Adipogenesis and metabolic health


Obesity is characterized by increased adipose tissue mass and has been associated with a strong predisposition towards metabolic diseases and cancer. Thus, it constitutes a public health issue of major proportion. The expansion of adipose depots can be driven either by the increase in adipocyte size (hypertrophy) or by the formation of new adipocytes from precursor differentiation in the process of adipogenesis (hyperplasia). Notably, adipocyte expansion through adipogenesis can offset the negative metabolic effects of obesity, and the mechanisms and regulators of this adaptive process are now emerging. Over the past several years, we have learned a considerable amount about how adipocyte fate is determined and how adipogenesis is regulated by signalling and systemic factors. We have also gained appreciation that the adipogenic niche can influence tissue adipogenic capability. Approaches aimed at increasing adipogenesis over adipocyte hypertrophy can now be explored as a means to treat metabolic diseases.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: Mechanisms of adipose tissue expansion.
Fig. 2: Overview of molecular mechanisms of adipogenesis.
Fig. 3: Sites of adult adipogenesis.
Fig. 4: Regulators of adipogenesis.


  1. 1.

    Spalding, K. L. et al. Dynamics of fat cell turnover in humans. Nature 453, 783–787 (2008).

  2. 2.

    Hirsch, J. & Han, P. W. Cellularity of rat adipose tissue: effects of growth, starvation, and obesity. J. Lipid Res. 10, 77–82 (1969).

  3. 3.

    Wang, Q. A., Tao, C., Gupta, R. K. & Scherer, P. E. Tracking adipogenesis during white adipose tissue development, expansion and regeneration. Nat. Med. 19, 1338–1344 (2013).

  4. 4.

    Vishvanath, L. et al. Pdgfrβ+ mural preadipocytes contribute to adipocyte hyperplasia induced by high-fat-diet feeding and prolonged cold exposure in adult mice. Cell Metab. 23, 350–359 (2016).

  5. 5.

    Tang, W. et al. White fat progenitor cells reside in the adipose vasculature. Science 322, 583–586 (2008). This foundational study is the first explicit in vivo lineage tracing to identify early molecular markers of preadipocytes and localize these cells to the vasculature.

  6. 6.

    Gupta, R. K. et al. Zfp423 expression identifies committed preadipocytes and localizes to adipose endothelial and perivascular cells. Cell Metab. 15, 230–239 (2012).

  7. 7.

    Salans, L. B., Knittle, J. L. & Hirsch, J. The role of adipose cell size and adipose tissue insulin sensitivity in the carbohydrate intolerance of human obesity. J. Clin. Invest. 47, 153–165 (1968).

  8. 8.

    Krotkiewski, M., Björntorp, P., Sjöström, L. & Smith, U. Impact of obesity on metabolism in men and women. Importance of regional adipose tissue distribution. J. Clin. Invest. 72, 1150–1162 (1983).

  9. 9.

    McLaughlin, T. et al. Enhanced proportion of small adipose cells in insulin-resistant versus insulin-sensitive obese individuals implicates impaired adipogenesis. Diabetologia 50, 1707–1715 (2007).

  10. 10.

    Lundgren, M. et al. Fat cell enlargement is an independent marker of insulin resistance and ‘hyperleptinaemia’. Diabetologia 50, 625–633 (2007).

  11. 11.

    Yang, J., Eliasson, B., Smith, U., Cushman, S. W. & Sherman, A. The size of large adipose cells is a predictor of insulin resistance in first-degree relatives of type 2 diabetics. Obesity 20, 932–938 (2012).

  12. 12.

    Lönn, M., Mehlig, K., Bengtsson, C. & Lissner, L. Adipocyte size predicts incidence of type 2 diabetes in women. FASEB J. 24, 326–331 (2010).

  13. 13.

    Halberg, N. et al. Hypoxia-inducible factor 1α induces fibrosis and insulin resistance in white adipose tissue. Mol. Cell. Biol. 29, 4467–4483 (2009).

  14. 14.

    Khan, T. et al. Metabolic dysregulation and adipose tissue fibrosis: role of collagen VI. Mol. Cell. Biol. 29, 1575–1591 (2009).

  15. 15.

    Laurencikiene, J. et al. Regulation of lipolysis in small and large fat cells of the same subject. J. Clin. Endocrinol. Metab. 96, E2045–E2049 (2011).

  16. 16.

    Skurk, T., Alberti-Huber, C., Herder, C. & Hauner, H. Relationship between adipocyte size and adipokine expression and secretion. J. Clin. Endocrinol. Metab. 92, 1023–1033 (2007).

  17. 17.

    Meyer, L. K., Ciaraldi, T. P., Henry, R. R., Wittgrove, A. C. & Phillips, S. A. Adipose tissue depot and cell size dependency of adiponectin synthesis and secretion in human obesity. Adipocyte 2, 217–226 (2013).

  18. 18.

    Bambace, C. et al. Adiponectin gene expression and adipocyte diameter: a comparison between epicardial and subcutaneous adipose tissue in men. Cardiovasc. Pathol. 20, e153–e156 (2011).

  19. 19.

    Harms, M. & Seale, P. Brown and beige fat: development, function and therapeutic potential. Nat. Med. 19, 1252 (2013).

  20. 20.

    Kajimura, S., Spiegelman, B. M. & Seale, P. Brown and beige fat: physiological roles beyond heat-generation. Cell Metab. 22, 546–559 (2015).

  21. 21.

    Wang, W. & Seale, P. Control of brown and beige fat development. Nat. Rev. Mol. Cell Biol. 17, 691–702 (2016).

  22. 22.

    Inagaki, T., Sakai, J. & Kajimura, S. Transcriptional and epigenetic control of brown and beige adipose cell fate and function. Nat. Rev. Mol. Cell Biol. 17, 480 (2016).

  23. 23.

    Stern, J. H., Rutkowski, J. M. & Scherer, P. E. Adiponectin, leptin, and fatty acids in the maintenance of metabolic homeostasis through adipose tissue crosstalk. Cell Metab. 23, 770–784 (2016).

  24. 24.

    Rosen, E. D. & Spiegelman, B. M. What we talk about when we talk about fat. Cell 156, 20–44 (2014).

  25. 25.

    Scherer, P. E. The multifaceted roles of adipose tissue-therapeutic targets for diabetes and beyond: the 2015 Banting lecture. Diabetes 65, 1452–1461 (2016).

  26. 26.

    Zhang, Y. et al. Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425 (1994).

  27. 27.

