Forming functional fat: a growing understanding of adipocyte differentiation (original) (raw)

• Galic, S., Oakhill, J. S. & Steinberg, G. R. Adipose tissue as an endocrine organ. Mol. Cell. Endocrinol. 316, 129–139 (2010).
  Article CAS PubMed Google Scholar
• Cinti, S. The adipose organ. Prostaglandins Leukot. Essent. Fatty Acids 73, 9–15 (2005).
  Article CAS PubMed Google Scholar
• Ibrahim, M. M. Subcutaneous and visceral adipose tissue: structural and functional differences. Obes. Rev. 11, 11–18 (2010).
  Article PubMed Google Scholar
• Girard, J. & Lafontan, M. Impact of visceral adipose tissue on liver metabolism and insulin resistance. Part II: visceral adipose tissue production and liver metabolism. Diabetes Metab. 34, 439–445 (2008).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• Yamamoto, Y. et al. Adipose depots possess unique developmental gene signatures. Obesity (Silver Spring) 18, 872–878 (2010).
  Article CAS Google Scholar
• Hamdy, O., Porramatikul, S. & Al-Ozairi, E. Metabolic obesity: the paradox between visceral and subcutaneous fat. Curr. Diabetes Rev. 2, 367–373 (2006).
  Article PubMed Google Scholar
• Tran, T. T., Yamamoto, Y., Gesta, S. & Kahn, C. R. Beneficial effects of subcutaneous fat transplantation on metabolism. Cell Metab. 7, 410–420 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Frontini, A. & Cinti, S. Distribution and development of brown adipocytes in the murine and human adipose organ. Cell Metab. 11, 253–256 (2010).
  Article CAS PubMed Google Scholar
• van Marken Lichtenbelt, W. D. et al. Cold-activated brown adipose tissue in healthy men. N. Engl. J. Med. 360, 1500–1508 (2009).
  Article CAS PubMed Google Scholar
• Virtanen, K. A. et al. Functional brown adipose tissue in healthy adults. N. Engl. J. Med. 360, 1518–1525 (2009).
  Article CAS PubMed Google Scholar
• Cypess, A. M. et al. Identification and importance of brown adipose tissue in adult humans. N. Engl. J. Med. 360, 1509–1517 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Gesta, S., Tseng, Y. H. & Kahn, C. R. Developmental origin of fat: tracking obesity to its source. Cell 131, 242–256 (2007).
  Article CAS PubMed Google Scholar
• Tang, W. et al. White fat progenitor cells reside in the adipose vasculature. Science 322, 583–586 (2008). Identifies preadipocytes that reside within the mouse adipose compartment using a novel lineage-tracing model.
  Article CAS PubMed PubMed Central Google Scholar
• Kirtland, J. & Harris, P. M. Changes in adipose tissue of the rat due early undernutrition followed by rehabilitation. 3. Changes in cell replication studied with tritiated thymidine. Br. J. Nutr. 43, 33–43 (1980).
  Article CAS PubMed Google Scholar
• Hirsch, J. & Han, P. W. Cellularity of rat adipose tissue: effects of growth, starvation, and obesity. J. Lipid Res. 10, 77–82 (1969).
  Article CAS PubMed Google Scholar
• Spalding, K. L. et al. Dynamics of fat cell turnover in humans. Nature 453, 783–787 (2008). Calculates rates of adipocyte differentiation and apoptosis in humans using a novel isotopic method.
  Article CAS PubMed Google Scholar
• Lemonnier, D. Effect of age, sex, and sites on the cellularity of the adipose tissue in mice and rats rendered obese by a high-fat diet. J. Clin. Invest. 51, 2907–2915 (1972).
  Article CAS PubMed PubMed Central Google Scholar
• Faust, I. M., Johnson, P. R., Stern, J. S. & Hirsch, J. Diet-induced adipocyte number increase in adult rats: a new model of obesity. Am. J. Physiol. 235, e279–e286 (1978).
  CAS PubMed Google Scholar
• Klyde, B. J. & Hirsch, J. Increased cellular proliferation in adipose tissue of adult rats fed a high-fat diet. J. Lipid Res. 20, 705–715 (1979).
  Article CAS PubMed Google Scholar
• Tchoukalova, Y. D. et al. Regional differences in cellular mechanisms of adipose tissue gain with overfeeding. Proc. Natl Acad. Sci. USA 107, 18226–18231 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• van Harmelen, V. et al. Effect of BMI and age on adipose tissue cellularity and differentiation capacity in women. Int. J. Obes. Relat. Metab. Disord. 27, 889–895 (2003).
