跳转到内容

脂肪细胞生成

维基百科,自由的百科全书
油红O染色的分化脂肪细胞。

脂肪细胞生成(英语:Adipogenesis)是从干细胞形成的脂肪细胞[1]它涉及两个阶段,分化确定和终末分化。分化确定是间充质干细胞致力于脂肪细胞前体细胞,也称为前脂肪细胞,它们失去了分化为其他类型细胞如软骨细胞肌细胞成骨细胞的潜力。[2]终末分化是前脂肪细胞分化成为成熟的脂肪细胞。脂肪细胞生成可以来自脂肪组织中的前脂肪细胞,也可以来自迁移到脂肪组织的源于骨髓祖细胞[3]

简介

脂肪细胞在能量稳态中起着至关重要的作用,并在动物体内处理最大的能量储备,甘油三酯[4]脂肪细胞处于动态状态,当能量摄入高于消耗时它们会开始扩张,而当能量消耗高于摄入时它们会进行运动。这个过程中会受到反调节激素的高度调节,脂肪细胞是非常敏感的。激素如胰岛素会促进扩张,而反激素如肾上腺素胰高血糖素ACTH则会促进运动。脂肪细胞生成是一个严格调节的细胞分化过程,其中间充质干细胞致力于前脂肪细胞和前脂肪细胞分化成脂肪细胞。细胞分化是基因传达模式的改变,多能基因传达改变为细胞类型特异性基因传达。因此,转录因子对于脂肪细胞生成至关重要。过氧化物酶体增殖物活化受体γ(PPARγ)和CCAAT增强子结合蛋白(C/EBPs)是脂肪生成的主要的调节因子。[5]与其他谱系的细胞相比,脂肪细胞的体外分化是真实的,并概括了体内分化的大部分特征。分化的脂肪细胞的主要特征是生长停滞、形态变化、脂肪生成基因的高表达和脂肪细胞因子的产生,如脂联素瘦素抵抗素(在老鼠中,而不是人类)和肿瘤坏死因子-α

分化

体外分化研究使用了预先确定的前脂肪细胞谱系,例如3T3-L1和3T3-F442A细胞系,或从白色脂肪组织的基质血管部分分离的前脂肪细胞。体外分化是一个高度有序的过程。首先,增殖的前脂肪细胞通常会通过接触抑制来阻止生长。生长停滞会在最早的事件(包括前脂肪细胞从成纤维细胞形状到圆形的形态变化以及转录因子C/EBPβC/EBPδ的诱导)之后出现。生长停滞的第二阶段是两个关键转录因子PPARγ和C/EBPα的表达,它们促进赋予成熟脂肪细胞特征的基因表达。这些基因包括脂肪细胞蛋白(aP2)、胰岛素受体磷酸甘油脱氢酶脂肪酸合酶乙酰辅酶A羧化酶葡萄糖转运蛋白4型(Glut 4)等。[6]通过这个过程,脂滴在脂肪细胞中积累。然而,前脂肪细胞细胞系难以分化成脂肪细胞。前脂肪细胞显示CD45- CD31- CD34+ CD29+ SCA1+ CD24+ 表面标志物可以在体内增殖和分化为脂肪细胞。[7]