    Scherer, P. E., Williams, S., Fogliano, M., Baldini, G. & Lodish, H. F. A. Novel serum protein similar to C1q, produced exclusively in adipocytes. J. Biol. Chem. 270, 26746–26749 (1995).

  28. 28.

    Zhu, Q. & Scherer, P. E. Immunologic and endocrine functions of adipose tissue: implications for kidney disease. Nat. Rev. Nephrol. 14, 105 (2017).

  29. 29.

    Fasshauer, M. & Blüher, M. Adipokines in health and disease. Trends Pharmacol. Sci. 36, 461–470 (2015).

  30. 30.

    Pflimlin, E. et al. Acute and repeated treatment with 5-PAHSA or 9-PAHSA isomers does not improve glucose control in mice. Cell Metab. 28, 217–227 (2018).

  31. 31.

    Yore, M. M. et al. Discovery of a class of endogenous mammalian lipids with anti-diabetic and anti-inflammatory effects. Cell 159, 318–332 (2014).

  32. 32.

    Cao, H. et al. Identification of a lipokine, a lipid hormone linking adipose tissue to systemic metabolism. Cell 134, 933–944 (2008).

  33. 33.

    Dobson, D. E. et al. 1-Butyryl-glycerol: a novel angiogenesis factor secreted by differentiating adipocytes. Cell 61, 223–230 (1990).

  34. 34.

    Holland, W. L. et al. Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-, and obesity-induced insulin resistance. Cell Metab. 5, 167–179 (2007).

  35. 35.

    Xia, J. Y. et al. Targeted induction of ceramide degradation leads to improved systemic metabolism and reduced hepatic steatosis. Cell Metab. 22, 266–278 (2015).

  36. 36.

    Sun, K. et al. Dichotomous effects of VEGF-A on adipose tissue dysfunction. Proc. Natl Acad. Sci. USA 109, 5874–5879 (2012).

  37. 37.

    Ye, R. et al. Impact of tamoxifen on adipocyte lineage tracing: inducer of adipogenesis and prolonged nuclear translocation of Cre recombinase. Mol. Metab. 4, 771–778 (2015). This study highlights some potential drawbacks to using tamoxifen-inducible genetic recombination systems to study adipogenesis. In particular, tamoxifen administration may itself induce adipogenesis, and has a lengthy wash-out period.

  38. 38.

    Farmer, S. R. Transcriptional control of adipocyte formation. Cell Metab. 4, 263–273 (2006).

  39. 39.

    Cristancho, A. G. & Lazar, M. A. Forming functional fat: a growing understanding of adipocyte differentiation. Nat. Rev. Mol. Cell Biol. 12, 722–734 (2011).

  40. 40.

    Cawthorn, W. P., Scheller, E. L. & MacDougald, O. A. Adipose tissue stem cells meet preadipocyte commitment: going back to the future. J. Lipid Res. 53, 227–246 (2012).

  41. 41.

    Wang, E. A., Israel, D. I., Kelly, S. & Luxenberg, D. P. Bone morphogenetic protein-2 causes commitment and differentiation in C3Hl0T1/2 and 3T3 cells. Growth Factors 9, 57–71 (1993). This early study identifies extracellular BMP signalling as a strong commitment stimulus in cultured preadipocyte cell lines.

  42. 42.

    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).

  43. 43.

    Bowers, R. R., Kim, J. W., Otto, T. C. & Lane, M. D. Stable stem cell commitment to the adipocyte lineage by inhibition of DNA methylation: role of the BMP-4 gene. Proc. Natl Acad. Sci. USA 103, 13022–13027 (2006).

  44. 44.

    Gupta, R. K. et al. Transcriptional control of preadipocyte determination by Zfp423. Nature 464, 619–623 (2010). This study identifies the intracellular transcription factor ZFP423 as a commitment factor to the adipocyte lineage.

  45. 45.

    Shao, M. et al. Fetal development of subcutaneous white adipose tissue is dependent on Zfp423. Mol. Metab. 6, 111–124 (2017).

  46. 46.

    Hepler, C. et al. Directing visceral white adipocyte precursors to a thermogenic adipocyte fate improves insulin sensitivity in obese mice. eLife 6, e27669 (2017).

  47. 47.

    Quach, J. M. et al. Zinc finger protein 467 is a novel regulator of osteoblast and adipocyte commitment. J. Biol. Chem. 286, 4186–4198 (2011).

  48. 48.

    Oishi, Y. et al. Krüppel-like transcription factor KLF5 is a key regulator of adipocyte differentiation. Cell Metab. 1, 27–39 (2005).

  49. 49.

    Tong, Q. et al. Function of GATA transcription factors in preadipocyte-adipocyte transition. Science 290, 134–138 (2000).

  50. 50.

    Boyle, K. B. et al. The transcription factors Egr1 and Egr2 have opposing influences on adipocyte differentiation. Cell Death Differ. 16, 782–789 (2009).

  51. 51.

    Tontonoz, P., Hu, E. & Spiegelman, B. M. Stimulation of adipogenesis in fibroblasts by PPARγ2, a lipid-activated transcription factor. Cell 79, 1147–1156 (1994). This study identifies PPARγ expression as sufficient to drive adipocyte differentiation in cell culture.

  52. 52.

    Barak, Y. et al. PPARγ is required for placental, cardiac, and adipose tissue development. Mol. Cell 4, 585–595 (1999).

  53. 53.

    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).

  54. 54.

    Wang, F., Mullican, S. E., DiSpirito, J. R., Peed, L. C. & Lazar, M. A. Lipoatrophy and severe metabolic disturbance in mice with fat-specific deletion of PPARγ. Proc. Natl Acad. Sci. USA 110, 18656–18661 (2013).

  55. 55.

    Schupp, M. & Lazar, M. A. Endogenous ligands for nuclear receptors: digging deeper. J. Biol. Chem. 285, 40409–40415 (2010).

  56. 56.

    Lago, R. M., Singh, P. P. & Nesto, R. W. Congestive heart failure and cardiovascular death in patients with prediabetes and type 2 diabetes given thiazolidinediones: a meta-analysis of randomised clinical trials. Lancet 370, 1129–1136 (2007).

  57. 57.

    Nissen, S. E. & Wolski, K. Rosiglitazone revisited: an updated meta-analysis of risk for myocardial infarction and cardiovascular mortality. Arch. Intern. Med. 170, 1191–1201 (2010).

  58. 58.

    Mahaffey, K. W. et al. Results of a reevaluation of cardiovascular outcomes in the RECORD trial. Am. Heart J. 166, 240–249 (2013).