  Article CAS PubMed Google Scholar
• Seale, P. et al. PRDM16 controls a brown fat/skeletal muscle switch. Nature 454, 961–967 (2008). Reveals that brown adipocytes and skeletal myocytes share a common progenitor, with transcription factor PRDM16 determining the brown adipogenic fate.
  Article CAS PubMed PubMed Central Google Scholar
• Lepper, C. & Fan, C.-M. Inducible lineage tracing of Pax7-descendant cells reveals embryonic origin of adult satellite cells. Genesis 48, 424–436 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Cousin, B. et al. Occurrence of brown adipocytes in rat white adipose tissue: molecular and morphological characterization. J. Cell Sci. 103, 931–942 1992).
  Article CAS PubMed Google Scholar
• Stefl, B. et al. Brown fat is essential for cold-induced thermogenesis but not for obesity resistance in aP2-Ucp mice. Am. J. Physiol. 274, e527–e533 (1998).
  CAS PubMed Google Scholar
• Seale, P. et al. Prdm16 determines the thermogenic program of subcutaneous white adipose tissue in mice. J. Clin. Invest. 121, 96–105 (2011).
  Article CAS PubMed Google Scholar
• Barbatelli, G. et al. The emergence of cold-induced brown adipocytes in mouse white fat depots is determined predominantly by white to brown adipocyte transdifferentiation. Am. J. Physiol. Endocrinol. Metab. 298, e1244–e1253 (2010).
  Article CAS PubMed Google Scholar
• Rodeheffer, M. S., Birsoy, K. & Friedman, J. M. Identification of white adipocyte progenitor cells in vivo. Cell 135, 240–249 (2008). Characterizes surface antigens that define preadipocytes within the adipose compartment.
  Article CAS PubMed Google Scholar
• Schulz, T. J. et al. Identification of inducible brown adipocyte progenitors residing in skeletal muscle and white fat. Proc. Natl Acad. Sci. USA 108, 143–148 (2011).
  Article CAS PubMed Google Scholar
• Takada, I., Kouzmenko, A. P. & Kato, S. Wnt and PPARγ signaling in osteoblastogenesis and adipogenesis. Nature Rev. Rheumatol. 5, 442–447 (2009).
  Article CAS Google Scholar
• Okamura, M. et al. COUP-TFII acts downstream of Wnt/β-catenin signal to silence PPARγ gene expression and repress adipogenesis. Proc. Natl Acad. Sci. USA 106, 5819–5824 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Xu, Z., Yu, S., Hsu, C.-H., Eguchi, J. & Rosen, E. D. The orphan nuclear receptor chicken ovalbumin upstream promoter-transcription factor II is a critical regulator of adipogenesis. Proc. Natl Acad. Sci. USA 105, 2421–2426 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Li, L. et al. The nuclear orphan receptor COUP-TFII plays an essential role in adipogenesis, glucose homeostasis, and energy metabolism. Cell Metab. 9, 77–87 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Ross, S. E. et al. Inhibition of adipogenesis by Wnt signaling. Science 289, 950–953 (2000). Identifies a crucial role of WNT signalling in adipogenesis.
  Article CAS PubMed Google Scholar
• Kawai, M. et al. Wnt/Lrp/β-catenin signaling suppresses adipogenesis by inhibiting mutual activation of PPARγ and C/EBPα. Biochem. Biophys. Res. Commun. 363, 276–282 (2007).
  Article CAS PubMed Google Scholar
• Longo, K. A. et al. Wnt10b inhibits development of white and brown adipose tissues. J. Biol. Chem. 279, 35503–35509 (2004).
  Article CAS PubMed Google Scholar
• Kang, S. et al. Wnt signaling stimulates osteoblastogenesis of mesenchymal precursors by suppressing CCAAT/enhancer-binding protein α and peroxisome proliferator-activated receptor γ. J. Biol. Chem. 282, 14515–14524 (2007).
  Article CAS PubMed Google Scholar
• Wang, L., Jin, Q., Lee, J.-E., Su, I-H. & Ge, K. Histone H3K27 methyltransferase Ezh2 represses Wnt genes to facilitate adipogenesis. Proc. Natl Acad. Sci. USA 107, 7317–7322 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Longo, K. A. et al. Wnt signaling protects 3T3-L1 preadipocytes from apoptosis through induction of insulin-like growth factors. J. Biol. Chem. 277, 38239–38244 (2002).
  Article CAS PubMed Google Scholar
• Gagnon, A., Dods, P., Roustan-Delatour, N., Chen, C. S. & Sorisky, A. Phosphatidylinositol-3,4,5-trisphosphate is required for insulin-like growth factor 1-mediated survival of 3T3-L1 preadipocytes. Endocrinology 142, 205–212 (2001).