体外分化模型

细胞系 来源 分化协议
定型脂肪细胞Committed Pre-adipocytes
3T3-L1 Swiss 3T3的亚克隆[8] FBS+I+D+M
3T3-F442A Swiss 3T3的亚克隆[9] FBS+I
Ob17 C57BL/6J肥胖型老鼠附睾脂肪垫的分化脂肪细胞[10] FBS+I+T3
TA1 C3H10T1/2的亚克隆[11] FBS+D+I
30A5 C3H10T1/2的亚克隆[12] FBS+D+M+I
1246 CH3老鼠畸胎癌细胞系T984的成脂亚克隆[13] D+M+I
非定型脂肪生成潜力Non-committed with adipogenic potential
NIH 3T3 NIH瑞士老鼠胚胎细胞[14] PPAR-γ的异位表达,C/EBP-α或C/EBP-β+D+M+I
Swiss 3T3 瑞士老鼠胚胎细胞[15] C/EBP-α的异位表达
Balb/3T3 Balb/c老鼠胚胎细胞[16] C/EBP-α的异位表达
C3H 10T1/2 C3H小鼠胚胎细胞[17] PPAR-γ配体
Kusa 4b10 老鼠骨髓基质细胞系[18] FBS+I+D+M
C2C12 C3H老鼠的大腿肌肉[19] 噻唑烷二酮类
G8 瑞士韦伯斯特老鼠胎儿的后肢肌肉[20] PPAR-γ的异位表达+C/EBP-α+D+I
FBS=胎牛血清,D=地塞米松I=胰岛素,M=3-异丁基-1-甲基黄嘌呤,T3=三碘甲状腺原氨酸

转录调控

过氧化物酶体增殖物活化受体γ(PPARγ)

PPARγ是核受体超家族的成员,是脂肪细胞生成的主要调节剂。PPARγ与维甲酸X受体(RXR)异二聚化,然后与DNA结合,从而激活下游基因的启动子。PPARγ诱导脂肪细胞特异性基因,包括脂肪细胞蛋白(aP2)、脂联素磷酸烯醇丙酮酸羧化激酶(PEPCK)。PPARγ激活对成熟脂肪细胞特征的几个方面有影响,例如形态变化、脂质积累和胰岛素敏感性的获得。[21]PPARγ是必要的并且足以促进脂肪细胞分化。PPARγ是胚胎干细胞(ES细胞)分化为脂肪细胞所必需的。[22]PPARγ本身的表达足以在体外将成纤维细胞转化为脂肪细胞。[23]其他促脂肪因子如C/EBPs和Kruppel样转录因子家族(KLFs)已被证明可诱导PPARγ启动子。此外,还需要PPARγ来维持表征成熟脂肪细胞的基因的表达。[24]噻唑烷二酮类(TZDs)是一种抗糖尿病药物,在体外很好地使用了分化混合物,促进了PPARγ的活性。

CCAAT增强子结合蛋白(C/EBPs)

C/EBPs,一种转录因子,是碱性亮氨酸拉链类的成员。环腺苷酸(cAMP)是脂肪细胞生成的诱导剂,可促进C/EBPβ和C/EBPδ的表达。[25]在分化的早期阶段,C/EBPβ和C/EBPδ的mRNA和蛋白质水平的短暂增加被认为会激活脂肪生成转录因子PPARγ和C/EBPα。PPARγ和C/EBPα可以反馈诱导彼此及其下游基因的表达。[26]C/EBPα在脂肪细胞的胰岛素敏感性中也起重要作用。[27]然而,C/EBPγ抑制分化,这可能是由于C/EBPβ 失活所致。

转录级联

尽管PPARγ和C/EBPα是脂肪细胞生成的主要调节因子,但其他转录因子在分化进程中也起作用。脂肪细胞定向和分化因子1(ADD1)与甾醇调节元件结合蛋白1(SREBP1)可以通过产生内源性PPARγ配体激活PPARγ或直接促进PPARγ的表达。cAMP反应元件结合蛋白促进分化,而PPARγ和C/EBPα的激活也对负调节有反应。cAMP响应元件结合蛋白促进分化,而PPARγ和C/EBPα的激活也对负调节有反应。T细胞因子/淋巴增强因子家族(TCF/LEF)、[28]GATA2/3、[29]维甲酸受体α[30]和SMAD6/7[31]不影响C/EBPβ和C/EBPδ但抑制PPARγ和C/EBPα的感应。

其他调控

内分泌系统的产物如胰岛素IGF-1环腺苷酸糖皮质激素三碘甲状腺原氨酸可有效诱导前脂肪细胞的脂肪细胞生成。[32][33][34]