  59. 59.

    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).

  60. 60.

    Freytag, S. O., Paielli, D. L. & Gilbert, J. D. Ectopic expression of the CCAAT/enhancer-binding protein alpha promotes the adipogenic program in a variety of mouse fibroblastic cells. Genes Dev. 8, 1654–1663 (1994).

  61. 61.

    Wu, Z., Bucher, N. L. & Farmer, S. R. Induction of peroxisome proliferator-activated receptor gamma during the conversion of 3T3 fibroblasts into adipocytes is mediated by C/EBPbeta, C/EBPdelta, and glucocorticoids. Mol. Cell. Biol. 16, 4128–4136 (1996).

  62. 62.

    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).Comprehensive mechanistic study describing the adipogenic transcriptional cooperation between PPARγ and C/EBP transcription factors on a genome-wide scale.

  63. 63.

    Wang, Q. A. et al. Distinct regulatory mechanisms govern embryonic versus adult adipocyte maturation. Nat. Cell Biol. 17, 1099–1111 (2015).

  64. 64.

    Plikus, M. V. et al. Regeneration of fat cells from myofibroblasts during wound healing. Science 355, 748–752 (2017). This study describes in vivo regeneration of adipocytes from fibroblast-like cells during wound healing.

  65. 65.

    Marangoni, R. G. et al. Myofibroblasts in murine cutaneous fibrosis originate from adiponectin-positive intradermal progenitors. Arthritis Rheumatol. 67, 1062–1073 (2015).

  66. 66.

    Zoico, E. et al. Adipocytes WNT5a mediated dedifferentiation: a possible target in pancreatic cancer microenvironment. Oncotarget 7, 20223–20235 (2016).

  67. 67.

    Bi, P. et al. Notch activation drives adipocyte dedifferentiation and tumorigenic transformation in mice. J. Exp. Med. 213, 2019–2037 (2016).

  68. 68.

    Wang, Q. A. et al. Reversible de-differentiation of mature white adipocytes into preadipocyte-like precursors during lactation. Cell Metab. 28, 282–288 (2018).This study uses in vivo lineage tracing to demonstrate that adipocytes may reversibly differentiate and de-differentiate in the mouse mammary gland.

  69. 69.

    Löfgren, P. et al. Long-term prospective and controlled studies demonstrate adipose tissue hypercellularity and relative leptin deficiency in the postobese state. J. Clin. Endocrinol. Metab. 90, 6207–6213 (2005).

  70. 70.

    Tseng, W., Somaiah, N., Lazar, A., Lev, D. & Pollock, R. Novel systemic therapies in advanced liposarcoma: a review of recent clinical trial results. Cancers 5, 529 (2013).

  71. 71.

    Sheybani, E. F., Eutsler, E. P. & Navarro, O. M. Fat-containing soft-tissue masses in children. Pediatr. Radiol. 46, 1760–1773 (2016).

  72. 72.

    Karastergiou, K. & Fried, S. K. Multiple adipose depots increase cardiovascular risk via local and systemic effects. Curr. Atheroscler. Rep. 15, 361–361 (2013).

  73. 73.

    Poissonnet, C. M., Burdi, A. R. & Garn, S. M. The chronology of adipose tissue appearance and distribution in the human fetus. Early Hum. Dev. 10, 1–11 (1984).

  74. 74.

    Jiang, Y., Berry, Daniel, C., Tang, W., Graff & Jonathan, M. Independent stem cell lineages regulate adipose organogenesis and adipose homeostasis. Cell Rep. 9, 1007–1022 (2014).

  75. 75.

    Hong, K. Y. et al. Perilipin+ embryonic preadipocytes actively proliferate along growing vasculatures for adipose expansion. Development 142, 2623–2632 (2015).

  76. 76.

    Kang, S., Kong, X. & Rosen, E. D. in Methods in Enzymology Vol. 537 (ed. MacDougald, O. A.) 1–16 (Academic Press, 2014).

  77. 77.

    Jeffery, E., Church, C. D., Holtrup, B., Colman, L. & Rodeheffer, M. S. Rapid depot-specific activation of adipocyte precursor cells at the onset of obesity. Nat. Cell Biol. 17, 376–385 (2015). This study demonstrates that high-fat feeding activates preadipocyte proliferation specifically in visceral depots of mice.

  78. 78.

    Kim, S. M. et al. Loss of white adipose hyperplastic potential is associated with enhanced susceptibility to insulin resistance. Cell Metab. 20, 1049–1058 (2014).

  79. 79.

    Macotela, Y. et al. Intrinsic differences in adipocyte precursor cells from different white fat depots. Diabetes 61, 1691–1699 (2012).

  80. 80.

    McLaughlin, T. M. et al. Pioglitazone increases the proportion of small cells in human abdominal subcutaneous adipose tissue. Obesity 18, 926–931 (2010).

  81. 81.

    Fujiwara, T., Yoshioka, S., Yoshioka, T., Ushiyama, I. & Horikoshi, H. Characterization of new oral antidiabetic agent CS-045: studies in KK and ob/ob mice and Zucker fatty rats. Diabetes 37, 1549–1558 (1988).

  82. 82.

    Combs, T. P. et al. A transgenic mouse with a deletion in the collagenous domain of adiponectin displays elevated circulating adiponectin and improved insulin sensitivity. Endocrinology 145, 367–383 (2004).

  83. 83.

    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).

  84. 84.

    van Harmelen, V., Röhrig, K. & Hauner, H. Comparison of proliferation and differentiation capacity of human adipocyte precursor cells from the omental and subcutaneous adipose tissue depot of obese subjects. Metabolism 53, 632–637 (2004).

  85. 85.

    Kruglikov, I. L. & Scherer, P. E. Dermal adipocytes: from irrelevance to metabolic targets? Trends Endocrinol. Metab. 27, 1–10 (2016).

  86. 86.

    Kasza, I. et al. Syndecan-1 is required to maintain intradermal fat and prevent cold stress. PLOS Genet. 10, e1004514 (2014).

  87. 87.

    Schmidt, B. & Horsley, V. Unraveling hair follicle-adipocyte communication. Exp. Dermatol. 21, 827–830 (2012).

  88. 88.

    Festa, E. et al. Adipocyte lineage cells contribute to the skin stem cell niche to drive hair cycling. Cell 146, 761–771 (2011).

  89. 89.

    Schmidt, B. A. & Horsley, V. Intradermal adipocytes mediate fibroblast recruitment during skin wound healing. Development 140, 1517–1527 (2013).