  Article CAS PubMed Google Scholar
• Takada, I. et al. A histone lysine methyltransferase activated by non-canonical Wnt signalling suppresses PPAR-γ transactivation. Nature Cell Biol. 9, 1273–1285 (2007).
  Article CAS PubMed Google Scholar
• Wakabayashi, K. et al. The peroxisome proliferator-activated receptor γ/retinoid X receptor α heterodimer targets the histone modification enzyme PR-Set7/Setd8 gene and regulates adipogenesis through a positive feedback loop. Mol. Cell. Biol. 29, 3544–3555 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Kennell, J. A. & MacDougald, O. A. Wnt signaling inhibits adipogenesis through β-catenin-dependent and -independent mechanisms. J. Biol. Chem. 280, 24004–24010 (2005).
  Article CAS PubMed Google Scholar
• Kanazawa, A. et al. Association of the gene encoding wingless-type mammary tumor virus integration-site family member 5B (WNT5B) with type 2 diabetes. Am. J. Hum. Genet. 75, 832–843 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• Fox, K. E. et al. Regulation of cyclin D1 and Wnt10b gene expression by cAMP-responsive element-binding protein during early adipogenesis involves differential promoter methylation. J. Biol. Chem. 283, 35096–35105 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Zamani, N. & Brown, C. W. Emerging roles for the transforming growth factor-β superfamily in regulating adiposity and energy expenditure. Endocr. Rev. 32, 387–403 (2011).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• Yadav, H. et al. Protection from obesity and diabetes by blockade of TGF-β/Smad3 signaling. Cell Metab. 14, 67–79 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Böttcher, Y. et al. Adipose tissue expression and genetic variants of the bone morphogenetic protein receptor 1A gene (BMPR1A) are associated with human obesity. Diabetes 58, 2119–2128 (2009).
  Article PubMed PubMed Central CAS Google Scholar
• Huang, H. et al. BMP signaling pathway is required for commitment of C3H10T1/2 pluripotent stem cells to the adipocyte lineage. Proc. Natl Acad. Sci. USA 106, 12670–12675 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Hata, K. et al. Differential roles of Smad1 and p38 kinase in regulation of peroxisome proliferator-activating receptor γ during bone morphogenetic protein 2-induced adipogenesis. Mol. Biol. Cell 14, 545–555 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Sottile, V. & Seuwen, K. Bone morphogenetic protein-2 stimulates adipogenic differentiation of mesenchymal precursor cells in synergy with BRL 49653 (rosiglitazone). FEBS Lett. 475, 201–204 (2000).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• Jin, W. et al. Schnurri-2 controls BMP-dependent adipogenesis via interaction with Smad proteins. Dev. Cell 10, 461–471 (2006). Characterizes SHN2 as a physiologic regulator of BMP-dependent adipose development.
  Article CAS PubMed Google Scholar
• Tseng, Y.-H. et al. New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure. Nature 454, 1000–1004 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Aratani, Y. & Kitagawa, Y. Enhanced synthesis and secretion of type IV collagen and entactin during adipose conversion of 3T3-L1 cells and production of unorthodox laminin complex. J. Biol. Chem. 263, 16163–16169 (1988).
  Article CAS PubMed Google Scholar
• Nakajima, I., Yamaguchi, T., Ozutsumi, K. & Aso, H. Adipose tissue extracellular matrix: newly organized by adipocytes during differentiation. Differentiation 63, 193–200 (1998).
  Article CAS PubMed Google Scholar
• Spiegelman, B. M. & Ginty, C. A. Fibronectin modulation of cell shape and lipogenic gene expression in 3T3-adipocytes. Cell 35, 657–666 (1983).
  Article CAS PubMed Google Scholar
• Liu, J. et al. Changes in integrin expression during adipocyte differentiation. Cell Metab. 2, 165–177 (2005).
  Article PubMed CAS Google Scholar
• Engler, A. J., Sen, S., Sweeney, H. L. & Discher, D. E. Matrix elasticity directs stem cell lineage specification. Cell 126, 677–689 (2006).
  Article CAS PubMed Google Scholar
• Rowlands, A. S., George, P. A. & Cooper-White, J. J. Directing osteogenic and myogenic differentiation of MSCs: interplay of stiffness and adhesive ligand presentation. Am. J. Physiol. Cell Physiol. 295, C1037–C1044 (2008).
  Article CAS PubMed Google Scholar
• Winer, J. P., Janmey, P. A., McCormick, M. E. & Funaki, M. Bone marrow-derived human mesenchymal stem cells become quiescent on soft substrates but remain responsive to chemical or mechanical stimuli. Tissue Eng. Part A 15, 147–154 (2009).
  Article CAS PubMed Google Scholar
• Chun, T.-H. et al. A pericellular collagenase directs the 3-dimensional development of white adipose tissue. Cell 125, 577–591 (2006). Demonstrates that the pericellular collagenase MMP14 is required for adipocyte differentiation in 3D.
