YY1-mediated transcriptional control of thermogenic-secreted factors in brown fat

 描述(由申请人提供)：YY1介导的棕色脂肪代谢紊乱(如肥胖)中热源性分泌因子的转录控制困扰着数百万美国人，是国家医疗保健系统的重大经济压力。肥胖是卡路里消耗和能量消耗失衡的结果。通过靶向脂肪组织或肌肉中的细胞生物能量来增加能量消耗可能是治疗肥胖症的一条有希望的途径。然而，关于特定组织调节全身能量消耗的细胞机制的基本问题必须首先解决。阴阳1号(YY1)是一种转录因子，通过与过氧化物酶体增殖物激活受体辅活化子1α(PGC-1α)或聚梳组(Polycomb Group，PcG)抑制因子相互作用，调节高代谢组织的产热和氧化代谢，提高线粒体基因表达。我们的初步数据显示，虽然棕色/米色脂肪组织特异性YY1基因敲除小鼠(YY1-Ucp1KO)在棕色脂肪组织(BAT)中表现出生热缺陷，但这些小鼠受到保护，免受饮食诱导的肥胖，并增加了能量消耗；这与GDF15和Bmp8b生热分泌因子的增加是一致的。因此，这些初步结果促使我们研究YY1是如何抑制BAT中的这些分泌因子的，以及识别和表征BMP8b和GDF15靶向的其他组织参与调节全身能量消耗的过程。我们推测这些分泌因子受YY1的直接调控，并可作用于其他代谢组织，增加全身能量消耗，补偿由于YY1缺乏而导致的蝙蝠产热缺陷。这项建议旨在研究YY1如何抑制GDF15和Bmp8b的基因表达，以促进肥胖和减少全身能量消耗。目的1阐明YY1转录复合体调控BAT中GDF15和Bmp8b的机制。我们将研究YY1‘S与已知的抑制基因如PCGS的相互作用，以及可能导致GDF15和Bmp8b基因表达下降的表观遗传组蛋白修饰。此外，我们还将研究YY1在存在生理刺激的情况下的相互作用，如过多的卡路里摄入和寒冷暴露。目的2将在YY1-Ucp1KO小鼠中鉴定和表征GDF15和BMP8b靶向组织，这些组织具有增加的能量消耗，以弥补BAT的部分生热缺陷。一旦我们确定了这些组织，我们将进一步研究GDF15和BMP8b在体外和体内对特定组织类型的获得和功能丧失的影响。这一研究结果将为揭示BAT中YY1转录复合体通过控制分泌因子来调节生物能量能力和全身能量消耗的分子机制提供新的见解。这些结果将在发现潜在的新的治疗靶点和机制方面开辟新的可能性，最终可用于治疗肥胖症及其相关疾病。

 DESCRIPTION (provided by applicant): YY1-mediated transcriptional control of thermogenic-secreted factors in brown fat Metabolic disorders such as obesity afflict millions of Americans and are a significant economic strain on the national healthcare system. Obesity is the result of an imbalance in caloric consumption and energy expenditure. Increasing energy expenditure by targeting cellular bioenergetics in adipose tissue or muscle may be a promising avenue in treating obesity. However, fundamental questions regarding the cellular mechanisms by which specific tissues regulate whole body energy expenditure must first be addressed. Yin- Yang1 (YY1) is a transcription factor that modulates thermogenesis and oxidative metabolism in highly metabolic tissues through interaction with either peroxisome-proliferator-activated receptor coactivator (PGC)- 1alpha to increase mitochondrial gene expression, or with Polycomb Group (PcG) repressors to suppress gene expression. Our preliminary data show that while brown/beige adipose tissue-specific YY1 knockout mice (YY1-Ucp1KO) exhibit a thermogenic deficiency in brown adipose tissue (BAT), these mice are protected from diet-induced obesity and have increased energy expenditure; this is consistent with increases in Gdf15 and Bmp8b thermogenic-secreted factors. Therefore, these preliminary results prompted us to investigate how YY1 suppresses these secreted factors in BAT as well as identifying and characterizing the involvement of other tissues targeted by BMP8b and GDF15 in mediating whole body energy expenditure. We hypothesize that these secreted factors are directly regulated by YY1 and can act on other metabolic tissues to increase whole body energy expenditure, compensating for thermogenic defects in BAT due to YY1 deficiency. This proposal aims to investigate how YY1 suppresses gene expression of Gdf15 and Bmp8b to promote obesity and to decrease whole body energy expenditure. Aim 1 will elucidate the mechanisms whereby the YY1 transcriptional complex regulates Gdf15 and Bmp8b in BAT. We will examine YY1's interactions with known repressors such as PcGs, as well as investigate epigenetic histone modifications that may result in a decrease in Gdf15 and Bmp8b gene expression. Additionally, we will also investigate YY1 interactions in the presence of physiological stimuli such as, excessive caloric intake and cold-exposure. Aim 2 will identify and characterize the GDF15- and BMP8b-targeted tissues in YY1-Ucp1KO mice with increased energy expenditure that compensate for partial thermogenic deficiencies in BAT. Once we have identified these tissues, we will further investigate gain- and loss-of-function effects of GDF15 and BMP8b both in vitro and in vivo for specific tissue types. The results of this proposal will provide new insights into the molecular mechanisms by which YY1 transcriptional complex in BAT regulates bioenergetics capacities and whole body energy expenditure through controlling secreted factors. These outcomes will open up new possibilities in discovering potential novel therapeutic targets and mechanisms that can ultimately be used to treat obesity and its associated disorders.