Adipocyte differentiation from the inside out

Nature Reviews Molecular Cell Biology

Volumn 7, Issue 12, 2006, Pages 885-896

  Rosen, Evan D ^a   MacDougald, Ormond A ^b  

^a BETH ISRAEL DEACONESS MEDICAL CENTER   (United States)

^b UNIVERSITY OF MICHIGAN   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CCAAT ENHANCER BINDING PROTEIN; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA; TRANSCRIPTION FACTOR;

ADIPOCYTE; ADIPOGENESIS; ADIPOSE TISSUE; CELL DIFFERENTIATION; CELL FATE; INSULIN RESISTANCE; MESENCHYMAL STEM CELL; MOLECULAR DYNAMICS; MOLECULAR INTERACTION; NONHUMAN; OBESITY; PRIORITY JOURNAL; REVIEW; SIGNAL TRANSDUCTION;

ADIPOCYTES; ADIPOGENESIS; ANIMALS; HUMANS; MESENCHYMAL STEM CELLS; OBESITY; SIGNAL TRANSDUCTION; TRANSCRIPTION FACTORS; TRANSCRIPTION, GENETIC;

EID: 33845325476     PISSN: 14710072     EISSN: 14710080     Source Type: Journal    
DOI: 10.1038/nrm2066     Document Type: Review

References (150)

1. Lau, D. C., Dhillon, B., Yan, H., Szmitko, P. E. & Verma, S. Adipokines: molecular links between obesity and atherosclerosis. Am. J. Physiol. Heart Circ. Physiol. 288, 2031-2041 (2005).
2. Ogden, C. L. et al. Prevalence of overweight and obesity in the United States, 1999-2004. JAMA 295, 1549-1555 (2006).
3. Giorgino, F., Laviola, L. & Eriksson, J. W. Regional differences of insulin action in adipose tissue: insights from in vivo and in vitro studies. Acta Physiol. Scand. 183, 13-30 (2005).
4. Gesta, S. et al. Evidence for a role of developmental genes in the origin of obesity and body fat distribution. Proc. Natl Acad. Sci. USA 103, 6676-6681 (2006).
5. Otto, T. C. & Lane, M. D. Adipose development: from stem cell to adipocyte. Crit. Rev. Biochem. Mol. Biol. 40, 229-242 (2005).
6. Rosen, E. D., Walkey, C. J., Puigserver, P. & Spiegelman, B. M. Transcriptional regulation of adipogenesis. Genes Dev. 14, 1293-1307 (2000).
7. MacDougald, O. A. & Mandrup, S. Adipogenesis: forces that tip the scales. Trends Endocrinol. Metab. 13, 5-11 (2002).
8. Tontonoz, P., Hu, E. & Spiegelman, B. M. Stimulation of adipogenesis in fibroblasts by PPARγ2, a lipid-activated transcription factor. Cell 79, 1147-1156 (1994). Although prior work had shown that PPARγ could induce adipose-specific enhancers, this paper showed that PPARγ could potently induce the entire adipogenic programme in fibroblasts.
9. Tong, Q. et al. Function of GATA transcription factors in preadipocyte-adipocyte transition. Science 290, 134-138 (2000).
10. Ren, D., Collingwood, T. N., Rebar, E. J., Wolffe, A. P. & Camp, H. S. PPARγ knockdown by engineered transcription factors: exogenous PPARγ2 but not PPARγ1 reactivates adipogenesis. Genes Dev. 16, 27-32 (2002).
11. Mueller, E. et al. Genetic analysis of adipogenesis through peroxisome proliferator-activated receptor γ isoforms. J. Biol. Chem. 277, 41925-41930 (2002).
12. Zhang, J. et al. Selective disruption of PPARγ2 impairs the development of adipose tissue and insulin sensitivity. Proc. Natl Acad. Sci. USA 101, 10703-10708 (2004).
13. Medina-Gomez, G. et al. The link between nutritional status and insulin sensitivity is dependent on the adipocyte-specific peroxisome proliferator-activated receptor-γ2 isoform. Diabetes 54, 1706-1716 (2005).
14. Tzameli, I. et al. Regulated production of a peroxisome proliferator-activated receptor-γ ligand during an early phase of adipocyte differentiation in 3T3-L1 adipocytes. J. Biol. Chem. 279, 36093-36102 (2004).