  Article CAS PubMed Google Scholar
• Akimoto, T. et al. Mechanical stretch inhibits myoblast-to-adipocyte differentiation through Wnt signaling. Biochem. Biophys. Res. Commun. 329, 381–385 (2005).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• Teboul, L. et al. Thiazolidinediones and fatty acids convert myogenic cells into adipose-like cells. J. Biol. Chem. 270, 28183–28187 (1995).
  Article CAS PubMed Google Scholar
• Hu, E., Tontonoz, P. & Spiegelman, B. M. Transdifferentiation of myoblasts by the adipogenic transcription factors PPARγ and C/EBPα. Proc. Natl Acad. Sci. USA 92, 9856–9860 (1995).
  Article CAS PubMed PubMed Central Google Scholar
• Sen, B. et al. Mechanical strain inhibits adipogenesis in mesenchymal stem cells by stimulating a durable β-catenin signal. Endocrinology 149, 6065–6075 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Visse, R. & Nagase, H. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ. Res. 92, 827–839 (2003).
  Article CAS PubMed Google Scholar
• Chavey, C. et al. Matrix metalloproteinases are differentially expressed in adipose tissue during obesity and modulate adipocyte differentiation. J. Biol. Chem. 278, 11888–11896 (2003).
  Article CAS PubMed Google Scholar
• Croissandeau, G., Chretien, M. & Mbikay, M. Involvement of matrix metalloproteinases in the adipose conversion of 3T3-L1 preadipocytes. Biochem. J. 364, 739–746 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Lijnen, H. R. et al. Matrix metalloproteinase inhibition impairs adipose tissue development in mice. Arterioscler. Thromb. Vasc. Biol. 22, 374–379 (2002).
  Article CAS PubMed Google Scholar
• Maquoi, E., Munaut, C., Colige, A., Collen, D. & Lijnen, H. R. Modulation of adipose tissue expression of murine matrix metalloproteinases and their tissue inhibitors with obesity. Diabetes 51, 1093–1101 (2002).
  Article CAS PubMed Google Scholar
• Itoh, Y. MT1-MMP: a key regulator of cell migration in tissue. IUBMB Life 58, 589–596 (2006).
  Article CAS PubMed Google Scholar
• Chun, T.-H. et al. Genetic link between obesity and MMP14-dependent adipogenic collagen turnover. Diabetes 59, 2484–2494 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Bernot, D. et al. Down-regulation of tissue inhibitor of metalloproteinase-3 (TIMP-3) expression is necessary for adipocyte differentiation. J. Biol. Chem. 285, 6508–6514 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Yu, W. H., Yu, S., Meng, Q., Brew, K. & Woessner, J. F. TIMP-3 binds to sulfated glycosaminoglycans of the extracellular matrix. J. Biol. Chem. 275, 31226–31232 (2000).
  Article CAS PubMed Google Scholar
• Demeulemeester, D. et al. Overexpression of tissue inhibitor of matrix metalloproteinases-1 (TIMP-1) in mice does not affect adipogenesis or adipose tissue development. Thromb. Haemost. 95, 1019–1024 (2006).
  Article CAS PubMed Google Scholar
• Scroyen, I., Jacobs, F., Cosemans, L., De Geest, B. & Lijnen, H. R. Blood vessel density in de novo formed adipose tissue is decreased upon overexpression of TIMP-1. Obesity (Silver Spring) 18, 638–640 (2010).
  Article Google Scholar
• Tran, T. T. & Kahn, C. R. Transplantation of adipose tissue and stem cells: role in metabolism and disease. Nature Rev. Endocrinol. 6, 195–213 (2010). Provides an overview of applications for adipose-derived stem cells, surveys methods of culturing and differentiating adipocyte precursor cells and discusses the potential clinical uses of adipose transplantation.
  Article Google Scholar
• Green, H. & Meuth, M. An established pre-adipose cell line and its differentiation in culture. Cell 3, 127–133 (1974).
  Article CAS PubMed Google Scholar
• Kuri-Harcuch, W. & Green, H. Adipose conversion of 3T3 cells depends on a serum factor. Proc. Natl Acad. Sci. USA 75, 6107–6109 (1978).
  Article CAS PubMed PubMed Central Google Scholar
• Grigoriadis, A. E., Heersche, J. N. & Aubin, J. E. Differentiation of muscle, fat, cartilage, and bone from progenitor cells present in a bone-derived clonal cell population: effect of dexamethasone. J. Cell Biol. 106, 2139–2151 (1988).
