QianRen Biology
Vol.02 No.02(2015), Article ID:15716,6 pages
10.12677/QRB.2015.22002

Research Progress of Key Factors for the Transformation of Adipose Tissue

Wanlong Zhu1, Jinlong Chen2, Zhengkun Wang1*

1Key Laboratory of Ecological Adaptive Evolution and Conservation on Animals-Plants in Southwest Mountain Ecosystem of Yunnan Province Higher Institutes College, School of Life Sciences of Yunnan Normal University, Kunming Yunnan

2Kunming Haikou Forest Farm, Kunming Yunnan

*通讯作者。

Email: zwl_8307@163.com, *wzk_930@126.com

Received: Jul. 1st, 2015; accepted: Jul. 15th, 2015; published: Jul. 21st, 2015

Copyright © 2014 by authors and Hans Publishers Inc.

This work is licensed under the Creative Commons Attribution International License (CC BY).

http://creativecommons.org/licenses/by/4.0/

ABSTRACT

Adipose tissue is divided into brown adipose tissue (BAT) and white adipose tissue (WAT). BAT was a specialized thermogenic tissue, which was the main site of nonshivering thermogenesis in small mammals. PR domain-containing 16 (PRDM16) was a brown adipose determination factor. It was selectively expressed in BAT and induced the expression of α subunit of peroxisome proliferators-activated receptor-γcoactivator-1 (PGC-1α) and uncoupling protein 1. BMP7 could stimulate brown adipocyte differentiation and enhance thermogenesis by activating the expression PRDM16 and PGC-1α genes. COXII, PPARα and PGC-1α were the key regulatory factors of differentiation and metabolism in brown adipocyte. COXII was an effector molecule of adrenergic pathway in WAT. It was necessary for the formation of brown adipocytes. PPARα expression level in BAT was higher than WAT. It could induce the expression of thermogenesis related genes and promote the generation of primary brown adipocyte. PGC-1α also could induce the formation of brown adipocytes in WAT. In the process of brown adipocytes differentiation, PGC-1α expression level increased. In this paper, the key factors of transformation of adipose tissue were studied, and some prospects for the study of the fat tissue transformation of small mammals were given.

Keywords:Brown Adipose Tissue, White Adipose Tissue, Transformation

脂肪组织转化关键因子的研究进展

朱万龙1,陈金龙2,王政昆1*

1云南师范大学生命科学学院,云南省高校西南山地生态系统动植物生态适应进化及保护重点实验室, 云南 昆明

2昆明市海口林场,云南 昆明

Email: zwl_8307@163.com, *wzk_930@126.com

收稿日期:2015年7月1日;录用日期:2015年7月15日;发布日期:2015年7月21日

摘 要

脂肪组织科分为褐色脂肪组织(Brown adipose tissue, BAT)和白色脂肪组织(white adipose tissue)。BAT为一种特化的产热组织,是小型哺乳动物非颤抖性产热的主要部位。PRDM16 (PR domain-con- taining 16)锌指蛋白在BAT中特异性表达,可触发BAT细胞中PGC-1α (Peroxisome proliferators-ac- tivated receptor-γcoactivator-1)和解偶联蛋白1基因等的表达,是促进褐色脂肪细胞形成的关键调控因子。BMP7 (Bone morphogenetic proteins 7)也可激活PRDM16和PGC-1α等基因的表达,刺激BAT细胞分化及产热增强。COXII (cyclooxygenase-2)、PPARα (peroxisome proliferator-activated receptor α)、PGC-1α是褐色脂肪细胞分化与代谢中的关键调控因子。在WAT中COXII是肾上腺素信号通路的一个效应分子,对于WAT中诱导形成褐色脂肪细胞是必需的。PPARα在BAT中的表达水平高于WAT,能诱导BAT中的产热相关基因的表达及原代褐色脂肪细胞的生成。PGC-1α也能诱导WAT中褐色脂肪细胞的形成,在褐色脂肪细胞分化的过程中PGC-1α表达量上升。本论文对脂肪转化过程中关键因子进行研究,并且对于小型哺乳动物的脂肪转化研究给出一些展望。

