brown/beige adipocytes remains unclear. We recently identify CycC as a regulator of brown adipocyte development and function. CycC knockout in Myf5+ cells reduces but does not eliminate brown adipose tissues. The residual brown adipocytes display a marked reduction in lipid accumulation in mice maintained on the standard chow diet. Gene expression analyses revealed that CycC knockout selectively impaired the expression of ChREBP target genes including Fasn, the key gene for de novo lipogenesis. The CycC-Mediator was found to physically interact with ChREBP and the transcriptional activity of ChREBP was reduced in CycC-knockout cells. These data suggest that under high-carbohydrate dietary conditions, brown adipocyte autonomous ChREBP-dependent de novo lipogenesis may be required for lipid droplet formation. Although CycC knockout had little effect on the overall integrity of the rest of the Mediator complex, differentiation was inhibited in CycC-knockout brown preadipocytes. This was likely due to the requirement of CycC for the expression of key adipogenic genes, including Zfp423 and Pparg. Overexpression of PPARg or addition of PPARg ligands rescued the defect in CycC-knockout cells, indicating that CycC is not required for PPARg transcriptional activity, but for Pparg gene expression. The expression of Zfp423 and Pparg are regulated by the EBF transcription factors and the CycC-Mediator also physically interacts with EBF1. Based on the preliminary studies, we hypothesize that CycC in the context of the Mediator complex regulates brown/beige adipocyte development and function through two distinct mechanisms. First, the CycC-Mediator complex is required for EBF1-mediated activation of Zfp423 and Pparg genes necessary for brown/beige preadipocyte determination. Second, the CycC-Mediator complex is also required for ChREBP transcriptional activity critical for brown/beige adipocyte lipogenic gene expression necessary for cell autonomous de novo lipogenesis. To test these hypotheses, we propose two related but independent Specific Aims. Aim 1 will examine the CycC-Mediator regulation of the transcriptional activity and expression of EBF1 and EBF2 in brown/beige preadipocytes, the Mediator functions in brown/beige adipocyte development in vivo, and the context-dependent regulation of CycC on the transcription program that controls the brown/beige preadipocyte determination. Aim 2 will examine the CycC-Mediator regulation of ChREBP in brown/beige adipocytes, and histologic, metabolic and molecular outcomes of Ucp1+ cell- specific knockout of CycC or ChREBP in mouse models under various dietary and temperature conditions. The long-term objective is to understand the molecular basis for brown and beige adipocyte lineage commitment and the role of de novo lipogenesis in the physiology of brown and beige adipocyte function.

介体复合物是一种多支亚基蛋白复合物，通过将许多转录因子与RNA聚合酶II连接起来作为转录辅助因子。 Cyclin c（Cycc）是介体复合物的高度保守亚基，但其在棕色/米色脂肪细胞中的作用尚不清楚。我们最近将CYCC识别为棕色脂肪细胞发育和功能的调节剂。 MyF5+细胞中的CYCC敲除可减少，但不会消除棕色脂肪组织。残留的棕色脂肪细胞显示出在标准食物饮食上维持的小鼠中脂质积累的显着降低。基因表达分析表明，CYCC敲除选择性损害Chrebp靶基因在内的表达，包括FASN，FASN是从头脂肪生成的关键基因。发现CYCC-辅助因子与Chrebp物理相互作用，并且Cycc-Knockout细胞中CHREBP的转录活性降低。这些数据表明，在高碳水化合物的饮食条件下，脂质液滴形成可能需要棕色脂肪细胞自动依赖性chrebp依赖性的从头脂肪生成。尽管CYCC敲除对其他介体复合物的整体完整性的影响很小，但在CYCC-KNOCKOUT BROWN前脂肪细胞中抑制了分化。这可能是由于CYCC需要表达关键脂肪生成基因的表达，包括ZFP423和PPARG。 PPARG的过表达或添加PPARG配体挽救了CYCC-KNOCKOUT细胞中的缺陷，表明PPARG转录活性的CYCC不是必需的，而是PPARG基因表达。 ZFP423和PPARG的表达受EBF转录因子的调节，CYCC-SEDIARS也与EBF1物理相互作用。基于初步研究，我们假设在介体复合物的背景下，CYCC通过两种不同的机制来调节棕色/米色脂肪细胞的发育和功能。首先，CYCC介导的复合物是EBF1介导的ZFP423激活和棕色/米色前脂肪细胞确定所需的PPARG基因所必需的。其次，CYCC介导剂复合物也需要Chrebp转录活性对于棕色/米色脂肪细胞脂肪结基因表达至关重要，而这些基因表达对于细胞自主性脂肪生成所必需的。为了检验这些假设，我们提出了两个相关但独立的目的。 AIM 1将检查棕色/米色前脂肪细胞中EBF1和EBF2转录活性和表达的CYCC-介导器调节，体内介体在棕色/米色脂肪细胞发育中的功能以及Cycc对转录程序的上下文依赖性调节的转录程序，以控制棕色/米米光preadipocyte确定。 AIM 2将检查棕色/米色脂肪细胞中CHREBP的CYCC-介导者调节，以及在各种饮食和温度条件下，在小鼠模型中，UCP1+细胞特异性敲除Cycc或Chrebp的组织学，代谢和分子结局。长期目标是了解棕色和米色脂肪细胞谱系承诺的分子基础，以及从头脂肪生成在棕色和米色脂肪细胞功能的生理学中的作用。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The Mediator Complex and Lipid Metabolism.

DOI：
发表时间：
2013-03
期刊：
Journal of biochemical and pharmacological research
影响因子：
0
作者：
Yi Zhang;Xiaoli;Xiaoping Zhao;Fajun Yang
通讯作者：
Yi Zhang;Xiaoli;Xiaoping Zhao;Fajun Yang

Natural Polyphenols Inhibit Lysine-Specific Demethylase-1 in vitro.

DOI：
发表时间：
2013-03
期刊：
Journal of biochemical and pharmacological research
影响因子：
0
作者：
A. Abdulla;Xiaoping Zhao;Fajun Yang
通讯作者：
A. Abdulla;Xiaoping Zhao;Fajun Yang

Inhibition of SREBP transcriptional activity by a boron-containing compound improves lipid homeostasis in diet-induced obesity.

DOI：
10.2337/db13-0835
发表时间：
2014-07
期刊：
Diabetes
影响因子：
7.7
作者：
Zhao X;Xiaoli;Zong H;Abdulla A;Yang ES;Wang Q;Ji JY;Pessin JE;Das BC;Yang F
通讯作者：
Yang F

Mediating lipid biosynthesis: implications for cardiovascular disease.

DOI：
10.1016/j.tcm.2013.03.002
发表时间：
2013-10
期刊：
Trends in cardiovascular medicine
影响因子：
9.3
作者：
Xiaoli;Yang F
通讯作者：
Yang F

CDK8-Cyclin C Mediates Nutritional Regulation of Developmental Transitions through the Ecdysone Receptor in Drosophila.

DOI：
10.1371/journal.pbio.1002207
发表时间：
2015-07
期刊：
PLoS biology
影响因子：
9.8
作者：
Xie XJ;Hsu FN;Gao X;Xu W;Ni JQ;Xing Y;Huang L;Hsiao HC;Zheng H;Wang C;Zheng Y;Xiaoli AM;Yang F;Bondos SE;Ji JY
通讯作者：
Ji JY