  Article CAS PubMed Google Scholar
• Pairault, J. & Green, H. A study of the adipose conversion of suspended 3T3 cells by using glycerophosphate dehydrogenase as differentiation marker. Proc. Natl Acad. Sci. USA 76, 5138–5142 (1979).
  Article CAS PubMed PubMed Central Google Scholar
• Tang, Q. Q., Otto, T. C. & Lane, M. D. Mitotic clonal expansion: a synchronous process required for adipogenesis. Proc. Natl Acad. Sci. USA 100, 44–49 (2003).
  Article CAS PubMed Google Scholar
• Dike, L. E. & Farmer, S. R. Cell adhesion induces expression of growth-associated genes in suspension-arrested fibroblasts. Proc. Natl Acad. Sci. USA 85, 6792–6796 (1988).
  Article CAS PubMed PubMed Central Google Scholar
• 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). Provides evidence for the role of cell shape and the RHO pathway in the regulation adipogenic/osteogenic cell fate decisions.
  Article CAS PubMed Google Scholar
• Kilian, K. A., Bugarija, B., Lahn, B. T. & Mrksich, M. Geometric cues for directing the differentiation of mesenchymal stem cells. Proc. Natl Acad. Sci. USA 107, 4872–4877 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Noguchi, M. et al. Genetic and pharmacological inhibition of Rho-associated kinase II enhances adipogenesis. J. Biol. Chem. 282, 29574–29583 (2007).
  Article CAS PubMed Google Scholar
• Dupont, S. et al. Role of YAP/TAZ in mechanotransduction. Nature 474, 179–183 (2011). Demonstrates that YAP and TAZ are transcription factors downstream of RHO-dependent mechanotransduction that regulate adipogenic commitment in MSCs.
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• Gupta, R. K. et al. Transcriptional control of preadipocyte determination by Zfp423. Nature 464, 619–623 (2010). Shows that the transcription factor ZFP423 is an adipogenic competency factor.
  Article CAS PubMed PubMed Central Google Scholar
• Cheng, L. E., Zhang, J. & Reed, R. R. The transcription factor Zfp423/OAZ is required for cerebellar development and CNS midline patterning. Dev. Biol. 307, 43–52 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676 (2006).
  Article CAS PubMed Google Scholar
• Cristancho, A. G. et al. Repressor transcription factor 7-like 1 promotes adipogenic competency in precursor cells. Proc. Natl Acad. Sci. USA 13 Sep 2011 (doi:10.1073/pnas.1109409108).
  Article CAS Google Scholar
• Yi, F. & Merrill, B. J. Stem cells and TCF proteins: a role for β-catenin-independent functions. Stem Cell Rev. 3, 39–48 (2007).
  Article CAS PubMed Google Scholar
• Lefterova, M. I. & Lazar, M. A. New developments in adipogenesis. Trends Endocrinol. Metab. 20, 107–114 (2009).
  Article CAS PubMed Google Scholar
• Hwang, C.-S., Loftus, T. M., Mandrup, S. & Lane, M. D. Adipocyte differentiation and leptin expression. Annu. Rev. Cell Dev. Biol. 13, 231–259 (1997).
  Article CAS PubMed Google Scholar
• Rosen, E. D. & MacDougald, O. A. Adipocyte differentiation from the inside out. Nature Rev. Mol. Cell Biol. 7, 885–896 (2006).
  Article CAS Google Scholar
• Yeh, W. C., Cao, Z., Classon, M. & McKnight, S. L. Cascade regulation of terminal adipocyte differentiation by three members of the C/EBP family of leucine zipper proteins. Genes Dev. 9, 168–181 (1995).
  Article CAS PubMed Google Scholar
• Wu, Z., Xie, Y., Bucher, N. L. & Farmer, S. R. Conditional ectopic expression of C/EBPβ in NIH-3T3 cells induces PPARγ and stimulates adipogenesis. Genes Dev. 9, 2350–2363 (1995).
  Article CAS PubMed Google Scholar
• Steger, D. J. et al. Propagation of adipogenic signals through an epigenomic transition state. Genes Dev. 24, 1035–1044 (2010). Identifies an epigenomic transition state in adipogenesis.
  Article CAS PubMed PubMed Central Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• Martini, C. N., Plaza, M. V. & Vila, M. del C. PKA-dependent and independent cAMP signaling in 3T3-L1 fibroblasts differentiation. Mol. Cell. Endocrinol. 298, 42–47 (2009).
  Article CAS PubMed Google Scholar
• Petersen, R. K. et al. Cyclic AMP (cAMP)-mediated stimulation of adipocyte differentiation requires the synergistic action of Epac- and cAMP-dependent protein kinase-dependent processes. Mol. Cell. Biol. 28, 3804–3816 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Kawai, M. & Rosen, C. J. PPARγ: a circadian transcription factor in adipogenesis and osteogenesis. Nature Rev. Endocrinol. 6, 629–636 (2010).