关键词 :褐色脂肪组织,白色脂肪组织,转化

1. 引言

哺乳动物体内的脂肪组织主要分为白色脂肪组织(white adipose tissue, WAT)和褐色脂肪组织(brown adipose tissue, BAT) [1] 。白色脂肪细胞脂滴较大,线粒体含量少,褐色脂肪细胞含多个小脂滴,线粒体较为富集。BAT主要以甘油三酯的形式储能,皮下脂肪和内脏脂肪为主要的贮存能量部位,当机体需要能量时输出化学能满足机体对能量的需要。另外,BAT还是一种重要的内分泌器官[2] [3] ,能产生许多信号分子,如抗肿瘤坏死因子a、瘦素(leptin)、脂连素(adiponectin)、抵抗素(resistin)等,在生理或病理条件下,这些信号分子主要或完全由WAT细胞合成并释放,它们在调节能量稳态中起着重要的作用[4] [5] 。BAT则主要在冷刺激下动员脂滴分解以进行适应性产热维持体温[6] 。研究表明,重量为50 g的BAT就能消耗人体20%的基础代谢能量 [7] 。BAT的产热功能受到神经系统的调节。在中枢神经系统中,下丘脑神经能对来自两条不同信号途径进行综合 [8] 。一条是来自皮肤温度感受器的感觉神经途径,这一途径通过位于下丘脑视前区的中间神经元将产热信号传递到下丘脑背中线处的促进产热神经元,从而驱动BAT的非颤抖性产热 [9] ;第二条途径是位于大脑内的温度敏感性神经元负反馈调节途径,这些神经元输出抑制BAT的神经冲动,传出的信号经过脑干中的背旁核,激活运动神经元而刺激颤抖性产热 [10] 。BAT的产热也受到内分泌激素的调节。BAT中的解偶联蛋白UCP1主要受到三碘甲状腺氨酸的调节,其可能是通过甲状腺激素受体中的b-亚单位进行调节的 [1] ,但是关于BAT细胞产热调节的精确分子机制目前仍然并不完全清楚 [11] 。

脂肪细胞分化过程中,伴随着细胞结构、功能和多种蛋白表达水平的改变。脂肪细胞分化是一个高度精细的调控过程,多种转录因子、信号通路在其中发挥着重要作用。脂肪细胞分化过程主要分为两个阶段:第一阶段间充质干细胞分化为脂肪母细胞并进一步形成脂肪细胞前体,第二阶段前体脂肪细胞最终分化为成熟的脂肪细胞 [12] 。褐色脂肪细胞与骨骼肌细胞具有共同的分化来源:Myf5+成肌细胞。PRDM16决定了Myf5+成肌细胞的分化方向。与褐色脂肪细胞不同,白色脂肪组织细胞由脂肪前体细胞分化而来(图1)。另有研究证实,长期的冷刺激会引起WAT中出现能够表达UCP1褐色脂肪细胞,但这些细胞与典型的褐色脂肪细胞不同,并非由Myf5+的细胞分化而来 [13] ,两者在基因表达与分化调控方式上也不相同。

传统的观念认为成年人体内不存在BAT,阻碍了BAT在人类肥胖防治领域的应用 [14] 。2009年相继发表在New England Journal of Medicine的几项研究结果表明成年人体内存在具有功能的BAT [15] [16] ,BAT再次受到研究者的关注。63 g完全活化的人体BAT燃烧的能量相当于4.1 kg WAT [17] 。鉴于BAT强大的耗能能力,有研究人员尝试通过激活或移植BAT的方法,提高肥胖患者的能耗水平,最终达到减肥的目的 [18] 。为了使这些方法得以不断完善,我们需要更加清晰地了解褐色脂肪细胞分化与代谢过程中的调控机制。