胰岛素和胰岛素样生长因子1(IGF1)

胰岛素通过胰岛素样生长因子1(IGF1)受体信号传导调节脂肪细胞生成。胰岛素或IGF1促进调节终末分化的诱导转录因子。

Wnt信号通路

Wnt或β-连环蛋白信号通过促进间充质干细胞分化为肌细胞和骨细胞但阻断对脂肪细胞谱系的分化来抑制脂肪生成。[35]Wnt或β-连环蛋白通过抑制PPARγ和C/EBPα的感应来抑制前脂肪细胞的分化。

骨塑型蛋白(BMPs)

骨塑型蛋白(BMPs)是转化生长因子β(TGFβ)超家族成员。BMPs可以刺激多能细胞的分化确定或是通过不同的受体异二聚提诱导成骨。[36]BMPs还促进前脂肪细胞的分化。

衰老细胞

已显示皮下脂肪组织中的衰老脂肪祖细胞抑制脂肪形成分化。[37]肥胖者的脂肪细胞生成减少是由于脂肪组织中的衰老细胞增加,而不是干细胞祖细胞数量减少。[38]

参考文献

  1. ^ Definition of ADIPOGENESIS. www.merriam-webster.com. [2022-09-17]. (原始内容存档于2022-09-22) (英语). 
  2. ^ Gregoire, Francine M.; Smas, Cynthia M.; Sul, Hei Sook. Understanding Adipocyte Differentiation. Physiological Reviews. 1998-01-07, 78 (3) [2022-09-17]. ISSN 0031-9333. doi:10.1152/physrev.1998.78.3.783. (原始内容存档于2022-09-22). 
  3. ^ Hausman, Gary J.; Hausman, Dorothy B. Search for the preadipocyte progenitor cell. Journal of Clinical Investigation. 2006-12-01, 116 (12) [2022-09-17]. ISSN 0021-9738. PMC 1679717可免费查阅. PMID 17143324. doi:10.1172/JCI30666. (原始内容存档于2022-09-20). 
  4. ^ Cornelius, P; MacDougald, O A; Lane, M D. Regulation of Adipocyte Development. Annual Review of Nutrition. 1994-07, 14 (1) [2022-09-17]. ISSN 0199-9885. doi:10.1146/annurev.nu.14.070194.000531. (原始内容存档于2022-09-22) (英语). 
  5. ^ Rosen, Evan D.; MacDougald, Ormond A. Adipocyte differentiation from the inside out. Nature Reviews Molecular Cell Biology. 2006-12, 7 (12) [2022-09-17]. ISSN 1471-0080. doi:10.1038/nrm2066. (原始内容存档于2022-10-12) (英语). 
  6. ^ Rosen, Evan D.; Walkey, Christopher J.; Puigserver, Pere; Spiegelman, Bruce M. Transcriptional regulation of adipogenesis. Genes & Development. 2000-06-01, 14 (11) [2022-09-18]. ISSN 0890-9369. PMID 10837022. doi:10.1101/gad.14.11.1293. (原始内容存档于2022-09-22) (英语). 
  7. ^ Rodeheffer, Matthew S.; Birsoy, Kıvanç; Friedman, Jeffrey M. Identification of White Adipocyte Progenitor Cells In Vivo. Cell. 2008-10-17, 135 (2) [2022-09-18]. ISSN 0092-8674. doi:10.1016/j.cell.2008.09.036. (原始内容存档于2016-05-07) (English). 
  8. ^ Green, Howard; Kehinde, Olaniyi. Sublines of mouse 3T3 cells that accumulate lipid. Cell. 1974-03-01, 1 (3). ISSN 0092-8674. doi:10.1016/0092-8674(74)90126-3 (English). 
  9. ^ Green, Howard; Kehinde, Olanlyl. Spontaneous heritable changes leading to increased adipose conversion in 3T3 cells. Cell. 1976-01-01, 7 (1). ISSN 0092-8674. PMID 949738. doi:10.1016/0092-8674(76)90260-9 (English). 
  10. ^ Négrel, R.; Grimaldi, P.; Ailhaud, G. Establishment of preadipocyte clonal line from epididymal fat pad of ob/ob mouse that responds to insulin and to lipolytic hormones. Proceedings of the National Academy of Sciences of the United States of America. 1978-12, 75 (12) [2022-09-18]. ISSN 0027-8424. PMID 216011. (原始内容存档于2022-09-22). 