  90. 90.

    Owczarczyk-Saczonek, A. et al. The use of adipose-derived stem cells in selected skin diseases (vitiligo, alopecia, and nonhealing wounds). Stem Cells Int. 2017, 11 (2017).

  91. 91.

    Na, Y. K., Ban, J.-J., Lee, M., Im, W. & Kim, M. Wound healing potential of adipose tissue stem cell extract. Biochem. Biophys. Res. Commun. 485, 30–34 (2017).

  92. 92.

    Marino, G. et al. Therapy with autologous adipose-derived regenerative cells for the care of chronic ulcer of lower limbs in patients with peripheral arterial disease. J. Surg. Res. 185, 36–44 (2013).

  93. 93.

    Holm, J. S., Toyserkani, N. M. & Sorensen, J. A. Adipose-derived stem cells for treatment of chronic ulcers: current status. Stem Cell Res. Ther. 9, 142–142 (2018).

  94. 94.

    Hamrick, M. W., McGee-Lawrence, M. E. & Frechette, D. M. Fatty infiltration of skeletal muscle: mechanisms and comparisons with bone marrow adiposity. Front. Endocrinol. 7, 69 (2016).

  95. 95.

    Uezumi, A., Fukada, S.-i, Yamamoto, N., Takeda, Si & Tsuchida, K. Mesenchymal progenitors distinct from satellite cells contribute to ectopic fat cell formation in skeletal muscle. Nat. Cell Biol. 12, 143–152 (2010).

  96. 96.

    Kopinke, D., Roberson, E. C. & Reiter, J. F. Ciliary Hedgehog signaling restricts injury-induced adipogenesis. Cell 170, 340–351 (2017).

  97. 97.

    Horowitz, M. C. et al. Bone marrow adipocytes. Adipocyte 6, 193–204 (2017).

  98. 98.

    Zhou, B. O. et al. Bone marrow adipocytes promote the regeneration of stem cells and haematopoiesis by secreting SCF. Nat. Cell Biol. 19, 891–903 (2017).

  99. 99.

    Yokota, T. et al. Adiponectin, a new member of the family of soluble defense collagens, negatively regulates the growth of myelomonocytic progenitors and the functions of macrophages. Blood 96, 1723–1732 (2000).

  100. 100.

    Bilwani, F. A. & Knight, K. L. Adipocyte-derived soluble factor(s) inhibits early stages of B lymphopoiesis. J. Immunol. 189, 4379–4386 (2012).

  101. 101.

    Kelly, K. A., Tanaka, S., Baron, R. & Gimble, J. M. Murine bone marrow stromally derived BMS2 adipocytes support differentiation and function of osteoclast-like cells in vitro. Endocrinology 139, 2092–2101 (1998).

  102. 102.

    Zhou, B. O., Yue, R., Murphy, M. M., Peyer, J. & Morrison, S. J. Leptin receptor-expressing mesenchymal stromal cells represent the main source of bone formed by adult bone marrow. Cell Stem Cell 15, 154–168 (2014).

  103. 103.

    Yue, R., Zhou, B. O., Shimada, I. S., Zhao, Z. & Morrison, S. J. Leptin receptor promotes adipogenesis and reduces osteogenesis by regulating mesenchymal stromal cells in adult bone marrow. Cell Stem Cell 18, 782–796 (2016).

  104. 104.

    Naveiras, O. et al. Bone marrow adipocytes as negative regulators of the hematopoietic microenvironment. Nature 460, 259–263 (2009).

  105. 105.

    Ambrosi, T. H. et al. Adipocyte accumulation in the bone marrow during obesity and aging impairs stem cell-based hematopoietic and bone regeneration. Cell Stem Cell 20, 771–784 (2017).

  106. 106.

    Jeffery, E. et al. The adipose tissue microenvironment regulates depot-specific adipogenesis in obesity. Cell Metab. 24, 142–150 (2016).

  107. 107.

    Lee, Y. H., Petkova, A. P., Mottillo, E. P. & Granneman, J. G. In vivo identification of bipotential adipocyte progenitors recruited by β3-adrenoceptor activation and high-fat feeding. Cell Metab. 15, 480–491 (2012).

  108. 108.

    Shao, M. et al. De novo adipocyte differentiation from Pdgfrβ(+) preadipocytes protects against pathologic visceral adipose expansion in obesity. Nat. Commun. 9, 890 (2018).

  109. 109.

    Burl, R. B. et al. Deconstructing adipogenesis induced by β3-adrenergic receptor activation with single-cell expression profiling. Cell Metab. 28, 300–309 (2018).

  110. 110.

    Schwalie, P. C. et al. A stromal cell population that inhibits adipogenesis in mammalian fat depots. Nature 559, 103–108 (2018). A study using single-cell sequencing to identify subpopulations of fibroblasts from subcutaneous adipose tissue in mice. The authors identify an anti-adipogenic population that may inhibit adipocyte differentiation in vitro.

  111. 111.

    Seale, P. et al. PRDM16 controls a brown fat/skeletal muscle switch. Nature 454, 961–967 (2008).

  112. 112.

    Cohen, P. et al. Ablation of PRDM16 and beige adipose causes metabolic dysfunction and a subcutaneous to visceral fat switch. Cell 156, 304–316 (2014).

  113. 113.

    Sanchez-Gurmaches, J. et al. PTEN loss in the Myf5 lineage redistributes body fat and reveals subsets of white adipocytes that arise from Myf5 precursors. Cell Metab. 16, 348–362 (2012).

  114. 114.

    Haeusler, R. A., McGraw, T. E. & Accili, D. Biochemical and cellular properties of insulin receptor signalling. Nat. Rev. Mol. Cell Biol. 19, 31 (2017).

  115. 115.

    Accili, D. & Taylor, S. I. Targeted inactivation of the insulin receptor gene in mouse 3T3-L1 fibroblasts via homologous recombination. Proc. Natl Acad. Sci. USA 88, 4708–4712 (1991). A study identifying the requirement for insulin signalling in adipocyte differentiation.

  116. 116.

    Chaika, O. V. et al. CSF-1 receptor/insulin receptor chimera permits CSF-1-dependent differentiation of 3T3-L1 preadipocytes. J. Biol. Chem. 272, 11968–11974 (1997).

  117. 117.

    Laustsen, P. G. et al. Lipoatrophic diabetes in Irs1(−/−)/Irs3(−/−) double knockout mice. Genes Dev. 16, 3213–3222 (2002).

  118. 118.

    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).

  119. 119.