2. 脂肪组织转化

2.1. PRDM16

PRDM16是Spiegelman研究组 [7] 在筛选小鼠的转录物时发现的相对分子质量为140 kDa的锌指蛋白,分子中包含两个锌指DNA结合结构域、阻遏物结构域、富含脯氨酸结构域及C末端的酸性结构域[19] ,是一种重要的转录调节因子(图2)。PRDM16主要通过与C末端结合蛋白(C-terminal-binding protein, CtBP) CtBP-1和CtBP-2结合发挥作用。PRDM16与CtBP1/2结合形成的复合物可结合在WAT特异表达的基因的启动子上,抑制其表达;PRDM16结合的CtBP1/2可以被PGC-1置换形成新的复合物,该复合物通过与PPARγ和辅激活因子PGC-1的相互作用,促进线粒体生成,有效的激活褐色脂肪基因的表达 [20] 。PRDM16具有促褐色脂肪细胞分化和抑制白色脂肪细胞分化的双重生理功能 [21] 。褐色脂肪细胞与骨骼肌细胞具有共同的分化来源:Myf5+成肌细胞。研究还发现,PRDM16表达量过低时,褐色脂肪细胞特异基因和产热基因(UCP1、Cidea、PGC-1α等)表达下调,而Myod、Myf6等肌细胞特异基因表达上调,褐色脂肪细胞的分化受到抑制,骨骼肌细胞的分化增强。反之,异位表达PRDM16基因时,褐色脂肪细胞分化能力明显增强 [13] 。PRDM16是决定褐色脂肪细胞形成的关键调控因子。

2.2. BMP7

骨骼形成蛋白BMP是转录生长因子β (transforming growth factor-β, TGF-β)超家族中的成员,具有调控细胞增殖、分化、凋亡等广泛的生物学功能 [22] - [24] 。迄今已发现BMP超过20个成员。BMP家族的不同成员在脂肪细胞生成的过程中发挥着不同的作用。BMP蛋白(BMP2、BMP4、BMP6、BMP7和BMP9)可作为配体首先与具有丝氨酸/苏氨酸激酶活性的II型受体结合,再结合同样具有丝氨酸/苏氨酸激酶活性的I型受体使之磷酸化,以启动下游的Smad蛋白信号通路和MAPK (mitogen activated protein kinase,丝裂原活化蛋白激酶)信号通路,进而调控脂肪细胞的发育 [25] 。在BMP蛋白中众多成员中,仅BMP7能促进褐色脂肪细胞的分化过程中UCP1的表达 [26] 。BMP7通过p38 MAPK和PGC-1依赖性途径激活

Figure 1. The differentiation pathways relevant to adipose tissue [12]

图1. 脂肪组织分化途径(数据引自Birerdinc等,2013) [12]

Figure 2. Structure chart of PRDM16 [19]

图2. PRDM16结构图(数据引自Frühbeck等2009) [19]

UCP1的表达,刺激线粒体生成。BMP7能够促进PRDM16、PGC-1α等基因的表达,激活褐色脂肪细胞形成的程序。研究发现 [26] ,间充质前细胞经BMP7诱导会向褐色脂肪细胞系分化,生脂基因表达上调,将这些细胞移植到小白鼠体内,导致整个脂肪组织大部分由表达UCP1的褐色脂肪细胞构成。BMP7敲除的小鼠仅含少量不表达UCP1的BAT,而BMP7过表达小鼠的BAT含量明显增加。由此可见,BMP7对于褐色脂肪细胞的分化具有重要意义。

2.3. COX-2

前列腺素是由脂肪酸转化而来的,包含一个五元环的结构,由20个碳原子组成 [27] 。COX (cyclooxygenase)是前列腺素生成过程中的限速酶,包括COX-1和COX-2两种同工酶。环氧合酶2 (cyclooxygenase-2, COX-2)能调节整体能量稳态和脂肪组织代谢。研究发现,选择性抑制COX-2的表达,可延缓小鼠的体重减轻程度 [28] ;COX-2部分敲除的小鼠会表现出脂肪积累的现象 [29] 。内脏WAT COX-2 mRNA表达水平的提高,促进WAT合成前列腺素 [30] ,促使WAT中具有产热能力的诱导性BAT的形成 [31] 。Vegiopoulos等人对环氧合酶2的研究结果显示,在WAT中COX-2的过表达能诱导褐色脂肪细胞的分化,增加小鼠的能量消耗 [32] ;同时他们也发现COX-2对WAT中诱导出现的褐色脂肪细胞中UCP1的表达意义重大,UCP1的表达依赖于COX-2 [1] 。COX-2是存在于WAT肾上腺素信号通路中的一个效应分子,对于诱导WAT中褐色脂肪细胞的形成具有极为重要的作用。