  11. ^ Chapman AB, Knight DM, Dieckmann BS, Ringold GM. Analysis of Gene Expression during Differentiationf Adipogenic Cells in Culture and Hormonal Control of the Developmental Program*. The Journal of Biological Chemistry: 15548–55. December 1984. PMID 6392298. doi:10.1016/S0021-9258(17)42583-X. 
  12. ^ Effect of Tumor Necrosis Factor on Acetyl-Coenzyme A Carboxylase Gene Expression and Preadipocyte Differentiation. academic.oup.com. [2022-09-18]. (原始内容存档于2022-09-22). 
  13. ^ Darmon, Michel; Serrero, Ginette; Rizzino, Angie; Sato, Gordon. Isolation of myoblastic, fibro-adipogenic, and fibroblastic clonal cell lines from a common precursor and study of their requirements for growth and differentiation. Experimental Cell Research. 1981-04-01, 132 (2). ISSN 0014-4827. doi:10.1016/0014-4827(81)90107-5 (英语). 
  14. ^ Jainchill, John L.; Aaronson, Stuart A.; Todaro, George J. Murine Sarcoma and Leukemia Viruses: Assay Using Clonal Lines of Contact-Inhibited Mouse Cells. Journal of Virology. 1969-11, 4 (5) [2022-09-18]. ISSN 0022-538X. PMID 4311790. (原始内容存档于2022-09-21). 
  15. ^ Todaro, George J.; Green, Howard. QUANTITATIVE STUDIES OF THE GROWTH OF MOUSE EMBRYO CELLS IN CULTURE AND THEIR DEVELOPMENT INTO ESTABLISHED LINES. The Journal of Cell Biology. 1963-05-01, 17 (2) [2022-09-18]. ISSN 0021-9525. PMC 2106200可免费查阅. PMID 13985244. (原始内容存档于2022-09-22). 
  16. ^ Aaronson, Stuart A.; Todaro, George J. Development of 3T3-like lines from Balb/c mouse embryo cultures: Transformation susceptibility to SV40. Journal of Cellular Physiology. 1968-10, 72 (2) [2022-09-18]. ISSN 0021-9541. doi:10.1002/jcp.1040720208. (原始内容存档于2022-09-22) (英语). 
  17. ^ Reznikoff, C. A.; Brankow, D. W.; Heidelberger, C. Establishment and characterization of a cloned line of C3H mouse embryo cells sensitive to postconfluence inhibition of division. Cancer Research. 1973-12, 33 (12) [2022-09-18]. ISSN 0008-5472. PMID 4357355. (原始内容存档于2022-09-22). 
  18. ^ Allan, Elizabeth H; Häusler, Karl D; Wei, Tao; Gooi, Jonathan H; Quinn, Julian MW; Crimeen-Irwin, Blessing; Pompolo, Sueli; Sims, Natalie A; Gillespie, Matthew T; Onyia, Jude E; Martin, T John. EphrinB2 Regulation by PTH and PTHrP Revealed by Molecular Profiling in Differentiating Osteoblasts. Journal of Bone and Mineral Research. 2008-03-24, 23 (8). doi:10.1359/jbmr.080324 (英语). 
  19. ^ Yaffe, David; Saxel, Ora. Serial passaging and differentiation of myogenic cells isolated from dystrophic mouse muscle. Nature. 1977-12, 270 (5639) [2022-09-18]. ISSN 1476-4687. doi:10.1038/270725a0. (原始内容存档于2022-09-22) (英语). 