    Tomiyama, K. et al. Wortmannin, a specific phosphatidylinositol 3-kinase inhibitor, inhibits adipocytic differentiation of 3T3-L1 cells. Biochem. Biophys. Res. Commun. 212, 263–269 (1995).

  120. 120.

    Solheim, M. H. et al. Mice carrying a dominant-negative human PI3K mutation are protected from obesity and hepatic steatosis but not diabetes. Diabetes 67, 1297–1309 (2018).

  121. 121.

    Park, J.-Y., Kim, Y., Im, J. A., You, S. & Lee, H. Inhibition of adipogenesis by oligonol through Akt-mTOR inhibition in 3T3-L1 adipocytes. Evid. Based Complement. Alternat. Med. 2014, 895272 (2014).

  122. 122.

    Xu, J. & Liao, K. Protein kinase B/AKT 1 plays a pivotal role in insulin-like growth factor-1 receptor signaling induced 3T3-L1 adipocyte differentiation. J. Biol. Chem. 279, 35914–35922 (2004).

  123. 123.

    George, S. et al. A family with severe insulin resistance and diabetes mellitus due to a missense mutation in AKT2. Science 304, 1325–1328 (2004).

  124. 124.

    Yeh, W. C., Bierer, B. E. & McKnight, S. L. Rapamycin inhibits clonal expansion and adipogenic differentiation of 3T3-L1 cells. Proc. Natl Acad. Sci. USA 92, 11086–11090 (1995).

  125. 125.

    Martin, S. K. et al. Brief report: the differential roles of mTORC1 and mTORC2 in mesenchymal stem cell differentiation. Stem Cells 33, 1359–1365 (2015).

  126. 126.

    Nakae, J. et al. The forkhead transcription factor Foxo1 regulates adipocyte differentiation. Dev. Cell 4, 119–129 (2003).

  127. 127.

    Blüher, M. et al. Adipose tissue selective insulin receptor knockout protects against obesity and obesity-related glucose intolerance. Dev. Cell 3, 25–38 (2002).

  128. 128.

    Bäck, K. & Arnqvist, H. J. Changes in insulin and IGF-I receptor expression during differentiation of human preadipocytes. Growth Horm. IGF Res. 19, 101–111 (2009).

  129. 129.

    Weitzman, E. D. et al. Twenty-four hour pattern of the episodic secretion of cortisol in normal subjects. J. Clin. Endocrinol. Metab. 33, 14–22 (1971).

  130. 130.

    Hackett, R. A., Steptoe, A. & Kumari, M. Association of diurnal patterns in salivary cortisol with type 2 diabetes in the Whitehall II study. J. Clin. Endocrinol. Metab. 99, 4625–4631 (2014).

  131. 131.

    Bruehl, H., Wolf, O. T. & Convit, A. A blunted cortisol awakening response and hippocampal atrophy in type 2 diabetes mellitus. Psychoneuroendocrinology 34, 815–821 (2009).

  132. 132.

    Chapman, A. B., Knight, D. M. & Ringold, G. M. Glucocorticoid regulation of adipocyte differentiation: hormonal triggering of the developmental program and induction of a differentiation-dependent gene. J. Cell Biol. 101, 1227–1235 (1985).

  133. 133.

    Hauner, H., Schmid, P. & Pfeiffer, E. F. Glucocorticoids and insulin promote the differentiation of human adipocyte precursor cells into fat cells. J. Clin. Endocrinol. Metab. 64, 832–835 (1987).

  134. 134.

    Shugart, E. & Umek, R. Dexamethasone signaling is required to establish the postmitotic state of adipocyte development. Cell Growth Differ. 8, 1091–1098 (1997).

  135. 135.

    Wiper-Bergeron, N., Salem, H. A., Tomlinson, J. J., Wu, D. & Haché, R. J. G. Glucocorticoid-stimulated preadipocyte differentiation is mediated through acetylation of C/EBPβ by GCN5. Proc. Natl Acad. Sci. USA 104, 2703–2708 (2007).

  136. 136.

    Tomlinson, J. J., Boudreau, A., Wu, D., Atlas, E. & Haché, R. J. Modulation of early human preadipocyte differentiation by glucocorticoids. Endocrinology 147, 5284–5293 (2006).

  137. 137.

    Tomlinson, J. J. et al. Insulin sensitization of human preadipocytes through glucocorticoid hormone induction of forkhead transcription factors. Mol. Endocrinol. 24, 104–113 (2010).

  138. 138.

    Tseng, Y.-H. et al. New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure. Nature 454, 1000–1004 (2008).

  139. 139.

    Modica, S. et al. Bmp4 promotes a brown to white-like adipocyte shift. Cell Rep. 16, 2243–2258 (2016).

  140. 140.

    Son, J.-W. et al. Association of serum bone morphogenetic protein 4 levels with obesity and metabolic syndrome in non-diabetic individuals. Endocr. J. 58, 39–46 (2011).

  141. 141.

    Ross, S. E. et al. Inhibition of adipogenesis by Wnt signaling. Science 289, 950–953 (2000).

  142. 142.

    Cawthorn, W. P. et al. Wnt6, Wnt10a and Wnt10b inhibit adipogenesis and stimulate osteoblastogenesis through a β-catenin-dependent mechanism. Bone 50, 477–489 (2012).

  143. 143.

    Isakson, P., Hammarstedt, A., Gustafson, B. & Smith, U. Impaired preadipocyte differentiation in human abdominal obesity: role of Wnt, tumor necrosis factor-alpha, and inflammation. Diabetes 58, 1550–1557 (2009).

  144. 144.

    Park, Y.-K. et al. Hypoxia-inducible factor-2α-dependent hypoxic induction of Wnt10b expression in adipogenic cells. J. Biol. Chem. 288, 26311–26322 (2013).

  145. 145.

    Nakamura, Y. et al. Repression of adipogenesis through promotion of Wnt/β-catenin signaling by TIS7 up-regulated in adipocytes under hypoxia. Biochim. Biophys. Acta 1832, 1117–1128 (2013).

  146. 146.

    Rajashekhar, G. et al. IFATS collection: adipose stromal cell differentiation is reduced by endothelial cell contact and paracrine communication: role of canonical Wnt signaling. Stem Cells 26, 2674–2681 (2008).

  147. 147.

    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).

  148. 148.

    Fontaine, C., Cousin, W., Plaisant, M., Dani, C. & Peraldi, P. Hedgehog signaling alters adipocyte maturation of human mesenchymal stem cells. Stem Cells 26, 1037–1046 (2008).

