脂肪細胞生成

脂肪細胞生成(英語:Adipogenesis)是從幹細胞形成的脂肪細胞[1]它涉及兩個階段,分化確定和終末分化。分化確定是間充質幹細胞致力於脂肪細胞前體細胞,也稱為前脂肪細胞,它們失去了分化為其他類型細胞如軟骨細胞肌細胞成骨細胞的潛力。[2]終末分化是前脂肪細胞分化成為成熟的脂肪細胞。脂肪細胞生成可以來自脂肪組織中的前脂肪細胞,也可以來自遷移到脂肪組織的源於骨髓祖細胞[3]

油紅O染色的分化脂肪細胞。

簡介

脂肪細胞在能量穩態中起着至關重要的作用,並在動物體內處理最大的能量儲備,三酸甘油酯[4]脂肪細胞處於動態狀態,當能量攝入高於消耗時它們會開始擴張,而當能量消耗高於攝入時它們會進行運動。這個過程中會受到反調節激素的高度調節,脂肪細胞是非常敏感的。激素如胰島素會促進擴張,而反激素如腎上腺素胰高血糖素ACTH則會促進運動。脂肪細胞生成是一個嚴格調節的細胞分化過程,其中間充質幹細胞致力於前脂肪細胞和前脂肪細胞分化成脂肪細胞。細胞分化是基因傳達模式的改變,多能基因傳達改變為細胞類型特異性基因傳達。因此,轉錄因子對於脂肪細胞生成至關重要。過氧化物酶體增殖物活化受體γ(PPARγ)和CCAAT增強子結合蛋白(C/EBPs)是脂肪生成的主要的調節因子。[5]與其他譜系的細胞相比,脂肪細胞的體外分化是真實的,並概括了體內分化的大部分特徵。分化的脂肪細胞的主要特徵是生長停滯、形態變化、脂肪生成基因的高表達和脂肪細胞因子的產生,如脂聯素瘦素抵抗素(在老鼠中,而不是人類)和腫瘤壞死因子-α

分化

體外分化研究使用了預先確定的前脂肪細胞譜系,例如3T3-L1和3T3-F442A細胞系,或從白色脂肪組織的基質血管部分分離的前脂肪細胞。體外分化是一個高度有序的過程。首先,增殖的前脂肪細胞通常會通過接觸抑制來阻止生長。生長停滯會在最早的事件(包括前脂肪細胞從成纖維細胞形狀到圓形的形態變化以及轉錄因子C/EBPβC/EBPδ的誘導)之後出現。生長停滯的第二階段是兩個關鍵轉錄因子PPARγ和C/EBPα的表達,它們促進賦予成熟脂肪細胞特徵的基因表達。這些基因包括脂肪細胞蛋白(aP2)、胰島素受體磷酸甘油脫氫酶脂肪酸合酶乙酰輔酶A羧化酶葡萄糖轉運蛋白4型(Glut 4)等。[6]通過這個過程,脂滴在脂肪細胞中積累。然而,前脂肪細胞細胞系難以分化成脂肪細胞。前脂肪細胞顯示CD45- CD31- CD34+ CD29+ SCA1+ CD24+ 表面標誌物可以在體內增殖和分化為脂肪細胞。[7]

體外分化模型

細胞系 來源 分化協議
定型脂肪細胞Committed Pre-adipocytes
3T3-L1 Swiss 3T3的亞克隆[8] FBS+I+D+M
3T3-F442A Swiss 3T3的亞克隆[9] FBS+I
Ob17 C57BL/6J肥胖型老鼠附睾脂肪墊的分化脂肪細胞[10] FBS+I+T3
TA1 C3H10T1/2的亞克隆[11] FBS+D+I
30A5 C3H10T1/2的亞克隆[12] FBS+D+M+I
1246 CH3老鼠畸胎癌細胞系T984的成脂亞克隆[13] D+M+I
非定型脂肪生成潛力Non-committed with adipogenic potential
NIH 3T3 NIH瑞士老鼠胚胎細胞[14] PPAR-γ的異位表達,C/EBP-α或C/EBP-β+D+M+I
Swiss 3T3 瑞士老鼠胚胎細胞[15] C/EBP-α的異位表達
Balb/3T3 Balb/c老鼠胚胎細胞[16] C/EBP-α的異位表達
C3H 10T1/2 C3H小鼠胚胎細胞[17] PPAR-γ配體
Kusa 4b10 老鼠骨髓基質細胞系[18] FBS+I+D+M
C2C12 C3H老鼠的大腿肌肉[19] 噻唑烷二酮類
G8 瑞士韋伯斯特老鼠胎兒的後肢肌肉[20] PPAR-γ的異位表達+C/EBP-α+D+I
FBS=胎牛血清,D=地塞米松I=胰島素,M=3-異丁基-1-甲基黃嘌呤,T3=三碘甲狀腺原氨酸

