運動對棕色脂肪功能的影響及作用機制

付鵬宇，龔麗景，胡 揚

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運動對棕色脂肪功能的影響及作用機制

付鵬宇1，龔麗景2，胡 揚2

1.北京體育大學(xué) 運動人體科學(xué)學(xué)院, 北京 100084; 2. 北京體育大學(xué) 中國運動與健康研究院, 北京 100084

研究綜述了運動對棕色脂肪組織（brown adipose tissue，BAT）功能的影響及其發(fā)揮作用的可能通路機制。隨著肥胖發(fā)病率的日益增加，由此引發(fā)的多種慢性疾病正嚴(yán)重威脅著人類的健康。近年來，BAT以其耗能產(chǎn)熱能力而備受關(guān)注。隨著研究的深入，發(fā)現(xiàn)活化的BAT具有對抗肥胖所致慢性炎癥狀態(tài)和促進(jìn)糖脂代謝的功能，以上特性都使BAT成為對抗肥胖及代謝相關(guān)疾病的新靶點。運動作為減脂降重和預(yù)防慢病的有效手段，其發(fā)揮促進(jìn)健康作用的機制可能與激活BAT有關(guān)。具體作用機制如下：1）運動發(fā)揮促進(jìn)BAT產(chǎn)熱功能可能與VEGF信號通路、PI3K-Akt信號通路、PPAR信號通路有關(guān)；2）發(fā)揮抗炎作用可能與ErbB信號通路、Jak-STAT信號通路、TGF-β信號通路、胰島素信號通路有關(guān)；3）發(fā)揮促進(jìn)糖脂代謝的作用可能與PPAR信號通路、AMPK信號通路、胰島素信號通路有關(guān)。綜上，運動可通過調(diào)控多條信號通路而發(fā)揮促進(jìn)BAT產(chǎn)熱、提高抗炎特性及調(diào)控糖脂代謝變化的作用。

運動；棕色脂肪；產(chǎn)熱；抗炎；糖脂代謝

1 前言

棕色脂肪組織（brown adipose tissue，BAT）可通過非顫抖性產(chǎn)熱調(diào)節(jié)體溫，其多室的棕色脂肪細(xì)胞以含有大量線粒體和高表達(dá)解耦聯(lián)蛋白1（uncoupling protein 1，UCP-1）等特異性基因為特征，在調(diào)節(jié)全身能量平衡中發(fā)揮關(guān)鍵作用，有助于控制肥胖及其相關(guān)疾病的發(fā)展[17,19,32]。BAT在調(diào)控代謝中也發(fā)揮著重要作用，表現(xiàn)在BAT氧化葡萄糖和脂質(zhì)，進(jìn)而調(diào)節(jié)血糖平衡并降低血脂；BAT還有抑制巨噬細(xì)胞炎性特征的能力，可抵抗肥胖所致慢性炎癥狀態(tài)[17]。此外，BAT調(diào)控多囊卵巢綜合征等疾病的研究也逐漸被報道[6,17,24,44]，提示需更加全面地審視BAT的功能。有研究證實，成人體內(nèi)存在有活性BAT[40,43]，且BAT的量和活性會受多種生理狀態(tài)（如性別[11,21]、激素水平[22,42]、肥胖易感性[1,28]、飲食狀況[35]）和外界刺激（如寒冷[46]、低氧環(huán)境[3,7]）的影響[15,30]。運動作為促進(jìn)能量代謝的有效手段，被證明有激活BAT產(chǎn)熱功能的作用[23,45]，但有關(guān)運動對BAT其他功能的研究還少有報道。而對運動調(diào)控BAT功能的探索多集中于白色脂肪棕色化的通路研究，缺少運動直接調(diào)控BAT功能的基因和通路研究。綜上所述，本研究將對運動調(diào)節(jié)BAT功能及其發(fā)揮作用的可能機制進(jìn)行闡述。

2 運動對BAT功能的影響

2.1 運動促進(jìn)BAT產(chǎn)熱

BAT產(chǎn)熱功能通過其線粒體內(nèi)膜上的氧化和ATP生成過程解耦聯(lián)實現(xiàn)[20]。線粒體發(fā)生和功能相關(guān)基因表達(dá)的增加以及募集能力的增強會提高BAT產(chǎn)熱能力，如環(huán)氧化酶-2（cyclooxygenase-2，COX-2）過表達(dá)可通過COX-2-前列腺素（prostaglandin，PG）途徑增加UCP-1含量和BAT產(chǎn)熱，提高基礎(chǔ)代謝率[48]。長期有氧運動可顯著增加BAT質(zhì)量、血流量和氧耗速率，增強線粒體生物發(fā)生、活性和呼吸功能[37,52]；還可上調(diào)諸如UCP-1等BAT特異性基因的表達(dá)，增加與線粒體功能相關(guān)的2型脫碘酶（type 2 deiodinase，DIO2）、細(xì)胞色素氧化酶（cytochrome oxidase）等酶的活性[27]。