15. Hamm, J. K., Park, B. H. & Farmer, S. R. A role for C/EBPβ in regulating peroxisome proliferator-activated receptor γ activity during adipogenesis in 3T3-L1 preadipocytes. J. Biol. Chem. 276, 18464-18471 (2001).
16. Kim, J. B., Wright, H. M., Wright, M. & Spiegelman, B. M. ADD1/SREBP1 activates PPARγ through the production of endogenous ligand. Proc. Natl Acad. Sci. USA 95, 4333-4337 (1998).
17. Tamori, Y., Masugi, J., Nishino, N. & Kasuga, M. Role of peroxisome proliferator-activated receptor-γ in maintenance of the characteristics of mature 3T3-L1 adipocytes. Diabetes 51, 2045-2055 (2002).
18. Imai, T. et al. Peroxisome proliferator-activated receptor γ is required in mature white and brown adipocytes for their survival in the mouse. Proc. Natl Acad. Sci. USA 101, 4543-4547 (2004).
19. Tang, Q. Q., Otto, T. C. & Lane, M. D. CCAAT/enhancer-binding protein β is required for mitotic clonal expansion during adipogenesis. Proc. Natl Acad. Sci. USA 100, 850-855 (2003).
20. Tanaka, T., Yoshida, N., Kishimoto, T. & Akira, S. Defective adipocyte differentiation in mice lacking the C/EBPβ and/or C/EBPδ gene. EMBO J. 16, 7432-7443 (1997).
21. Linhart, H. G. et al. C/EBPα is required for differentiation of white, but not brown, adipose tissue. Proc. Natl Acad. Sci. USA 98, 12532-12537 (2001).
22. Chen, S. S., Chen, J. F., Johnson, P. F., Muppala, V. & Lee, Y. H. C/EBPβ, when expressed from the C/ebpα gene locus, can functionally replace C/EBPα in liver but not in adipose tissue. Mol. Cell Biol. 20, 7292-7299 (2000).
23. Darlington, G. J., Ross, S. E. & MacDougald, O. A. The role of C/EBP genes in adipocyte differentiation. J. Biol. Chem. 273, 30057-30060 (1998).
24. Zuo, Y., Qiang, L. & Farmer, S. R. Activation of CCAAT/enhancer- binding protein (C/EBP)α expression by C/EBPβ during adipogenesis requires a peroxisome proliferator-activated receptor-γ-associated repression of HDAC1 at the C/ebpα gene promoter. J. Biol. Chem. 281, 7960-7967 (2006).
25. Rosen, E. D. et al. C/EBPα induces adipogenesis through PPARγ: a unified pathway. Genes Dev. 16, 22-26 (2002).
26. Wu, Z. et al. Cross-regulation of C/EBPα and PPARγ controls the transcriptional pathway of adipogenesis and insulin sensitivity. Mol. Cell 3, 151-158 (1999).
27. El-Jack, A. K., Hamm, J. K., Pilch, P. F. & Farmer, S. R. Reconstitution of insulin-sensitive glucose transport in fibroblasts requires expression of both PPARγ and C/EBPα. J. Biol. Chem. 274, 7946-7951 (1999).
28. Mori, T. et al. Role of Kruppel-like factor 15 (KLF15) in transcriptional regulation of adipogenesis. J. Biol. Chem. 280, 12867-12875 (2005).
29. Gray, S. et al. The Kruppel-like factor KLF15 regulates the insulin-sensitive glucose transporter GLUT4. J. Biol. Chem. 277, 34322-34328 (2002).
30. Oishi, Y. et al. Kruppel-like transcription factor KLF5 is a key regulator of adipocyte differentiation. Cell Metab. 1, 27-39 (2005). This paper expanded our knowledge of KLF family members in adipogenesis by showing a role for KLF5 and showing how KLF5 integrates into the known transcriptional cascade.
31. Li, D. et al. Kruppel-like factor-6 promotes preadipocyte differentiation through histone deacetylase 3-dependent repression of DLK1. J. Biol. Chem. 280, 26941-26952 (2005).
32. Wu, J., Srinivasan, S. V., Neumann, J. C. & Lingrel, J. B. The KLF2 transcription factor does not affect the formation of preadipocytes but inhibits their differentiation into adipocytes. Biochemistry 44, 11098-11105 (2005).
