Adipogenesis is a highly regulated process that converts fibroblast-like precursor cells into round and lipid-laden adipocytes.
White and brown adipocyte differentiation share many key important features, such as a requirement for the master adipogenic regulator, peroxisome proliferator-activated receptor-γ (PPARγ), but they also have important differences.
The identification of committed precursor cells within adipose tissue has been important for understanding adipogenesis in vivo.
Adipogenic stimuli activate signalling pathways that coordinate transcription factors to promote stem cell commitment to an adipogenic fate.
Extensive epigenomic modifications underlie the commitment and stability of differentiation into adipocytes.
Adipose tissue, which is primarily composed of adipocytes, is crucial for maintaining energy and metabolic homeostasis. Adipogenesis is thought to occur in two stages: commitment of mesenchymal stem cells to a preadipocyte fate and terminal differentiation. Cell shape and extracellular matrix remodelling have recently been found to regulate preadipocyte commitment and competency by modulating WNT and RHO-family GTPase signalling cascades. Adipogenic stimuli induce terminal differentiation in committed preadipocytes through the epigenomic activation of peroxisome proliferator-activated receptor-γ (PPARγ). The coordination of PPARγ with CCAAT/enhancer-binding protein (C/EBP) transcription factors maintains adipocyte gene expression. Improving our understanding of these mechanisms may allow us to identify therapeutic targets against metabolic diseases that are rapidly becoming epidemic globally.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Key circRNAs from goat: discovery, integrated regulatory network and their putative roles in the differentiation of intramuscular adipocytes
BMC Genomics Open Access 28 January 2023
Ca2+ dysregulation in cardiac stromal cells sustains fibro-adipose remodeling in Arrhythmogenic Cardiomyopathy and can be modulated by flecainide
Journal of Translational Medicine Open Access 12 November 2022
The comprehensive detection of miRNA and circRNA in the regulation of intramuscular and subcutaneous adipose tissue of Laiwu pig
Scientific Reports Open Access 03 October 2022
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Get just this article for as long as you need it
Prices may be subject to local taxes which are calculated during checkout
Galic, S., Oakhill, J. S. & Steinberg, G. R. Adipose tissue as an endocrine organ. Mol. Cell. Endocrinol. 316, 129–139 (2010).
Cinti, S. The adipose organ. Prostaglandins Leukot. Essent. Fatty Acids 73, 9–15 (2005).
Ibrahim, M. M. Subcutaneous and visceral adipose tissue: structural and functional differences. Obes. Rev. 11, 11–18 (2010).
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).
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).
Yamamoto, Y. et al. Adipose depots possess unique developmental gene signatures. Obesity (Silver Spring) 18, 872–878 (2010).
Hamdy, O., Porramatikul, S. & Al-Ozairi, E. Metabolic obesity: the paradox between visceral and subcutaneous fat. Curr. Diabetes Rev. 2, 367–373 (2006).
Tran, T. T., Yamamoto, Y., Gesta, S. & Kahn, C. R. Beneficial effects of subcutaneous fat transplantation on metabolism. Cell Metab. 7, 410–420 (2008).
Frontini, A. & Cinti, S. Distribution and development of brown adipocytes in the murine and human adipose organ. Cell Metab. 11, 253–256 (2010).
van Marken Lichtenbelt, W. D. et al. Cold-activated brown adipose tissue in healthy men. N. Engl. J. Med. 360, 1500–1508 (2009).
Virtanen, K. A. et al. Functional brown adipose tissue in healthy adults. N. Engl. J. Med. 360, 1518–1525 (2009).
Cypess, A. M. et al. Identification and importance of brown adipose tissue in adult humans. N. Engl. J. Med. 360, 1509–1517 (2009).
Gesta, S., Tseng, Y. H. & Kahn, C. R. Developmental origin of fat: tracking obesity to its source. Cell 131, 242–256 (2007).
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.
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).
Hirsch, J. & Han, P. W. Cellularity of rat adipose tissue: effects of growth, starvation, and obesity. J. Lipid Res. 10, 77–82 (1969).
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.
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).
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).
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).
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).
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).
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.
Lepper, C. & Fan, C.-M. Inducible lineage tracing of Pax7-descendant cells reveals embryonic origin of adult satellite cells. Genesis 48, 424–436 (2010).
Cousin, B. et al. Occurrence of brown adipocytes in rat white adipose tissue: molecular and morphological characterization. J. Cell Sci. 103, 931–942 1992).
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).
Seale, P. et al. Prdm16 determines the thermogenic program of subcutaneous white adipose tissue in mice. J. Clin. Invest. 121, 96–105 (2011).
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).
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.
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).
Takada, I., Kouzmenko, A. P. & Kato, S. Wnt and PPARγ signaling in osteoblastogenesis and adipogenesis. Nature Rev. Rheumatol. 5, 442–447 (2009).
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).
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).
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).
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.
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).
Longo, K. A. et al. Wnt10b inhibits development of white and brown adipose tissues. J. Biol. Chem. 279, 35503–35509 (2004).
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).
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).
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).
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).
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).
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).