  20. ^ Christian, C. N.; Nelson, P. G.; Peacock, J.; Nirenberg, M. Synapse Formation Between Two Clonal Cell Lines. Science. 1977-05-27, 196 (4293) [2022-09-18]. ISSN 0036-8075. doi:10.1126/science.193191. (原始内容存档于2022-09-22) (英语). 
  21. ^ Terjung, Ronald (编). Comprehensive Physiology. Transcriptional Regulation of Adipogenesis 1. Wiley. 2011-01-17 [2022-09-19]. ISBN 978-0-470-65071-4. doi:10.1002/cphy.c160022. (原始内容存档于2022-11-12) (英语). 
  22. ^ Rosen, Evan D.; Sarraf, Pasha; Troy, Amy E.; Bradwin, Gary; Moore, Kathryn; Milstone, David S.; Spiegelman, Bruce M.; Mortensen, Richard M. PPARγ Is Required for the Differentiation of Adipose Tissue In Vivo and In Vitro. Molecular Cell. 1999-10-01, 4 (4). ISSN 1097-2765. PMID 10549292. doi:10.1016/S1097-2765(00)80211-7 (English). 
  23. ^ Tontonoz, Peter; Hu, Erding; Spiegelman, Bruce M. Stimulation of adipogenesis in fibroblasts by PPARγ2, a lipid-activated transcription factor. Cell. 1994-12-30, 79 (7). ISSN 0092-8674. PMID 8001151. doi:10.1016/0092-8674(94)90006-X (English). 
  24. ^ Role of Peroxisome Proliferator-Activated Receptor-γ in Maintenance of the Characteristics of Mature 3T3-L1 Adipocytes. diabetesjournals.org. [2022-09-19]. (原始内容存档于2022-11-03). 
  25. ^ Cao Z, Umek RM, McKnight SL. Regulated expression of three C/EBP isoforms during adipose conversion of 3T3-L1 cells. Genes & Development. September 1991, 5 (9): 1538–52. PMID 1840554. doi:10.1101/gad.5.9.1538可免费查阅. 
  26. ^ MacDougald, Ormond A.; Mandrup, Susanne. Adipogenesis: forces that tip the scales. Trends in Endocrinology & Metabolism. 2002-01-01, 13 (1) [2022-09-19]. ISSN 1043-2760. PMID 11750856. doi:10.1016/S1043-2760(01)00517-3. (原始内容存档于2013-10-12) (English). 
  27. ^ Wu, Zhidan; Rosen, Evan D.; Brun, Regina; Hauser, Stefanie; Adelmant, Guillaume; Troy, Amy E.; McKeon, Catherine; Darlington, Gretchen J.; Spiegelman, Bruce M. Cross-Regulation of C/EBPα and PPARγ Controls the Transcriptional Pathway of Adipogenesis and Insulin Sensitivity. Molecular Cell. 1999-02-01, 3 (2). ISSN 1097-2765. PMID 10078198. doi:10.1016/S1097-2765(00)80306-8 (English). 
  28. ^ Ross, Sarah E.; Hemati, Nahid; Longo, Kenneth A.; Bennett, Christina N.; Lucas, Peter C.; Erickson, Robin L.; MacDougald, Ormond A. Inhibition of Adipogenesis by Wnt Signaling. Science. 2000-08-01, 289 [2022-09-20]. ISSN 0036-8075. doi:10.1126/science.289.5481.950. (原始内容存档于2022-09-22). 
  29. ^ Tong, Qiang; Dalgin, Gökhan; Xu, Haiyan; Ting, Chao-Nan; Leiden, Jeffrey M.; Hotamisligil, Gökhan S. Function of GATA Transcription Factors in Preadipocyte-Adipocyte Transition. Science. 2000-10-01, 290 [2022-09-20]. ISSN 0036-8075. doi:10.1126/science.290.5489.134. (原始内容存档于2022-09-20). 