33. Banerjee, S. S. et al. The Kruppel-like factor KLF2 inhibits peroxisome proliferator-activated receptor-γ expression and adipogenesis. J. Biol. Chem. 278, 2581-2584 (2003).
34. Kanazawa, A. et al. Single nucleotide polymorphisms in the gene encoding Kruppel-like factor 7 are associated with type 2 diabetes. Diabetol. 48, 1315-1322 (2005).
35. Chen, Z., Torrens, J. I., Anand, A., Spiegelman, B. M. & Friedman, J. M. Krox20 stimulates adipogenesis via C/EBPβ-dependent and -independent mechanisms. Cell Metab. 1, 93-106 (2005). One of the few papers to focus on transcriptional events prior to the induction of C/EBPβ and C/EBPδ early in the adipogenic transcriptional cascade.
36. Akerblad, P., Lind, U., Liberg, D., Bamberg, K. & Sigvardsson, M. Early B-cell factor (O/E-1) is a promoter of adipogenesis and involved in control of genes important for terminal adipocyte differentiation. Mol. Cell Biol. 22, 8015-8025 (2002).
37. Seo, J. B. et al. Activated liver X receptors stimulate adipocyte differentiation through induction of peroxisome proliferator-activated receptor γ expression. Mol. Cell Biol. 24, 3430-3444 (2004).
38. Ross, S. E. et al. Microarray analyses during adipogenesis: understanding the effects of Wnt signaling on adipogenesis and the roles of liver X receptor α in adipocyte metabolism. Mol. Cell Biol. 22, 5989-5999 (2002).
39. Hummasti, S. et al. Liver X receptors are regulators of adipocyte gene expression but not differentiation: identification of apoD as a direct target. J. Lipid Res. 45, 616-625 (2004).
40. Gerin, I. et al. LXRβ is required for adipocyte growth, glucose homeostasis, and β cell function. J. Biol. Chem. 280, 23024-23031 (2005).
41. Kim, J. B. & Spiegelman, B. M. ADD1/SREBP1 promotes adipocyte differentiation and gene expression linked to fatty acid metabolism. Genes Dev. 10, 1096-1107 (1996).
42. Kim, J. B. et al. Nutritional and insulin regulation of fatty acid synthetase and leptin gene expression through ADD1/SREBP1. J. Clin. Invest. 101, 1-9 (1998).
43. Shimano, H. et al. Elevated levels of SREBP-2 and cholesterol synthesis in livers of mice homozygous for a targeted disruption of the SREBP-1 gene. J. Clin. Invest. 100, 2115-2124 (1997).
44. Shimomura, I. et al. Insulin resistance and diabetes mellitus in transgenic mice expressing nuclear SREBP-1c in adipose tissue: model for congenital generalized lipodystrophy. Genes Dev. 12, 3182-3194 (1998).
45. Shimba, S., Wada, T., Hara, S. & Tezuka, M. EPAS1 promotes adipose differentiation in 3T3-L1 cells. J. Biol. Chem. 279, 40946-40953 (2004).
46. Nanbu-Wakao, R. et al. Stimulation of 3T3-L1 adipogenesis by signal transducer and activator of transcription 5. Mol. Endocrinol. 16, 1565-1576 (2002).
47. Floyd, Z. E. & Stephens, J. M. STAT5A promotes adipogenesis in nonprecursor cells and associates with the glucocorticoid receptor during adipocyte differentiation. Diabetes 52, 308-314 (2003).
48. Zhang, J. W., Klemm, D. J., Vinson, C. & Lane, M. D. Role of CREB in transcriptional regulation of CCAAT/enhancer-binding protein β gene during adipogenesis. J. Biol. Chem. 279, 4471-4478 (2004).
49. Shimba, S. et al. Brain and muscle Arnt-like protein-1 (BMAL1), a component of the molecular clock, regulates adipogenesis. Proc. Natl Acad. Sci. USA 102, 12071-12076 (2005).
50. Fu, M. et al. A nuclear receptor atlas: 3T3-L1 adipogenesis. Mol. Endocrinol. 19, 2437-2450 (2005). A comprehensive look at nuclear-hormone receptor expression during adipogenesis, which has spurred interest in how these factors regulate adipocyte-cell biology.