2.2 運動促進(jìn)BAT的抗炎功能

4周的中等強度跑臺訓(xùn)練干預(yù)后可以下調(diào)BAT中巨噬細(xì)胞表達(dá)基因1（macrophage expressed gene 1，Mpeg1）、單核細(xì)胞向巨噬細(xì)胞轉(zhuǎn)化基因（monocyte to macrophage differentiation-associated，Mmd）、趨化因子配體28 [chemokine (C-C motif) ligand 28，Ccl28]、白介素-6受體α（interleukin 6 receptor alpha，Il6ra）、腫瘤壞死因子受體超家族成員1b（tumor necrosis factor receptor superfamily member 1b，Tnfrsf1b）和瘦素受體（leptin receptor，Lepr）等由肥胖所上調(diào)的炎癥反應(yīng)和促炎相關(guān)基因，并通過調(diào)節(jié)Janus激酶/信號轉(zhuǎn)導(dǎo)和轉(zhuǎn)錄激活子（Janus kinases signal transducer and activator of transcription, Jak-STAT）、ErbB、轉(zhuǎn)化生長因子-β（transforming growth factor-beta，TGF-β）和胰島素（Insulin）信號通路而促進(jìn)BAT發(fā)揮抵抗肥胖所致的慢性炎癥狀態(tài)的作用[5]。

運動調(diào)控BAT抗炎功能的可能機制在于：1）脂肪酸（fatty acid，F(xiàn)A）釋放可刺激巨噬細(xì)胞的浸潤[29]，而運動可以提高BAT的β氧化能力，使FA在局部的釋放速率減慢[54]；2）運動所誘導(dǎo)的去甲腎上腺素等激素可在重塑BAT免疫細(xì)胞（B細(xì)胞）的表型中發(fā)揮重要作用[38]；3）運動可以抑制BAT中促炎因子的表達(dá)[51]；4）長期適宜強度的運動可以促進(jìn)BAT中氧化系統(tǒng)和抗氧化系統(tǒng)平衡，改善炎癥狀態(tài)[10]。

2.3 運動促進(jìn)BAT的糖脂代謝

運動刺激交感神經(jīng)，誘發(fā)成熟的BAT細(xì)胞釋放去甲腎上腺素，后者與β-腎上腺素能受體結(jié)合后，激活G-蛋白激活腺苷酸環(huán)化酶（adenylyl cyclase，AC），促進(jìn)環(huán)磷酸腺苷（cyclic Adenosine monophosphate，cAMP）、蛋白激酶A（protein kinase A，PKA）和p38分裂原激活的蛋白激酶（mitogen activated protein kinases，MAPK）對脂多糖刺激酶（激素敏感脂肪酶、脂肪三?；视椭久负蛦熙；视椭久福┑募せ钭饔?；同時，運動引起的去甲腎上腺素水平上調(diào)可促進(jìn)BAT細(xì)胞對葡萄糖的攝取，增加BAT的糖代謝能力?？棺栌?xùn)練可激活PI3K/Akt/mTOR/PGC-1α/UCP-1信號通路，增加BAT中Glut4 mRNA和蛋白表達(dá)，促進(jìn)BAT對葡萄糖的攝取，降低血糖，從而改善高脂膳食所致的機體糖耐量和胰島素耐量降低，下調(diào)胰島素抵抗大鼠的Lee’s指數(shù)和體重[2]。脂質(zhì)組學(xué)研究發(fā)現(xiàn)，自由轉(zhuǎn)輪運動可以顯著下調(diào)BAT中甘油三酯（triglyceride，TG）的總豐度及磷脂代謝和脂肪酸生物合成相關(guān)基因的表達(dá)[33]。

3 運動干預(yù)調(diào)控BAT功能的可能機制

運動激活BAT可能由以下過程介導(dǎo)：1）BAT受交感神經(jīng)系統(tǒng)的支配，運動可通過提高交感神經(jīng)興奮性而刺激BAT功能的增強[55]；2）由于BAT與肌細(xì)胞同源，而運動可促進(jìn)肌源性細(xì)胞因子——鳶尾素（Irisin）[18]及β氨基異丁酸（beta aminoisobutyric acid，BAIBA）[41]表達(dá)，且可通過調(diào)節(jié)Irisin（運動-PGC-1α-FNDC5- PPARα軸）和Sirt1信號途徑[39]激活BAT；3）運動可通過對其他組織產(chǎn)生適應(yīng)性改變而提高BAT活性，如運動可促進(jìn)下丘腦腦源性的神經(jīng)營養(yǎng)因子表達(dá)以增強線粒體活性和促進(jìn)血管生成[8]。長期運動可增加小鼠肩胛間BAT前體細(xì)胞募集和增加BAT相對數(shù)量和活性[25,50]。綜上研究，運動可通過激活BAT在促進(jìn)產(chǎn)熱、抑制肥胖所致的慢性炎癥狀態(tài)和增加糖脂代謝方面發(fā)揮著重要作用。本實驗室前期通過mRNA表達(dá)譜芯片研究發(fā)現(xiàn)，運動可通過以下信號通路調(diào)控BAT的不同功能（表1）。