2.4. PGC-1α

PGC-1α是PPARγ的辅激活因子,可共活化其他转录因子,能作用于脑、肝脏、骨骼肌、心脏等器官,对生物体能量平衡的调节具有重要作用 [33] 。在褐色脂肪细胞分化的过程中,PGC-1α表达上调 [34] 。冷刺激能诱导褐色脂肪组织中PGC-1α的表达 [35] ,这一过程由PKA-CREB通路所介导 [36] 。对转基因鼠的研究发现,PGC-1α过表达时WAT中出现UCP1表达的褐色脂肪细胞,其它产热基因的表达也相应增强 [37] 。PGC-1α敲除小鼠,褐色脂肪细胞产热基因表达减弱,小鼠冷适应产热能力明显下降 [38] 。由此可知,PGC-1α对于褐色脂肪细胞的分化和代谢有重要的影响。PGC-1α在褐色脂肪组织和白色脂肪组织中的表达主要依赖于cAMP表达,CCAAT增强子结合蛋白(CCAAT/enhancer binding protein, C/EBP)可与PGC-1α启动子区近端的cAMP反应元件结合,促进PGC-1α表达,最终促使白色脂肪细胞向褐色脂肪细胞转换 [39] 。

2.5. PPARα

PPAR是一类以脂肪酸为配体的核受体,目前认为,PPAR包括PPARα、PPARγ和PPARβ/δ。PPARα主要在肝脏中表达,心脏、肾脏和脂肪组织中也存在,它的功能主要是调控脂肪酸的合成 [40] 。PPARγ在脂肪组织中大量表达,能促进脂肪细胞的形成。PPARβ/δ在肌肉、肝脏等代谢旺盛的组织中表达量比较高。研究结果显示,PPARα在褐色脂肪组织中的表达水平高于白色脂肪组织,PPARα配体能诱导原代褐色脂肪细胞和BAT中的UCP1表达 [41] 。PPARα能激活UCP1的启动子,在其辅因子PGC-1的参与下,这一作用能够增加 [42] 。PPARα是BAT分化与代谢中重要的转录因子。

3. 展望

成年人体内具有功能活性的BAT的发现之后,关于BAT的研究越来越成为生物学领域的一个热点问题。对于人类而言,可通过借助小分子药物或生长因子来刺激体内BAT的分化以及体外诱导干细胞分化成褐色脂肪细胞,植入肥胖患者体内两条途径增加褐色脂肪组织含量,从而增加能量消耗,已被视为治疗、预防肥胖及其相关疾病的一个重要策略 [43] 。而对于小型哺乳动物而言,BAT对其能量稳态调节也发挥着至关重要的作用。因此,了解脂肪细胞分化和代谢的调控机制意义重大。

PRDM16和BMP7在褐色脂肪细胞分化过程中具有重要作用[44] ,PPARα、COXII及PGC-1α也是褐色脂肪细胞分化和代谢过程中的关键因子。脂肪细胞分化及其调控的研究已经引起医学界和生物学界的极大兴趣。目前关于脂肪组织已有的研究资料大多来自于啮齿类动物,对PRDM16和BMP7蛋白等褐色脂肪细胞分化过程中转录及辅助因子的生理作用及分子机制的认识,为了解小型哺乳动物生存适应对策提供了一定的基础资料,但是这些研究资料并不全面,研究治疗肥胖症和相对应药物筛选仍受到很大的限制,急需建立可用的人体模型细胞或找到可用的替代灵长类的医学模式动物。将来,BAT的研究将会不断深入,探索安全有效的诱导褐色脂肪细胞分化和WAT中褐色脂肪细胞形成的方法将成为研究的一个新方向,PRDM16和BMP7诱导褐色脂肪细胞分化以及COXII、PGC-1α、PPARα等因子诱导WAT中褐色脂肪细胞生成的策略,将在治疗肥胖方面具有极为重要的潜在医学价值。希望在不久的将来PRDM16、BMP7以及PPARα、COXII及PGC-1α等其他相关因子能在人类肥胖及其相关疾病的治疗中发挥作用。

文章引用

朱万龙,陈金龙,王政昆, (2015) 脂肪组织转化关键因子的研究进展
Research Progress of Key Factors for the Transformation of Adipose Tissue. 千人·生物,02,11-17. doi: 10.12677/QRB.2015.22002

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