  149. 149.

    Suh, J. M. et al. Hedgehog signaling plays a conserved role in inhibiting fat formation. Cell Metab. 3, 25–34 (2006).

  150. 150.

    Gustafson, B. & Smith, U. Cytokines promote Wnt signaling and inflammation and impair the normal differentiation and lipid accumulation in 3T3-L1 preadipocytes. J. Biol. Chem. 281, 9507–9516 (2006).

  151. 151.

    Weisberg, S. P. et al. Obesity is associated with macrophage accumulation in adipose tissue. J. Clin. Invest. 112, 1796–1808 (2003).

  152. 152.

    Cancello, R. et al. Increased infiltration of macrophages in omental adipose tissue is associated with marked hepatic lesions in morbid human obesity. Diabetes 55, 1554–1561 (2006).

  153. 153.

    Samad, F., Yamamoto, K., Pandey, M. & Loskutoff, D. J. Elevated expression of transforming growth factor-beta in adipose tissue from obese mice. Mol. Med. 3, 37–48 (1997).

  154. 154.

    Alessi, M. C. et al. Plasminogen activator inhibitor 1, transforming growth factor-beta1, and BMI are closely associated in human adipose tissue during morbid obesity. Diabetes 49, 1374–1380 (2000).

  155. 155.

    Ignotz, R. A. & Massagué, J. Type beta transforming growth factor controls the adipogenic differentiation of 3T3 fibroblasts. Proc. Natl Acad. Sci. USA 82, 8530–8534 (1985).

  156. 156.

    Clouthier, D. E., Comerford, S. A. & Hammer, R. E. Hepatic fibrosis, glomerulosclerosis, and a lipodystrophy-like syndrome in PEPCK-TGF-beta1 transgenic mice. J. Clin. Invest. 100, 2697–2713 (1997).

  157. 157.

    Torti, F., Dieckmann, B., Beutler, B., Cerami, A. & Ringold, G. A macrophage factor inhibits adipocyte gene expression: an in vitro model of cachexia. Science 229, 867–869 (1985).

  158. 158.

    Charrière, G. et al. Preadipocyte conversion to macrophage: evidence of plasticity. J. Biol. Chem. 278, 9850–9855 (2003).

  159. 159.

    Marcelin, G. et al. A PDGFRα-mediated switch toward CD9high adipocyte progenitors controls obesity-induced adipose tissue fibrosis. Cell Metab. 25, 673–685 (2017).

  160. 160.

    Hepler, C. et al. Identification of functionally distinct fibro-inflammatory and adipogenic stromal subpopulations in visceral adipose tissue of adult mice. eLife 7, e39636 (2018). Study using single-cell sequencing to characterize functionally distinct populations of PDGFRβ + fibroblasts in visceral mouse adipose tissue. The authors identify a population primed for adipogenesis in vitro as well as a population that inhibits adipogenesis in vitro.

  161. 161.

    Qiu, Y. et al. Eosinophils and type 2 cytokine signaling in macrophages orchestrate development of functional beige fat. Cell 157, 1292–1308 (2014).

  162. 162.

    Lee, M.-W. et al. Activated type 2 innate lymphoid cells regulate beige fat biogenesis. Cell 160, 74–87 (2015).

  163. 163.

    Brestoff, J. R. et al. Group 2 innate lymphoid cells promote beiging of adipose and limit obesity. Nature 519, 242–246 (2015).

  164. 164.

    Wernstedt, A. I. et al. Adipocyte inflammation is essential for healthy adipose tissue expansion and remodeling. Cell Metab. 20, 103–118 (2014).

  165. 165.

    Sun, M. et al. Meta-analysis on shift work and risks of specific obesity types. Obes. Rev. 19, 28–40 (2018).

  166. 166.

    Yang, X. et al. Nuclear receptor expression links the circadian clock to metabolism. Cell 126, 801–810 (2006).

  167. 167.

    Aggarwal, A. et al. The circadian clock regulates adipogenesis by a Per3 crosstalk pathway to Klf15. Cell Rep. 21, 2367–2375 (2017).

  168. 168.

    Grimaldi, B. et al. PER2 controls lipid metabolism by direct regulation of PPARγ. Cell Metab. 12, 509–520 (2010).

  169. 169.

    Costa, M. J. et al. Circadian rhythm gene period 3 Is an inhibitor of the adipocyte cell fate. J. Biol. Chem. 286, 9063–9070 (2011).

  170. 170.

    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).

  171. 171.

    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).

  172. 172.

    Bahrami-Nejad, Z. et al. A transcriptional circuit filters oscillating circadian hormonal inputs to regulate fat cell differentiation. Cell Metab. 27, 854–868 (2018). This study identifies how disruption of circadian glucocorticoid signalling leads to increased preadipocyte differentiation in 3T3-L1 cell lines.

  173. 173.

    Rolo, A. P., Teodoro, J. S. & Palmeira, C. M. Role of oxidative stress in the pathogenesis of nonalcoholic steatohepatitis. Free Radic. Biol. Med. 52, 59–69 (2012).

  174. 174.

    Carrière, A., Fernandez, Y., Rigoulet, M., Pénicaud, L. & Casteilla, L. Inhibition of preadipocyte proliferation by mitochondrial reactive oxygen species. FEBS Lett. 550, 163–167 (2003).

  175. 175.

    Lee, H., Lee, Y. J., Choi, H., Ko, E. H. & Kim, J.-W. Reactive oxygen species facilitate adipocyte differentiation by accelerating mitotic clonal expansion. J. Biol. Chem. 284, 10601–10609 (2009).

  176. 176.

    Tormos, K. V. et al. Mitochondrial complex III ROS regulate adipocyte differentiation. Cell Metab. 14, 537–544 (2011).

  177. 177.

    Calzadilla, P. et al. N-acetylcysteine reduces markers of differentiation in 3T3-L1 adipocytes. Int. J. Mol. Sci. 12, 6936–6951 (2011).

  178. 178.

    Kanda, Y., Hinata, T., Kang, S. W. & Watanabe, Y. Reactive oxygen species mediate adipocyte differentiation in mesenchymal stem cells. Life Sci. 89, 250–258 (2011).

  179. 179.

    Vigilanza, P., Aquilano, K., Baldelli, S., Rotilio, G. & Ciriolo Maria, R. Modulation of intracellular glutathione affects adipogenesis in 3T3-L1 cells. J. Cell. Physiol. 226, 2016–2024 (2010).

  180. 180.