51. Tong, Q., Tsai, J., Tan, G., Dalgin, G. & Hotamisligil, G. S. Interaction between GATA and the C/EBP family of transcription factors is critical in GATA-mediated suppression of adipocyte differentiation. Mol. Cell Biol. 25, 706-715 (2005).
52. Spiegelman, B. M. & Heinrich, R. Biological control through regulated transcriptional coactivators. Cell 119, 157-167 (2004).
53. Yamauchi, T. et al. Increased insulin sensitivity despite lipodystrophy in Crebbp heterozygous mice. Nature Genet. 30, 221-226 (2002).
54. Takahashi, N. et al. Overexpression and ribozyme-mediated targeting of transcriptional coactivators CREB-binding protein and p300 revealed their indispensable roles in adipocyte differentiation through the regulation of peroxisome proliferator-activated receptor γ. J. Biol. Chem. 277, 16906-16912 (2002).
55. Pedersen, T. A., Kowenz-Leutz, E., Leutz, A. & Nerlov, C. Cooperation between C/EBPα TBP/TFIIB and SWI/SNF recruiting domains is required for adipocyte differentiation. Genes Dev. 15, 3208-3216 (2001).
56. Salma, N., Xiao, H., Mueller, E. & Imbalzano, A. N. Temporal recruitment of transcription factors and SWI/SNF chromatin-remodeling enzymes during adipogenic induction of the peroxisome proliferator-activated receptor γ nuclear hormone receptor. Mol. Cell Biol. 24, 4651-4663 (2004).
57. Ge, K. et al. Transcription coactivator TRAP220 is required for PPARγ2-stimulated adipogenesis. Nature 417, 563-567 (2002).
58. Qi, C. et al. Transcriptional coactivator PRIP, the peroxisome proliferator-activated receptor γ (PPARγ)-interacting protein, is required for PPARγ-mediated adipogenesis. J. Biol. Chem. 278, 25281-25284 (2003).
59. Yu, C. et al. The nuclear receptor corepressors NCoR and SMRT decrease peroxisome proliferator-activated receptor γ transcriptional activity and repress 3T3-L1 adipogenesis. J. Biol. Chem. 280, 13600-13605 (2005).
60. Rochford, J. J. et al. ETO/MTG8 is an inhibitor of C/EBPβ activity and a regulator of early adipogenesis. Mol. Cell Biol. 24, 9863-9872 (2004).
61. Yoo, E. J., Chung, J. J., Choe, S. S., Kim, K. H. & Kim, J. B. Down-regulation of histone deacetylases stimulates adipocyte differentiation. J. Biol. Chem. 281, 6608-6615 (2006).
62. Wiper-Bergeron, N., Wu, D., Pope, L., Schild-Poulter, C. & Hache, R. J. Stimulation of preadipocyte differentiation by steroid through targeting of an HDAC1 complex. EMBO J. 22, 2135-2145 (2003).
63. Lagace, D. C. & Nachtigal, M. W. Inhibition of histone deacetylase activity by valproic acid blocks adipogenesis. J. Biol. Chem. 279, 18851-18860 (2004).
64. Picard, F. et al. Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-γ. Nature 429, 771-776 (2004). Interesting paper that looks at how sirtuins might regulate metabolism in part through interactions with PPARγ.
65. Guermah, M., Ge, K., Chiang, C. M. & Roeder, R. G. The TBN protein, which is essential for early embryonic mouse development, is an inducible TAFII implicated in adipogenesis. Mol. Cell 12, 991-1001 (2003).
66. Sarruf, D. A. et al. Cyclin D3 promotes adipogenesis through activation of peroxisome proliferator-activated receptor γ. Mol. Cell Biol. 25, 9985-9995 (2005).
67. Abella, A. et al. Cdk4 promotes adipogenesis through PPARγ activation. Cell Metab. 2, 239-249 (2005).
68. Fu, M. et al. Cyclin D1 inhibits peroxisome proliferator-activated receptor γ-mediated adipogenesis through histone deacetylase recruitment. J. Biol. Chem. 280, 16934-16941 (2005).
69. Drori, S. et al. Hic-5 regulates an epithelial program mediated by PPARγ. Genes Dev. 19, 362-375 (2005).
70. Hong, J. H. et al. TAZ, a transcriptional modulator of mesenchymal stem cell differentiation. Science 309, 1074-1078 (2005). Shows that TAZ binds and co-activates RUNX2 to promote osteoblastogenesis, and TAZ binds to and co-represses PPARγ to inhibit adipogenesis.