  Article CAS Google Scholar
• Lefterova, M. I. et al. PPARγ and C/EBP factors orchestrate adipocyte biology via adjacent binding on a genome-wide scale. Genes Dev. 22, 2941–2952 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Nielsen, R. et al. Genome-wide profiling of PPARγ:RXR and RNA polymerase II occupancy reveals temporal activation of distinct metabolic pathways and changes in RXR dimer composition during adipogenesis. Genes Dev. 22, 2953–2967 (2008). References 110 and 111 describe the genome-wide binding of PPARγ in 3T3-L1 adipocytes and identify cooperation with C/EBPs as a hallmark of genomic PPARγ binding in adipocytes.
  Article CAS PubMed PubMed Central Google Scholar
• Siersbæk, R. et al. Extensive chromatin remodelling and establishment of transcription factor “hotspots” during early adipogenesis. EMBO J. 30, 1459–1472 (2011). Uses DNase hypersensitivity followed by deep sequencing to identify open chromatin regions during early adipogenesis and in mature adipocytes.
  Article PubMed PubMed Central CAS Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• Wang, D. et al. Signal transducer and activator of transcription 3 (STAT3) regulates adipocyte differentiation via peroxisome-proliferator-activated receptor γ (PPARγ). Biol. Cell 102, 1–12 (2010).
  Article CAS Google Scholar
• Zhang, K., Guo, W., Yang, Y. & Wu, J. JAK2/STAT3 pathway is involved in the early stage of adipogenesis through regulating C/EBPβ transcription. J. Cell. Biochem. 112, 488–497 (2011).
  Article CAS PubMed Google Scholar
• Birsoy, K., Chen, Z. & Friedman, J. Transcriptional regulation of adipogenesis by KLF4. Cell Metab. 7, 339–347 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• Park, B.-H., Qiang, L. & Farmer, S. R. Phosphorylation of C/EBPβ at a consensus extracellular signal-regulated kinase/glycogen synthase kinase 3 site is required for the induction of adiponectin gene expression during the differentiation of mouse fibroblasts into adipocytes. Mol. Cell. Biol. 24, 8671–8680 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Tang, Q.-Q. et al. Sequential phosphorylation of CCAAT enhancer-binding protein β by MAPK and glycogen synthase kinase 3β is required for adipogenesis. Proc. Natl Acad. Sci. USA 102, 9766–9771 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Asada, M. et al. DNA binding-dependent glucocorticoid receptor activity promotes adipogenesis via Krüppel-like factor 15 gene expression. Lab. Invest. 91, 203–215 (2011).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• Wiper-Bergeron, N., Salem, H. A., Tomlinson, J. J., Wu, D. & Hache, R. J. Glucocorticoid-stimulated preadipocyte differentiation is mediated through acetylation of C/EBPβ by GCN5. Proc. Natl Acad. Sci. USA 104, 2703–2708 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• Tang, Q. Q., Zhang, J. W. & Daniel Lane, M. Sequential gene promoter interactions of C/EBPβ, C/EBPα, and PPARγ during adipogenesis. Biochem. Biophys. Res. Commun. 319, 235–239 (2004).
  Article CAS PubMed Google Scholar
• Rosen, E. D. et al. PPARγ is required for the differentiation of adipose tissue in vivo and in vitro. Mol. Cell 4, 611–617 (1999).
  Article CAS PubMed Google Scholar
• Lehmann, J. M. et al. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor γ (PPARγ). J. Biol. Chem. 270, 12953–12956 (1995).
  Article CAS PubMed Google Scholar
• Tang, W., Zeve, D., Seo, J., Jo, A.-Y. & Graff, J. M. Thiazolidinediones regulate adipose lineage dynamics. Cell Metab. 14, 116–122 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Tontonoz, P., Hu, E., Graves, R. A., Budavari, A. I. & Spiegelman, B. M. mPPAR gamma 2: tissue-specific regulator of an adipocyte enhancer. Genes Dev. 8, 1224–1234 (1994).
  Article CAS PubMed Google Scholar
• Chawla, A., Schwarz, E. J., Dimaculangan, D. D. & Lazar, M. A. Peroxisome proliferator-activated receptor (PPAR) gamma: adipose-predominant expression and induction early in adipocyte differentiation. Endocrinology 135, 798–800 (1994).
  Article CAS PubMed Google Scholar
• Mikkelsen, T. S. et al. Comparative epigenomic analysis of murine and human adipogenesis. Cell 143, 156–169 (2010). Provides an extensive collection of genome-wide profiles of transcription factor binding and histone modifications in human and mouse adipogenesis.