    Mahadev, K. et al. The NAD(P)H oxidase homolog Nox4 modulates insulin-stimulated generation of H2O2 and plays an integral role in insulin signal transduction. Mol. Cell. Biol. 24, 1844–1854 (2004).

  181. 181.

    Mahadev, K. et al. Hydrogen peroxide generated during cellular insulin stimulation is integral to activation of the distal insulin signaling cascade in 3T3-L1 adipocytes. J. Biol. Chem. 276, 48662–48669 (2001).

  182. 182.

    Furukawa, S. et al. Increased oxidative stress in obesity and its impact on metabolic syndrome. J. Clin. Invest. 114, 1752–1761 (2017).

  183. 183.

    Houstis, N., Rosen, E. D. & Lander, E. S. Reactive oxygen species have a causal role in multiple forms of insulin resistance. Nature 440, 944–948 (2006).

  184. 184.

    Anderson, E. J. et al. Mitochondrial H2O2 emission and cellular redox state link excess fat intake to insulin resistance in both rodents and humans. J. Clin. Invest. 119, 573–581 (2009).

  185. 185.

    Agarwal, A. K. et al. AGPAT2 is mutated in congenital generalized lipodystrophy linked to chromosome 9q34. Nat. Genet. 31, 21–23 (2002).

  186. 186.

    Magré, J. et al. Identification of the gene altered in Berardinelli–Seip congenital lipodystrophy on chromosome 11q13. Nat. Genet. 28, 365–370 (2001).

  187. 187.

    Kim, C. A. et al. Association of a homozygous nonsense caveolin-1 mutation with Berardinelli-Seip congenital lipodystrophy. J. Clin. Endocrinol. Metab. 93, 1129–1134 (2008).

  188. 188.

    Hayashi, Y. K. et al. Human PTRF mutations cause secondary deficiency of caveolins resulting in muscular dystrophy with generalized lipodystrophy. J. Clin. Invest. 119, 2623–2633 (2009).

  189. 189.

    Bi, J. et al. Seipin promotes adipose tissue fat storage through the ER Ca2+-ATPase SERCA. Cell Metab. 19, 861–871 (2014).

  190. 190.

    Gale, S. E. et al. A regulatory role for 1-acylglycerol-3-phosphate-O-acyltransferase 2 in adipocyte differentiation. J. Biol. Chem. 281, 11082–11089 (2006).

  191. 191.

    Chen, W. et al. The human lipodystrophy gene product Berardinelli-Seip congenital lipodystrophy 2/seipin plays a key role in adipocyte differentiation. Endocrinology 150, 4552–4561 (2009).

  192. 192.

    Payne, V. A. et al. The human lipodystrophy gene BSCL2/seipin may be essential for normal adipocyte differentiation. Diabetes 57, 2055–2060 (2008).

  193. 193.

    Fan, J. Y. et al. Morphological changes of the 3T3-L1 fibroblast plasma membrane upon differentiation to the adipocyte form. J. Cell Sci. 61, 219–230 (1983).

  194. 194.

    Razani, B. et al. Caveolin-1-deficient mice are lean, resistant to diet-induced obesity, and show hypertriglyceridemia with adipocyte abnormalities. J. Biol. Chem. 277, 8635–8647 (2002).

  195. 195.

    Nystrom, F. H., Chen, H., Cong, L.-N., Li, Y. & Quon, M. J. Caveolin-1 interacts with the insulin receptor and can differentially modulate insulin signaling in transfected COS-7 cells and rat adipose cells. Mol. Endocrinol. 13, 2013–2024 (1999).

  196. 196.

    Hill, M. M. et al. PTRF-cavin, a conserved cytoplasmic protein required for caveola formation and function. Cell 132, 113–124 (2008).

  197. 197.

    Crewe, C. et al. An endothelial-to-adipocyte extracellular vesicle axis governed by metabolic state. Cell 175, 695–708 (2018).

  198. 198.

    Conlan, R. S., Pisano, S., Oliveira, M. I., Ferrari, M. & Mendes Pinto, I. Exosomes as reconfigurable therapeutic systems. Trends Mol. Med. 23, 636–650 (2017).

  199. 199.

    Oral, E. A. et al. Leptin-replacement therapy for lipodystrophy. N. Engl. J. Med. 346, 570–578 (2002).

  200. 200.

    Shimomura, I., Hammer, R. E., Ikemoto, S., Brown, M. S. & Goldstein, J. L. Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy. Nature 401, 73 (1999).

  201. 201.

    Pajvani, U. B. et al. Fat apoptosis through targeted activation of caspase 8: a new mouse model of inducible and reversible lipoatrophy. Nat. Med. 11, 797–803 (2005).

  202. 202.

    Hussain, I. & Garg, A. Lipodystrophy syndromes. Endocrinol. Metab. Clin. North Am. 45, 783–797 (2016). Recent review on the pathophysiology of human lipodystrophies and treatment options.

  203. 203.

    Wojtanik, K. M. et al. The role of LMNA in adipose: a novel mouse model of lipodystrophy based on the Dunnigan-type familial partial lipodystrophy mutation. J. Lipid Res. 50, 1068–1079 (2009).

  204. 204.

    Arioglu, E. et al. Efficacy and safety of troglitazone in the treatment of lipodystrophy syndromes. Ann. Intern. Med. 133, 263–274 (2000).

  205. 205.

    Owen, K. R., Donohoe, M., Ellard, S. & Hattersley, A. T. Response to treatment with rosiglitazone in familial partial lipodystrophy due to a mutation in the LMNA gene. Diabet. Med. 20, 823–827 (2003).

  206. 206.

    Lüdtke, A. et al. Long-term treatment experience in a subject with Dunnigan-type familial partial lipodystrophy: efficacy of rosiglitazone. Diabet. Med. 22, 1611–1613 (2005).

  207. 207.

    Palmer, A. K. & Kirkland, J. L. Aging and adipose tissue: potential interventions for diabetes and regenerative medicine. Exp. Gerontol. 86, 97–105 (2016).

  208. 208.

    Karagiannides, I. et al. Altered expression of C/EBP family members results in decreased adipogenesis with aging. Am. J. Physiol. Regul. Integr. Comp. Physiol. 280, R1772–R1780 (2001).

  209. 209.

    Caso, G. et al. Peripheral fat loss and decline in adipogenesis in older humans. Metabolism 62, 337–340 (2013).

  210. 210.