71. Jakkaraju, S., Zhe, X., Pan, D., Choudhury, R. & Schuger, L. TIPs are tension-responsive proteins involved in myogenic versus adipogenic differentiation. Dev. Cell 9, 39-49 (2005).
72. Picard, F. et al. SRC-1 and TIF2 control energy balance between white and brown adipose tissues. Cell 111, 931-941 (2002).
73. Logan, C. Y. & Nusse, R. The Wnt signaling pathway in development and disease. Annu. Rev. Cell Dev. Biol. 20, 781-810 (2004).
74. Ross, S. E. et al. Inhibition of adipogenesis by Wnt signaling. Science 289, 950-953 (2000). First of a series of papers investigating how WNT10b inhibits C/EBPα and PPARγ to block adipogenesis and alternative cell fates such as osteoblastogenesis.
75. Bennett, C. N. et al. Regulation of Wnt signaling during adipogenesis. J. Biol. Chem. 277, 30998-31004 (2002).
76. Moldes, M. et al. Peroxisome-proliferator-activated receptor γ suppresses Wnt/β-catenin signalling during adipogenesis. Biochem. J. 376, 607-613 (2003).
77. Longo, K.A. et al. Wnt10b inhibits development of white and brown adipose tissues. J. Biol. Chem. 279, 35503-35509 (2004).
78. Tseng, Y. H. et al. Prediction of preadipocyte differentiation by gene expression reveals role of insulin receptor substrates and necdin. Nature Cell Biol. 7, 601-611 (2005).
79. Tseng, Y. H., Kriauciunas, K. M., Kokkotou, E. & Kahn, C. R. Differential roles of insulin receptor substrates in brown adipocyte differentiation. Mol. Cell Biol. 24, 1918-1929 (2004).
80. Kanazawa, A. et al. Wnt5b partially inhibits canonical Wnt/β-catenin signaling pathway and promotes adipogenesis in 3T3-L1 preadipocytes. Biochem. Biophys. Res. Commun. 330, 505-510 (2005).
81. Singh, R. et al. Testosterone inhibits adipogenic differentiation in 3T3-L1 cells: nuclear translocation of androgen receptor complex with β-catenin and T-cell factor 4 may bypass canonical Wnt signaling to down-regulate adipogenic transcription factors. Endocrinology 147, 141-154 (2006).
82. Westendorf, J. J., Kahler, R. A. & Schroeder, T. M. Wnt signaling in osteoblasts and bone diseases. Gene 341, 19-39 (2004).
83. Jackson, A. et al. Gene array analysis of Wnt-regulated genes in C3H10T1/2 cells. Bone 36, 585-598 (2005).
84. Bennett, C. N. et al. Regulation of osteoblastogenesis and bone mass by Wnt10b. Proc. Natl Acad. Sci. USA 102, 3324-3329 (2005).
85. Clement-Lacroix, P. et al. Lrp5-independent activation of Wnt signaling by lithium chloride increases bone formation and bone mass in mice. Proc. Natl Acad. Sci. USA 102, 17406-17411 (2005).
86. Taylor-Jones, J. M. et al. Activation of an adipogenic program in adult myoblasts with age. Mech. Ageing Dev. 123, 649-661 (2002).
87. Vertino, A. M. et al. Wnt10b deficiency promotes coexpression of myogenic and adipogenic programs in myoblasts. Mol. Biol. Cell 16, 2039-2048 (2005).
88. Arango, N. A. et al. Conditional deletion of β-catenin in the mesenchyme of the developing mouse uterus results in a switch to adipogenesis in the myometrium. Dev. Biol. 288, 276-283 (2005).
89. Hooper, J. E. & Scott, M. P. Communicating with Hedgehogs. Nature Rev. Mol. Cell Biol. 6, 306-317 (2005).
90. Spinella-Jaegle, S. et al. Sonic hedgehog increases the commitment of pluripotent mesenchymal cells into the osteoblastic lineage and abolishes adipocytic differentiation. J. Cell Sci. 114, 2085-2094 (2001).