Kennell, J. A. & MacDougald, O. A. Wnt signaling inhibits adipogenesis through β-catenin-dependent and -independent mechanisms. J. Biol. Chem. 280, 24004–24010 (2005).
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).
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).
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).
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).
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).
Yadav, H. et al. Protection from obesity and diabetes by blockade of TGF-β/Smad3 signaling. Cell Metab. 14, 67–79 (2011).
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).
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).
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).
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).
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).
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.
Tseng, Y.-H. et al. New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure. Nature 454, 1000–1004 (2008).
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).
Nakajima, I., Yamaguchi, T., Ozutsumi, K. & Aso, H. Adipose tissue extracellular matrix: newly organized by adipocytes during differentiation. Differentiation 63, 193–200 (1998).
Spiegelman, B. M. & Ginty, C. A. Fibronectin modulation of cell shape and lipogenic gene expression in 3T3-adipocytes. Cell 35, 657–666 (1983).
Liu, J. et al. Changes in integrin expression during adipocyte differentiation. Cell Metab. 2, 165–177 (2005).
Engler, A. J., Sen, S., Sweeney, H. L. & Discher, D. E. Matrix elasticity directs stem cell lineage specification. Cell 126, 677–689 (2006).
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).
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).
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.
Akimoto, T. et al. Mechanical stretch inhibits myoblast-to-adipocyte differentiation through Wnt signaling. Biochem. Biophys. Res. Commun. 329, 381–385 (2005).
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).
Teboul, L. et al. Thiazolidinediones and fatty acids convert myogenic cells into adipose-like cells. J. Biol. Chem. 270, 28183–28187 (1995).
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).
Sen, B. et al. Mechanical strain inhibits adipogenesis in mesenchymal stem cells by stimulating a durable β-catenin signal. Endocrinology 149, 6065–6075 (2008).
Visse, R. & Nagase, H. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ. Res. 92, 827–839 (2003).
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).
Croissandeau, G., Chretien, M. & Mbikay, M. Involvement of matrix metalloproteinases in the adipose conversion of 3T3-L1 preadipocytes. Biochem. J. 364, 739–746 (2002).
Lijnen, H. R. et al. Matrix metalloproteinase inhibition impairs adipose tissue development in mice. Arterioscler. Thromb. Vasc. Biol. 22, 374–379 (2002).
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).
Itoh, Y. MT1-MMP: a key regulator of cell migration in tissue. IUBMB Life 58, 589–596 (2006).
Chun, T.-H. et al. Genetic link between obesity and MMP14-dependent adipogenic collagen turnover. Diabetes 59, 2484–2494 (2010).
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).
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).
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).
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).
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.
Green, H. & Meuth, M. An established pre-adipose cell line and its differentiation in culture. Cell 3, 127–133 (1974).
Kuri-Harcuch, W. & Green, H. Adipose conversion of 3T3 cells depends on a serum factor. Proc. Natl Acad. Sci. USA 75, 6107–6109 (1978).
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).
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).
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).
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).
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.
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).
Noguchi, M. et al. Genetic and pharmacological inhibition of Rho-associated kinase II enhances adipogenesis. J. Biol. Chem. 282, 29574–29583 (2007).
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.
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).
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).
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.
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).
Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676 (2006).
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).
Yi, F. & Merrill, B. J. Stem cells and TCF proteins: a role for β-catenin-independent functions. Stem Cell Rev. 3, 39–48 (2007).
Lefterova, M. I. & Lazar, M. A. New developments in adipogenesis. Trends Endocrinol. Metab. 20, 107–114 (2009).
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).
Rosen, E. D. & MacDougald, O. A. Adipocyte differentiation from the inside out. Nature Rev. Mol. Cell Biol. 7, 885–896 (2006).
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).
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).
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.
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).
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).
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).
Kawai, M. & Rosen, C. J. PPARγ: a circadian transcription factor in adipogenesis and osteogenesis. Nature Rev. Endocrinol. 6, 629–636 (2010).
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).
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.
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.
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).
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).
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).
Birsoy, K., Chen, Z. & Friedman, J. Transcriptional regulation of adipogenesis by KLF4. Cell Metab. 7, 339–347 (2008).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Tang, W., Zeve, D., Seo, J., Jo, A.-Y. & Graff, J. M. Thiazolidinediones regulate adipose lineage dynamics. Cell Metab. 14, 116–122 (2011).
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).
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).
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.
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).
Kim, S.-N., Choi, H.-Y. & Kim, Y. K. Regulation of adipocyte differentiation by histone deacetylase inhibitors. Arch. Pharm. Res. 32, 535–541 (2009).
Lagace, D. C. & Nachtigal, M. W. Inhibition of histone deacetylase activity by valproic acid blocks adipogenesis. J. Biol. Chem. 279, 18851–18860 (2004).
Chatterjee, T. K. et al. Histone deacetylase 9 is a negative regulator of adipogenic differentiation. J. Biol. Chem. 286, 27836–27847 (2011).
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).
Nebbioso, A. et al. HDACs class II-selective inhibition alters nuclear receptor-dependent differentiation. J. Mol. Endocrinol. 45, 219–228 (2010).