表1 運動調(diào)控BAT功能的信號通路

Table 1 Signaling Pathways for BAT Functions Regulating by Exercise

3.1 運動調(diào)控BAT產(chǎn)熱功能相關(guān)通路

血管內(nèi)皮生長因子B（vascular endothelial cell growth factor B，VEGF-B）大量表達(dá)于BAT，可通過調(diào)節(jié)脂肪酸轉(zhuǎn)運蛋白（fatty acid transport proteins，F(xiàn)ATPs）在血管內(nèi)皮細(xì)胞表達(dá)，增加FA的攝取和代謝[31]。其下游的前列腺素E合酶（prostaglandin E synthase，ptges）和前列腺素I2合酶/環(huán)前列腺素（prostaglandin I2 synthase，ptgis）均為PG家族成員，可抑制白色脂肪細(xì)胞分化，增加BAT細(xì)胞氧耗。運動激活VEGF/COX-2/PG信號通路可提高BAT活性，而其下游的PG(I2)/Ptgir（prostaglandin receptor）/PPARγ信號通路可促進(jìn)間充質(zhì)干細(xì)胞（mesenchymal stem cell，MSC）向BAT細(xì)胞分化，有助于增加機體產(chǎn)熱和能耗[13]。此外，運動還可通過激活VEGF通路下游的PI3K/Akt通路而激活哺乳動物雷帕霉素靶蛋白（mammalian target of rapamycin，mTOR），進(jìn)而通過PPAR通路提高UCP-1的表達(dá)。有氧運動可通過上調(diào)上述這些通路而增強BAT的產(chǎn)熱能力[4]（圖1）。

圖1 運動通過VEGF、PPAR和PI3K-Akt信號通路調(diào)控BAT產(chǎn)熱功能

Figure 1. Exercise Regulates Thermogenesis of BAT by VEGF, PPAR and PI3K-Akt Signaling Pathways

注：圖中紅色部分表示上調(diào)表達(dá)基因，實線箭頭表示直接調(diào)控作用，虛線箭頭表示間接調(diào)控作用，-p表示去磷酸化，下同。

3.2 運動調(diào)控BAT炎癥相關(guān)通路

神經(jīng)調(diào)節(jié)因子-1（Neuregulin1，NRG1）通過與表皮生長因子受體ErbB3/4結(jié)合，介導(dǎo)ErbB2受體活化，進(jìn)一步激活細(xì)胞外調(diào)節(jié)蛋白激酶1/2（extracellular regulated protein kinases，ERK1/2）和/或PI3K（Akt）通路促進(jìn)血管新生[26]，以使促炎因子大量轉(zhuǎn)運至循環(huán)系統(tǒng)，加劇機體代謝性病變的進(jìn)程。促炎因子IL-6與其受體結(jié)合后，激活JAK激酶，通過JAK-STAT通路參與機體的炎癥反應(yīng)[47]，細(xì)胞因子信號轉(zhuǎn)導(dǎo)抑制因子-3（suppressor of cytokine signaling 3，SOCS-3）是JAK-STAT下游的基因，SOCS-3過表達(dá)可參與瘦素抵抗的發(fā)生。轉(zhuǎn)化生長因子-β（transforming growth factor-β，TGF-β）在炎癥介質(zhì)（IL、NF-κB）及活性氧（reactive oxygen species，ROS）作用下被激活上調(diào)，發(fā)揮調(diào)控炎癥細(xì)胞、參與免疫反應(yīng)的作用[12]。Smad在TGF-β/Smad通路中作為負(fù)反饋調(diào)節(jié)信號[9]，可單獨發(fā)揮抑制巨噬細(xì)胞標(biāo)記基因的作用。飽和FA作為一種炎癥介質(zhì)，可激活脂肪組織巨噬細(xì)胞中的NF-κB，提高炎癥和胰島素抵抗水平，破壞Insulin信號通路[36]。運動可通過上調(diào)BAT中Insulin信號通路和下調(diào)Jak-STAT、ErbB、TGF-β信號通路而發(fā)揮抗炎作用（圖2）。

圖2 運動通過ErbB、Jak-STAT、TGF-β和Insulin信號通路調(diào)控BAT抗炎功能

Figure 2. Exercise Regulates Anti-inflammatory Function of BAT by ErbB, Jak-STAT, TGF-β and INSULIN Signaling Pathways