91. Zehentner, B. K., Leser, U. & Burtscher, H. BMP-2 and sonic hedgehog have contrary effects on adipocyte-like differentiation of C3H10T1/2 cells. DNA Cell Biol. 19, 275-281 (2000).
92. Suh, J. M. et al. Hedgehog signaling plays a conserved role in inhibiting fat formation. Cell Metab. 3, 25-34 (2006). Shows the utility of lower organisms in the study of adipogenesis and identifies hedgehog signalling as another evolutionarily ancient pathway that regulates cell-fate choice in mesenchymal stem cells and pre-adipocytes.
93. Rosen, E. D. New drugs from fat bugs? Cell Metab. 3, 1-2 (2006).
94. Massague, J., Seoane, J. & Wotton, D. Smad transcription factors. Genes Dev. 19, 2783-2810 (2005).
95. Rahimi, N., Tremblay, E., McAdam, L., Roberts, A. & Elliott, B. Autocrine secretion of TGF-β and TGF-β2 by pre-adipocytes and adipocytes: a potent negative regulator of adipocyte differentiation and proliferation of mammary carcinoma cells. In Vitro Cell Dev. Biol. Anim. 34, 412-420 (1998).
96. Choy, L. & Derynck, R. Transforming growth factor-β inhibits adipocyte differentiation by Smad3 interacting with CCAAT/enhancer-binding protein (C/EBP) and repressing C/EBP transactivation function. J. Biol. Chem. 278, 9609-9619 (2003).
97. Choy, L., Skillington, J. & Derynck, R. Roles of autocrine TGF-β receptor and Smad signaling in adipocyte differentiation. J. Cell Biol. 149, 667-682 (2000). First mechanistic description of how TGFβ inhibits adipogenesis through regulation of several members of the SMAD family.
98. Clouthier, D. E., Comerford, S. A. & Hammer, R. E. Hepatic fibrosis, glomerulosclerosis, and a lipodystrophy-like syndrome in PEPCK-TGF-β1 transgenic mice. J. Clin. Invest. 100, 2697-2713 (1997).
99. Artaza, J. N. et al. Myostatin inhibits myogenesis and promotes adipogenesis in C3H 10T(1/2) mesenchymal multipotent cells. Endocrinology 146, 3547-3557 (2005).
100. Hirai, S. et al. Myostatin inhibits differentiation of bovine preadipocyte. Domest. Anim. Endocrinol. (In the press).
101. Kim, H. S. et al. Inhibition of preadipocyte differentiation by myostatin treatment in 3T3-L1 cultures. Biochem. Biophys. Res. Commun. 281, 902-906 (2001).
102. Rebbapragada, A., Benchabane, H., Wrana, J. L., Celeste, A. J. & Attisano, L. Myostatin signals through a transforming growth factor β-like signaling pathway to block adipogenesis. Mol. Cell Biol. 23, 7230-7242 (2003).
103. McPherron, A. C. & Lee, S. J. Suppression of body fat accumulation in myostatin-deficient mice. J. Clin. Invest. 109, 595-601 (2002).
104. Tang, Q. Q., Otto, T. C. & Lane, M. D. Commitment of C3H10T1/2 pluripotent stem cells to the adipocyte lineage. Proc. Natl Acad. Sci. USA 101, 9607-9611 (2004).
105. zur Nieden, N. I., Kempka, G., Rancourt, D. E. & Ahr, H. J. Induction of chondro-, osteo- and adipogenesis in embryonic stem cells by bone morphogenetic protein-2: effect of cofactors on differentiating lineages. BMC Dev. Biol. 5, 1 (2005).
106. Wang, E. A., Israel, D. I., Kelly, S. & Luxenberg, D. P. Bone morphogenetic protein-2 causes commitment and differentiation in C3H10T1/2 and 3T3 cells. Growth Factors 9, 57-71 (1993).
107. Skillington, J., Choy, L. & Derynck, R. Bone morphogenetic protein and retinoic acid signaling cooperate to induce osteoblast differentiation of preadipocytes. J. Cell Biol. 159, 135-146 (2002).
108. Jin, W. et al. Schnurri-2 controls BMP-dependent adipogenesis via interaction with Smad proteins. Dev. Cell 10, 461-471 (2006).
109. Garces, C. et al. Notch-1 controls the expression of fatty acid-activated transcription factors and is required for adipogenesis. J. Biol. Chem. 272, 29729-29734 (1997).