Picard, F. et al. Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-γ. Nature 429, 771–776 (2004).
Jing, E., Gesta, S. & Kahn, C. R. SIRT2 regulates adipocyte differentiation through FoxO1 acetylation/deacetylation. Cell Metab. 6, 105–114 (2007).
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).
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).
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).
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).
Wang, J. & Lazar, M. A. Bifunctional role of Rev-erbα in adipocyte differentiation. Mol. Cell. Biol. 28, 2213–2220 (2008).
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).
Tong, Q. et al. Function of GATA transcription factors in preadipocyte–adipocyte transition. Science 290, 134–138 (2000).
Villanueva, C. J. et al. TLE3 is a dual-function transcriptional coregulator of adipogenesis. Cell Metab. 13, 413–427 (2011).
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).
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).
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).
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).
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).
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).
Soccio, R. E. et al. Species-specific strategies underlying conserved functions of metabolic transcription factors. Mol. Endocrinol. 25, 694–706 (2011).
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).
Kajimura, S. et al. Initiation of myoblast to brown fat switch by a PRDM16-C/EBP-β transcriptional complex. Nature 460, 1154–1158 (2009).
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).
Puigserver, P. et al. A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell 92, 829–839 (1998).
Uldry, M. et al. Complementary action of the PGC-1 coactivators in mitochondrial biogenesis and brown fat differentiation. Cell Metab. 3, 333–341 (2006).
Tontonoz, P. & Spiegelman, B. M. Fat and beyond: the diverse biology of PPARγ. Annu. Rev. Biochem. 77, 289–312 (2008).
Müller, S. & Krämer, O. H. Inhibitors of HDACs — effective drugs against cancer? Curr. Cancer Drug Targets 10, 210–228 (2010).
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).
Sauer, B. Inducible gene targeting in mice using the Cre/lox system. Methods 14, 381–392 (1998).
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).
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).
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).
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).
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).
MacDougald, O. A. & Lane, M. D. Transcriptional regulation of gene expression during adipocyte differentiation. Annu. Rev. Biochem. 64, 345–373 (1995).
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).
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).
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).
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).
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).
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).
Calo, E. et al. Rb regulates fate choice and lineage commitment in vivo. Nature 466, 1110–1114 (2010).
We thank P. Seale and members of the Lazar laboratory for insightful discussions. Work on adipogenesis in the Lazar laboratory is supported by US National Institutes of Health grant number DK49780. A.G.C. was supported by the Gilliam Fellowship from the Howard Hughes Medical Institute. We apologize for not being able to discuss and cite all worthy papers and topics as a result of space limitations.
The authors declare no competing financial interests.
- Type 2 diabetes
A chronic disease that is characterized by increased blood glucose and is related to insulin resistance and pancreatic failure.
- Cancer cachexia
Loss of weight, muscle atrophy, fatigue, weakness and loss of appetite in the setting of cancer.
Reduced or abnormally redistributed adipose compartments (acquired or genetic).
Having one large lipid droplet.
The process of producing heat.
- Fluorodeoxyglucose positron emission tomography
A molecular imaging technique that uses a labelled glucose analogue.
Of the epigenome; that is, chromatin modifications, including DNA methylation and histone modification, that regulate gene expression and function without a corresponding alteration in DNA sequence.
Referring to the region below the scapula (the shoulder blade).
- Uncoupling protein 1
(UCP1). A mitochondrial protein that dissociates oxidative phosphorylation from energy production, leading to increased thermogenesis.
- A-Zip mice
Mice in which a dominant-negative transcription factor that interferes with CCAAT/enhancer-binding protein (C/EBP) function is expressed by adipocytes, leading to lipodystrophy.
A heterodimeric, cation-dependent cell surface receptor that attaches cells to their surrounding environment, connecting extracellular matrix cues to intracellular signalling.
Rights and permissions
About this article
Cite this article
Cristancho, A., Lazar, M. Forming functional fat: a growing understanding of adipocyte differentiation. Nat Rev Mol Cell Biol 12, 722–734 (2011). https://doi.org/10.1038/nrm3198
This article is cited by
Key circRNAs from goat: discovery, integrated regulatory network and their putative roles in the differentiation of intramuscular adipocytes
BMC Genomics (2023)
Pituitary Adenylate Cyclase-activating Polypeptide (PACAP) -derived Peptide MPAPO Stimulates Adipogenic Differentiation by Regulating the Early Stage of Adipogenesis and ERK Signaling Pathway
Stem Cell Reviews and Reports (2023)
Ca2+ dysregulation in cardiac stromal cells sustains fibro-adipose remodeling in Arrhythmogenic Cardiomyopathy and can be modulated by flecainide
Journal of Translational Medicine (2022)
Comparative transcriptome analysis of longissimus dorsi tissues with different intramuscular fat contents from Guangling donkeys
BMC Genomics (2022)
MiR-146a-5p, targeting ErbB4, promotes 3T3-L1 preadipocyte differentiation through the ERK1/2/PPAR-γ signaling pathway
Lipids in Health and Disease (2022)