注：圖中藍(lán)色部分表示下調(diào)表達(dá)基因；+p表示磷酸化；/表示抑制作用，下同。

3.3 運動調(diào)控BAT糖脂代謝功能相關(guān)通路

PPARγ對BAT功能的影響表現(xiàn)為調(diào)節(jié)其細(xì)胞分化成熟和產(chǎn)熱，促進(jìn)脂質(zhì)分解，增加BAT的產(chǎn)熱原料[14]，而運動可促進(jìn)脂肪酸結(jié)合蛋白5（fatty acid binding protein 5，F(xiàn)abp5）-PPARβ/γ信號通路上調(diào)，促進(jìn)脂代謝，維持能量平衡[16,53]。AMPK可促進(jìn)BAT對FA的攝取和氧化，調(diào)節(jié)脂解作用并增加產(chǎn)熱，抑制AMPK表達(dá)會阻止BAT細(xì)胞正常分化[34]，運動可通過調(diào)控AMPK-Acaca/Fans途徑促進(jìn)BAT合成，Insulin通路在BAT維持葡萄糖穩(wěn)態(tài)方面發(fā)揮著重要的作用，運動通過激活BAT中Insulin通路可顯著提高葡萄糖清除能力和胰島素敏感性[49]，而使BAT更高效地獲取葡萄糖用于產(chǎn)熱。運動可通過上調(diào)PPAR、AMPK和Insulin信號通路提高BAT中糖脂代謝相關(guān)基因長鏈酰基輔酶A合成酶家族成員5（acyl-CoA synthetase long-chain family member 5，Acsl5）、脂肪酸合成酶（fatty acid synthase，F(xiàn)asn）、乙酰輔酶A羧化酶α（acetyl-Coenzyme A carboxylase alpha，Acaca）、1,6-二磷酸果糖酶1（fructose bisphosphatase 1，F(xiàn)bp1）的表達(dá)，而調(diào)控糖脂代謝能力[4]（圖3）。

圖3 運動通過PPAR、AMPK和Insulin信號通路調(diào)控BAT糖脂代謝功能

Figure 3. Exercise Regulates Glycolipid Metabolism Function of BAT by PPAR, AMPK and Insulin Signaling Pathways

4 小結(jié)與展望

研究BAT功能及運動適應(yīng)機制，可為治療肥胖及其所引發(fā)的慢性炎癥狀態(tài)、糖脂代謝紊亂提供新的研究靶點。但BAT的功能受多種因素的調(diào)控，不同的生理病理狀態(tài)和不同的環(huán)境刺激都會對BAT產(chǎn)生不同的影響，需要進(jìn)一步探究不同的運動形式及運動方案對BAT活性及功能的影響。

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The Effect of Exercise on Function of Brown Adipose Tissue and Its Mechanism

FU Peng-yu1，GONG Li-jing2，HU Yang2

1.Beijing Sport University, College of Sports Human Sciences, Beijing 100084, China; 2.Beijing Sport University, China Institute of Sport and Health Science, Beijing 100084, China.

This study elaborates the effect of exercise on the function of brown adipose tissue (BAT) and its possible pathway mechanism. The incidence of obesity is increasing and induce many chronic diseases, which is seriously threatening human health. In recent years, the thermogenesis and energy consumption characteristics of BAT has made it widely concerned. With the deepening of research, it was found that activated BAT also has the function of combating the chronic inflammatory state and promoting glycolipid metabolism caused by obesity. All of these make it a new target against obesity and metabolic related diseases. Exercise, as an effective means of reducing fat and weight and preventing chronic diseases, may play a role in promoting health by activating BAT. The specific mechanisms are as follows: Exercise promoting the thermogenesis function of BAT may be related to VEGF signaling pathway, PI3K-Akt signaling pathway and PPAR signaling pathway; The function of combating the chronic inflammatory state may be related to ErbB signaling pathway, Jak-STAT signaling pathway, TGF-beta signaling pathway and insulin signaling pathway; The function of regulating glycolipid metabolism may be related to PPAR signaling pathway, AMPK signaling pathway and insulin signaling pathway. In conclusion, exercise can promote thermogenesis of BAT, improve anti-inflammatory properties and regulate glycolipid metabolism by regulating multiple signaling pathways.

G804.7

A

1000-677X(2018)11-0092-06

10.16469/j.css.201811010

2017-11-07；

2018-10-29

中央高?；究蒲袠I(yè)務(wù)費專項資金資助課題(2016YB037)。

付鵬宇,女,在讀博士研究生,主要研究方向為運動生物化學(xué), E-mail:1402884452@qq.com。

龔麗景,女,實驗師,博士,主要研究方向為運動與脂肪代謝、低氧與胃腸道,E-mail:lijing.gong@bsu.edu.cn。