110. Ross, D. A., Rao, P. K. & Kadesch, T. Dual roles for the Notch target gene Hes-1 in the differentiation of 3T3-L1 preadipocytes. Mol. Cell Biol. 24, 3505-3513 (2004).
111. Nichols, A. M. et al. Notch pathway is dispensable for adipocyte specification. Genesis 40, 40-44 (2004).
112. Smas, C. M. & Sul, H. S. Molecular mechanisms of adipocyte differentiation and inhibitory action of pref-1. Crit. Rev. Eukaryot. Gene Expr. 7, 281-298 (1997).
113. Moon, Y. S. et al. Mice lacking paternally expressed Pref-1/Dlk1 display growth retardation and accelerated adiposity. Mol. Cell Biol. 22, 5585-5592 (2002).
114. Lee, K. et al. Inhibition of adipogenesis and development of glucose intolerance by soluble preadipocyte factor-1 (Pref-1). J. Clin. Invest. 111, 453-461 (2003).
115. Wolfrum, C. et al. Role of Foxa-2 in adipocyte metabolism and differentiation. J. Clin. Invest. 112, 345-356 (2003).
116. Bost, F., Aouadi, M., Caron, L. & Binetruy, B. The role of MAPKs in adipocyte differentiation and obesity. Biochimie 87, 51-56 (2005).
117. Sakaue, H. et al. Role of MAPK phosphatase-1 (MKP-1) in adipocyte differentiation. J. Biol. Chem. 279, 39951-39957 (2004).
118. Aouadi, M. et al. Inhibition of p38MAPK increases adipogenesis from embryonic to adult stages. Diabetes 55, 281-289 (2006).
119. Xing, H. et al. TNFα-mediated inhibition and reversal of adipocyte differentiation is accompanied by suppressed expression of PPARγ without effects on Pref-1 expression. Endocrinology 138, 2776-2783 (1997).
120. Kawaguchi, N. et al. De novo adipogenesis in mice at the site of injection of basement membrane and basic fibroblast growth factor. Proc. Natl Acad. Sci. USA 95, 1062-1066 (1998).
121. Hutley, L. et al. Fibroblast growth factor 1: a key regulator of human adipogenesis. Diabetes 53, 3097-3106 (2004).
122. Sakaue, H. et al. Requirement of fibroblast growth factor 10 in development of white adipose tissue. Genes Dev. 16, 908-912 (2002). Shows that FGF10 is an endogenous activator of adipocyte differentiation, and that FGF10 functions upstream of C/EBPβ.
123. Smith, P. J., Wise, L. S., Berkowitz, R., Wan, C. & Rubin, C. S. Insulin-like growth factor-I is an essential regulator of the differentiation of 3T3-L1 adipocytes. J. Biol. Chem. 263, 9402-9408 (1988).
124. Bluher, M. et al. Adipose tissue selective insulin receptor knockout protects against obesity and obesity-related glucose intolerance. Dev. Cell 3, 25-38 (2002).
125. -/- double knockout mice. Genes Dev. 16, 3213-3222 (2002).
126. Garofalo, R. S. et al. Severe diabetes, age-dependent loss of adipose tissue, and mild growth deficiency in mice lacking Akt2/PKBβ. J. Clin. Invest. 112, 197-208 (2003).
127. George, S. et al. A family with severe insulin resistance and diabetes due to a mutation in AKT2. Science 304, 1325-1328 (2004).
128. Kim, J. E. & Chen, J. Regulation of peroxisome proliferator-activated receptor-γ activity by mammalian target of rapamycin and amino acids in adipogenesis. Diabetes 53, 2748-2756 (2004).
129. Klemm, D. J. et al. Insulin-induced adipocyte differentiation. Activation of CREB rescues adipogenesis from the arrest caused by inhibition of prenylation. J. Biol. Chem. 276, 28430-28435 (2001).
130. Nakae, J. et al. The forkhead transcription factor Foxo1 regulates adipocyte differentiation. Dev. Cell 4, 119-129 (2003). Describes an important mechanism by which insulin regulates the transcriptional cascade of adipogenesis.
131. Menghini, R. et al. Phosphorylation of GATA2 by Akt increases adipose tissue differentiation and reduces adipose tissue-related inflammation: a novel pathway linking obesity to atherosclerosis. Circulation 111, 1946-1953 (2005).