  Article CAS PubMed PubMed Central Google Scholar
• Haberland, M., Carrer, M., Mokalled, M. H., Montgomery, R. L. & Olson, E. N. Redundant control of adipogenesis by histone deacetylases 1 and 2. J. Biol. Chem. 285, 14663–14670 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Kim, S.-N., Choi, H.-Y. & Kim, Y. K. Regulation of adipocyte differentiation by histone deacetylase inhibitors. Arch. Pharm. Res. 32, 535–541 (2009).
  Article CAS PubMed Google Scholar
• Lagace, D. C. & Nachtigal, M. W. Inhibition of histone deacetylase activity by valproic acid blocks adipogenesis. J. Biol. Chem. 279, 18851–18860 (2004).
  Article CAS PubMed Google Scholar
• Chatterjee, T. K. et al. Histone deacetylase 9 is a negative regulator of adipogenic differentiation. J. Biol. Chem. 286, 27836–27847 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• Nebbioso, A. et al. HDACs class II-selective inhibition alters nuclear receptor-dependent differentiation. J. Mol. Endocrinol. 45, 219–228 (2010).
  Article CAS PubMed Google Scholar
• Picard, F. et al. Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-γ. Nature 429, 771–776 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Jing, E., Gesta, S. & Kahn, C. R. SIRT2 regulates adipocyte differentiation through FoxO1 acetylation/deacetylation. Cell Metab. 6, 105–114 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Lee, J. et al. Targeted inactivation of MLL3 histone H3-Lys-4 methyltransferase activity in the mouse reveals vital roles for MLL3 in adipogenesis. Proc. Natl Acad. Sci. USA 105, 19229–19234 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Lizcano, F., Romero, C. & Vargas, D. Regulation of adipogenesis by nuclear receptor PPARγ is modulated by the histone demethylase JMJD2C. Genet. Mol. Biol. 34, 19–24 (2011).
  CAS PubMed PubMed Central Google Scholar
• Cho, Y.-W. et al. Histone methylation regulator PTIP is required for PPARγ and C/EBPα expression and adipogenesis. Cell Metab. 10, 27–39 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Park, U.-H., Yoon, S. K., Park, T., Kim, E.-J. & Um, S.-J. Additional sex comb-like (ASXL) proteins 1 and 2 play opposite roles in adipogenesis via reciprocal regulation of peroxisome proliferator-activated receptor γ. J. Biol. Chem. 286, 1354–1363 (2011).
  Article CAS PubMed Google Scholar
• Wang, J. & Lazar, M. A. Bifunctional role of Rev-erbα in adipocyte differentiation. Mol. Cell. Biol. 28, 2213–2220 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Kawai, M. et al. A circadian-regulated gene, Nocturnin, promotes adipogenesis by stimulating PPAR-γ nuclear translocation. Proc. Natl Acad. Sci. USA 107, 10508–10513 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Tong, Q. et al. Function of GATA transcription factors in preadipocyte–adipocyte transition. Science 290, 134–138 (2000).
  Article CAS PubMed Google Scholar
• Villanueva, C. J. et al. TLE3 is a dual-function transcriptional coregulator of adipogenesis. Cell Metab. 13, 413–427 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• Schupp, M. et al. Re-expression of GATA2 cooperates with peroxisome proliferator-activated receptor-γ depletion to revert the adipocyte phenotype. J. Biol. Chem. 284, 9458–9464 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Liao, W. et al. Suppression of PPAR-γ attenuates insulin-stimulated glucose uptake by affecting both GLUT1 and GLUT4 in 3T3-L1 adipocytes. Am. J. Physiol. Endocrinol. Metab. 293, e219–e227 (2007).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• He, W. et al. Adipose-specific peroxisome proliferator-activated receptor γ knockout causes insulin resistance in fat and liver but not in muscle. Proc. Natl Acad. Sci. USA 100, 15712–15717 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Schmidt, S. F. et al. Cross species comparison of C/EBPα and PPARγ profiles in mouse and human adipocytes reveals interdependent retention of binding sites. BMC Genomics 12, 152 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Soccio, R. E. et al. Species-specific strategies underlying conserved functions of metabolic transcription factors. Mol. Endocrinol. 25, 694–706 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Nedergaard, J., Petrovic, N., Lindgren, E. M., Jacobsson, A. & Cannon, B. PPARγ in the control of brown adipocyte differentiation. Biochim. Biophys. Acta 1740, 293–304 (2005).
  Article CAS PubMed Google Scholar
• Kajimura, S. et al. Initiation of myoblast to brown fat switch by a PRDM16-C/EBP-β transcriptional complex. Nature 460, 1154–1158 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Kajimura, S. et al. Regulation of the brown and white fat gene programs through a PRDM16/CtBP transcriptional complex. Genes Dev. 22, 1397–1409 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Puigserver, P. et al. A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell 92, 829–839 (1998).