轉錄調控

過氧化物酶體增殖物活化受體γ(PPARγ)

PPARγ是核受體超家族的成員,是脂肪細胞生成的主要調節劑。PPARγ與維甲酸X受體(RXR)異二聚化,然後與DNA結合,從而激活下游基因的啟動子。PPARγ誘導脂肪細胞特異性基因,包括脂肪細胞蛋白(aP2)、脂聯素磷酸烯醇丙酮酸羧化激酶(PEPCK)。PPARγ激活對成熟脂肪細胞特徵的幾個方面有影響,例如形態變化、脂質積累和胰島素敏感性的獲得。[21]PPARγ是必要的並且足以促進脂肪細胞分化。PPARγ是胚胎幹細胞(ES細胞)分化為脂肪細胞所必需的。[22]PPARγ本身的表達足以在體外將成纖維細胞轉化為脂肪細胞。[23]其他促脂肪因子如C/EBPs和Kruppel樣轉錄因子家族(KLFs)已被證明可誘導PPARγ啟動子。此外,還需要PPARγ來維持表徵成熟脂肪細胞的基因的表達。[24]噻唑烷二酮類(TZDs)是一種抗糖尿病藥物,在體外很好地使用了分化混合物,促進了PPARγ的活性。

CCAAT增強子結合蛋白(C/EBPs)

C/EBPs,一種轉錄因子,是鹼性亮氨酸拉鏈類的成員。環腺苷酸(cAMP)是脂肪細胞生成的誘導劑,可促進C/EBPβ和C/EBPδ的表達。[25]在分化的早期階段,C/EBPβ和C/EBPδ的mRNA和蛋白質水平的短暫增加被認為會激活脂肪生成轉錄因子PPARγ和C/EBPα。PPARγ和C/EBPα可以反饋誘導彼此及其下游基因的表達。[26]C/EBPα在脂肪細胞的胰島素敏感性中也起重要作用。[27]然而,C/EBPγ抑制分化,這可能是由於C/EBPβ 失活所致。

轉錄級聯

儘管PPARγ和C/EBPα是脂肪細胞生成的主要調節因子,但其他轉錄因子在分化進程中也起作用。脂肪細胞定向和分化因子1(ADD1)與甾醇調節元件結合蛋白1(SREBP1)可以通過產生內源性PPARγ配體激活PPARγ或直接促進PPARγ的表達。cAMP反應元件結合蛋白促進分化,而PPARγ和C/EBPα的激活也對負調節有反應。cAMP響應元件結合蛋白促進分化,而PPARγ和C/EBPα的激活也對負調節有反應。T細胞因子/淋巴增強因子家族(TCF/LEF)、[28]GATA2/3、[29]維甲酸受體α[30]和SMAD6/7[31]不影響C/EBPβ和C/EBPδ但抑制PPARγ和C/EBPα的感應。

其他調控

內分泌系統的產物如胰島素IGF-1環腺苷酸糖皮質激素三碘甲狀腺原氨酸可有效誘導前脂肪細胞的脂肪細胞生成。[32][33][34]

胰島素和胰島素樣生長因子1(IGF1)

胰島素通過胰島素樣生長因子1(IGF1)受體信號傳導調節脂肪細胞生成。胰島素或IGF1促進調節終末分化的誘導轉錄因子。

Wnt信號通路

Wnt或β-連環蛋白信號通過促進間充質幹細胞分化為肌細胞和骨細胞但阻斷對脂肪細胞譜系的分化來抑制脂肪生成。[35]Wnt或β-連環蛋白通過抑制PPARγ和C/EBPα的感應來抑制前脂肪細胞的分化。

骨塑型蛋白(BMPs)

骨塑型蛋白(BMPs)是轉化生長因子β(TGFβ)超家族成員。BMPs可以刺激多能細胞的分化確定或是通過不同的受體異二聚提誘導成骨。[36]BMPs還促進前脂肪細胞的分化。

衰老細胞

已顯示皮下脂肪組織中的衰老脂肪祖細胞抑制脂肪形成分化。[37]肥胖者的脂肪細胞生成減少是由於脂肪組織中的衰老細胞增加,而不是幹細胞祖細胞數量減少。[38]

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外部連結