  30. ^ Schwarz, E J; Reginato, M J; Shao, D; Krakow, S L; Lazar, M A. Retinoic acid blocks adipogenesis by inhibiting C/EBPbeta-mediated transcription.. Molecular and Cellular Biology. 1997-03, 17 (3) [2022-09-20]. ISSN 0270-7306. PMID 9032283. (原始内容存档于2022-09-20). 
  31. ^ Choy, Lisa; Skillington, Jeremy; Derynck, Rik. Roles of Autocrine TGF-β Receptor and Smad Signaling in Adipocyte Differentiation. The Journal of Cell Biology. 2000-05-01, 149 (3) [2022-09-20]. ISSN 0021-9525. PMC 2174852可免费查阅. PMID 10791980. (原始内容存档于2022-09-21). 
  32. ^ Student AK, Hsu RY, Lane MD. Induction of fatty acid synthetase synthesis in differentiating 3T3-L1 preadipocytes. The Journal of Biological Chemistry. May 1980, 255 (10): 4745–50. PMID 7372608. doi:10.1016/S0021-9258(19)85559-X可免费查阅. 
  33. ^ Spiegelman BM, Green H. Control of specific protein biosynthesis during the adipose conversion of 3T3 cells. The Journal of Biological Chemistry. September 1980, 255 (18): 8811–18. PMID 6773950. doi:10.1016/S0021-9258(18)43575-2可免费查阅. 
  34. ^ Amri EZ, Dani C, Doglio A, Etienne J, Grimaldi P, Ailhaud G. Adipose cell differentiation: evidence for a two-step process in the polyamine-dependent Ob1754 clonal line. The Biochemical Journal. August 1986, 238 (1): 115–22. PMC 1147104可免费查阅. PMID 3800927. doi:10.1042/bj2380115. 
  35. ^ Christodoulides, Constantinos; Lagathu, Claire; Sethi, Jaswinder K.; Vidal-Puig, Antonio. Adipogenesis and WNT signalling. Trends in endocrinology and metabolism: TEM. 2009-1, 20 (1) [2022-09-19]. ISSN 1043-2760. PMC 4304002可免费查阅. PMID 19008118. doi:10.1016/j.tem.2008.09.002. (原始内容存档于2022-09-22). 
  36. ^ Chen, D.; Ji, X.; Harris, M.A.; Feng, J.Q.; Karsenty, G.; Celeste, A.J.; Rosen, V.; Mundy, G.R.; Harris, S.E. Differential Roles for Bone Morphogenetic Protein (BMP) Receptor Type IB and IA in Differentiation and Specification of Mesenchymal Precursor Cells to Osteoblast and Adipocyte Lineages. The Journal of Cell Biology. 1998-07-13, 142 (1) [2022-09-19]. ISSN 0021-9525. PMC 2133031可免费查阅. PMID 9660882. (原始内容存档于2022-09-22). 
  37. ^ Eckel-Mahan, Kristin; Ribas Latre, Aleix; Kolonin, Mikhail G. Adipose Stromal Cell Expansion and Exhaustion: Mechanisms and Consequences. Cells. 2020-04-02, 9 (4) [2022-09-19]. ISSN 2073-4409. PMC 7226766可免费查阅. PMID 32252348. doi:10.3390/cells9040863. (原始内容存档于2022-09-22). 
  38. ^ Gustafson, Birgit; Nerstedt, Annika; Smith, Ulf. Reduced subcutaneous adipogenesis in human hypertrophic obesity is linked to senescent precursor cells. Nature Communications. 2019-06-21, 10 [2022-09-19]. ISSN 2041-1723. PMC 6588633可免费查阅. PMID 31227697. doi:10.1038/s41467-019-10688-x. (原始内容存档于2022-09-21). 

外部链接