  Article CAS PubMed Google Scholar
• Uldry, M. et al. Complementary action of the PGC-1 coactivators in mitochondrial biogenesis and brown fat differentiation. Cell Metab. 3, 333–341 (2006).
  Article CAS PubMed Google Scholar
• Tontonoz, P. & Spiegelman, B. M. Fat and beyond: the diverse biology of PPARγ. Annu. Rev. Biochem. 77, 289–312 (2008).
  Article CAS PubMed Google Scholar
• Müller, S. & Krämer, O. H. Inhibitors of HDACs — effective drugs against cancer? Curr. Cancer Drug Targets 10, 210–228 (2010).
  Article PubMed Google Scholar
• Sugii, S. et al. Human and mouse adipose-derived cells support feeder-independent induction of pluripotent stem cells. Proc. Natl Acad. Sci. USA 107, 3558–3563 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Sauer, B. Inducible gene targeting in mice using the Cre/lox system. Methods 14, 381–392 (1998).
  Article CAS PubMed Google Scholar
• Chang, T. H. & Polakis, S. E. Differentiation of 3T3-L1 fibroblasts to adipocytes. Effect of insulin and indomethacin on the levels of insulin receptors. J. Biol. Chem. 253, 4693–4696 (1978).
  Article CAS PubMed Google Scholar
• Costa, M., Manen, C. A. & Russell, D. H. In vivo activation of cAMP-dependent protein kinase by aminophylline and 1-methyl, 3-isobutylxanthine. Biochem. Biophys. Res. Commun. 65, 75–81 (1975).
  Article CAS PubMed Google Scholar
• Elks, M. L., Manganiello, V. C. & Vaughan, M. Hormone-sensitive particulate cAMP phosphodiesterase activity in 3T3-L1 adipocytes. Regulation of responsiveness by dexamethasone. J. Biol. Chem. 258, 8582–8587 (1983).
  Article CAS PubMed Google Scholar
• Fischer-Posovszky, P., Newell, F. S., Wabitsch, M. & Tornqvist, H. E. Human SGBS cells — a unique tool for studies of human fat cell biology. Obes. Facts 1, 184–189 (2008).
  Article PubMed PubMed Central Google Scholar
• Mandrup, S., Loftus, T. M., MacDougald, O. A., Kuhajda, F. P. & Lane, M. D. Obese gene expression at in vivo levels by fat pads derived from s.c. implanted 3T3-F442A preadipocytes. Proc. Natl Acad. Sci. USA 94, 4300–4305 (1997).
  Article CAS PubMed PubMed Central Google Scholar
• MacDougald, O. A. & Lane, M. D. Transcriptional regulation of gene expression during adipocyte differentiation. Annu. Rev. Biochem. 64, 345–373 (1995).
  Article CAS PubMed Google Scholar
• Ross, S. R. et al. A fat-specific enhancer is the primary determinant of gene expression for adipocyte P2 in vivo. Proc. Natl Acad. Sci. USA 87, 9590–9594 (1990).
  Article CAS PubMed PubMed Central Google Scholar
• Hunt, C. R., Ro, J. H., Dobson, D. E., Min, H. Y. & Spiegelman, B. M. Adipocyte P2 gene: developmental expression and homology of 5′-flanking sequences among fat cell-specific genes. Proc. Natl Acad. Sci. USA 83, 3786–3790 (1986).
  Article CAS PubMed PubMed Central Google Scholar
• Makowski, L. et al. Lack of macrophage fatty-acid-binding protein aP2 protects mice deficient in apolipoprotein E against atherosclerosis. Nature Med. 7, 699–705 (2001).
  Article CAS PubMed Google Scholar
• Urs, S., Harrington, A., Liaw, L. & Small, D. Selective expression of an aP2/fatty acid binding protein 4-Cre transgene in non-adipogenic tissues during embryonic development. Transgenic Res. 15, 647–653 (2006).
  Article CAS PubMed Google Scholar
• Martens, K., Bottelbergs, A. & Baes, M. Ectopic recombination in the central and peripheral nervous system by aP2/FABP4-Cre mice: implications for metabolism research. FEBS Lett. 584, 1054–1058 (2010).
  Article CAS PubMed Google Scholar
• Wang, Z. V., Deng, Y., Wang, Q. A., Sun, K. & Scherer, P. E. Identification and characterization of a promoter cassette conferring adipocyte-specific gene expression. Endocrinology 151, 2933–2939 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Calo, E. et al. Rb regulates fate choice and lineage commitment in vivo. Nature 466, 1110–1114 (2010).
  Article PubMed PubMed Central Google Scholar