132. Hansen, J. B. et al. Retinoblastoma protein functions as a molecular switch determining white versus brown adipocyte differentiation. Proc. Natl Acad. Sci. USA 101, 4112-4117 (2004). Shows that the decreased expression or activity of retinoblastoma protein in several cell lines is associated with precursor cells or white adipocytes converting to brown adipocytes.
133. Scime, A. et al. Rb and p107 regulate preadipocyte differentiation into white versus brown fat through repression of PGC-1α. Cell Metab. 2, 283-295 (2005).
134. Hansen, J. B. & Kristiansen, K. Regulatory circuits controlling white versus brown adipocyte differentiation. Biochem. J. 398, 153-168 (2006).
135. Moulin, K. et al. Emergence during development of the white-adipocyte cell phenotype is independent of the brown-adipocyte cell phenotype. Biochem. J. 356, 659-664 (2001).
136. Himms-Hagen, J. et al. Multilocular fat cells in WAT of CL-316243-treated rats derive directly from white adipocytes. Am. J. Physiol. Cell Physiol. 279, C670-C681 (2000).
137. Cheng, S. L., Shao, J. S., Charlton-Kachigian, N., Loewy, A. P. & Towler, D. A. MSX2 promotes osteogenesis and suppresses adipogenic differentiation of multipotent mesenchymal progenitors. J. Biol. Chem. 278, 45969-45977 (2003).
138. Ichida, F. et al. Reciprocal roles of MSX2 in regulation of osteoblast and adipocyte differentiation. J. Biol. Chem. 279, 34015-34022 (2004).
139. Jeon, M. J. et al. Activation of peroxisome proliferator-activated receptor-γ inhibits the Runx2-mediated transcription of osteocalcin in osteoblasts. J. Biol. Chem. 278, 23270-23277 (2003).
140. Akune, T. et al. PPARγ insufficiency enhances osteogenesis through osteoblast formation from bone marrow progenitors. J. Clin. Invest. 113, 846-855 (2004).
141. Ali, A. A. et al. Rosiglitazone causes bone loss in mice by suppressing osteoblast differentiation and bone formation. Endocrinology 146, 1226-35 (2005).
142. Kawaguchi, H. et al. Distinct effects of PPARγ insufficiency on bone marrow cells, osteoblasts, and osteoclastic cells. J. Bone Miner. Metab. 23, 275-279 (2005).
143. Sordella, R., Jiang, W., Chen, G. C., Curto, M. & Settleman, J. Modulation of Rho GTPase signaling regulates a switch between adipogenesis and myogenesis. Cell 113, 147-158 (2003). Defines how regulation of Rho GTPase activity by p190-B RhoGAP determines whether IGF1 stimulates adipogenesis or myogenesis.
144. Bryan, B. A. et al. Modulation of muscle regeneration, myogenesis, and adipogenesis by the Rho family guanine nucleotide exchange factor GEFT. Mol. Cell Biol. 25, 11089-11101 (2005).
145. McBeath, R., Pirone, D. M., Nelson, C. M., Bhadriraju, K. & Chen, C. S. Cell shape, cytoskeletal tension, and RhoA regulate stem cell lineage commitment. Dev. Cell 6, 483-495 (2004).
146. Cleary, M. P., Brasel, J. A. & Greenwood, M. R. Developmental changes in thymidine kinase, DNA, and fat cellularity in Zucker rats. Am. J. Physiol. 236, E508-E513 (1979).
147. Johnson, P. R. & Hirsch, J. Cellularity of adipose depots in six strains of genetically obese mice. J. Lipid Res. 13, 2-11 (1972).
148. Hauner, H. et al. Promoting effect of glucocorticoids on the differentiation of human adipocyte precursor cells cultured in a chemically defined medium. J. Clin. Invest. 84, 1663-1670 (1989).
149. Agarwal, A. K. & Garg, A. Genetic basis of lipodystrophies and management of metabolic complications. Annu. Rev. Med. 57, 297-311 (2006).
150. Peterfy, M., Phan, J. & Reue, K. Alternatively spliced lipin isoforms exhibit distinct expression pattern, subcellular localization, and role in adipogenesis. J. Biol. Chem. 280, 32883-32889 (2005).