    Xu, M. et al. Targeting senescent cells enhances adipogenesis and metabolic function in old age. eLife 4, e12997 (2015). This study demonstrates that removal of senescent cells from aged adipose tissue enhances adipogenesis in vivo. Interestingly, the authors demonstrate that FDA-approved JAK1/JAK2 inhibitors may be effective at reducing ageing phenotypes in vivo.

  211. 211.

    Xu, M. et al. JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age. Proc. Natl Acad. Sci. USA 112, E6301–E6310 (2015).

  212. 212.

    Baker, D. J. et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479, 232–236 (2011).

  213. 213.

    Berry, D. C. et al. Cellular aging contributes to failure of cold-induced beige adipocyte formation in old mice and humans. Cell Metab. 25, 166–181 (2017).

  214. 214.

    van Heemst, D. Insulin, IGF-1 and longevity. Aging Dis. 1, 147–157 (2010).

  215. 215.

    Zhang, Y. et al. The starvation hormone, fibroblast growth factor-21, extends lifespan in mice. eLife 1, e00065 (2012).

  216. 216.

    Dutchak, P. A. et al. Fibroblast growth factor-21 regulates PPARγ activity and the antidiabetic actions of thiazolidinediones. Cell 148, 556–567 (2012).

  217. 217.

    Lotta, L. A. et al. Integrative genomic analysis implicates limited peripheral adipose storage capacity in the pathogenesis of human insulin resistance. Nat. Genet. 49, 17–26 (2016).

  218. 218.

    Chu, A. Y. et al. Multiethnic genome-wide meta-analysis of ectopic fat depots identifies loci associated with adipocyte development and differentiation. Nat. Genet. 49, 125–130 (2017).

  219. 219.

    Kusminski, C. M. et al. MitoNEET-driven alterations in adipocyte mitochondrial activity reveal a crucial adaptive process that preserves insulin sensitivity in obesity. Nat. Med. 18, 1539–1549 (2012).

  220. 220.

    Senol-Cosar, O. et al. Tenomodulin promotes human adipocyte differentiation and beneficial visceral adipose tissue expansion. Nat. Commun. 7, 10686 (2016).

  221. 221.

    Morley, T. S., Xia, J. Y. & Scherer, P. E. Selective enhancement of insulin sensitivity in the mature adipocyte is sufficient for systemic metabolic improvements. Nat. Commun. 6, 7906 (2015).

  222. 222.

    Kim, J.-Y. et al. Obesity-associated improvements in metabolic profile through expansion of adipose tissue. J. Clin. Invest. 117, 2621–2637 (2007).

  223. 223.

    Shepherd, P. R. et al. Adipose cell hyperplasia and enhanced glucose disposal in transgenic mice overexpressing GLUT4 selectively in adipose tissue. J. Biol. Chem. 268, 22243–22246 (1993).

  224. 224.

    Okuno, A. et al. Troglitazone increases the number of small adipocytes without the change of white adipose tissue mass in obese Zucker rats. J. Clin. Invest. 101, 1354–1361 (1998).

  225. 225.

    Adams, M. et al. Activators of peroxisome proliferator-activated receptor gamma have depot-specific effects on human preadipocyte differentiation. J. Clin. Invest. 100, 3149–3153 (1997).

  226. 226.

    Saiki, A. et al. Tenomodulin is highly expressed in adipose tissue, increased in obesity, and down-regulated during diet-induced weight loss. J. Clin. Endocrinol. Metab. 94, 3987–3994 (2009).

  227. 227.

    Hammarstedt, A., Graham, T. E. & Kahn, B. B. Adipose tissue dysregulation and reduced insulin sensitivity in non-obese individuals with enlarged abdominal adipose cells. Diabetol. Metab. Syndr. 4, 42 (2012). This is a human correlational study establishing a link between increased fat cell size and reduced insulin sensitivity in non-obese individuals.

  228. 228.

    Arner, E. et al. Adipocyte turnover: relevance to human adipose tissue morphology. Diabetes 59, 105–109 (2010).

  229. 229.

    Acosta, J. R. et al. Increased fat cell size: a major phenotype of subcutaneous white adipose tissue in non-obese individuals with type 2 diabetes. Diabetologia 59, 560–570 (2016).

  230. 230.

    Fall, C. H. et al. Fetal and infant growth and cardiovascular risk factors in women. BMJ 310, 428–432 (1995).

  231. 231.

    Hales, C. N. et al. Fetal and infant growth and impaired glucose tolerance at age 64. BMJ 303, 1019–1022 (1991).

  232. 232.

    Ravelli, G.-P., Stein, Z. A. & Susser, M. W. Obesity in young men after famine exposure in utero and early infancy. N. Engl. J. Med. 295, 349–353 (1976).

  233. 233.

    Yajnik, C. S. et al. Neonatal anthropometry: the thin-fat Indian baby. The Pune Maternal Nutrition Study. Int. J. Obes. Relat. Metab. Disord. 27, 173–180 (2003).

  234. 234.

    Krishnaveni, G. et al. Truncal adiposity is present at birth and in early childhood in South Indian children. Indian Pediatr. 42, 527–538 (2005).

  235. 235.

    Wang, W. et al. Ebf2 is a selective marker of brown and beige adipogenic precursor cells. Proc. Natl Acad. Sci. USA 111, 14466–14471 (2014).

  236. 236.

    Rajakumari, S. et al. EBF2 determines and maintains brown adipocyte identity. Cell Metab. 17, 562–574 (2013).

  237. 237.

    Shao, M. et al. Zfp423 maintains white adipocyte identity through suppression of the beige cell thermogenic gene program. Cell Metab. 23, 1167–1184 (2016).

  238. 238.

    Stine, R. R. et al. EBF2 promotes the recruitment of beige adipocytes in white adipose tissue. Mol. Metab. 5, 57–65 (2016).

  239. 239.

    Khanh, V. C. et al. Aging impairs beige adipocyte differentiation of mesenchymal stem cells via the reduced expression of Sirtuin 1. Biochem. Biophys. Res. Commun. 500, 682–690 (2018).

  240. 240.

    Berry, R. & Rodeheffer, M. S. Characterization of the adipocyte cellular lineage in vivo. Nat. Cell Biol. 15, 302–308 (2013).

  241. 241.

    Hepler, C., Vishvanath, L. & Gupta, R. K. Sorting out adipocyte precursors and their role in physiology and disease. Genes Dev. 31, 127–140 (2017).

Download references


The authors apologize to their colleagues for not being able to include all their important work related to adipogenesis and metabolic health. The authors also thank members of the Touchstone Diabetes Center for their helpful critical reading of this manuscript. P.E.S. is supported by US National Institutes of Health (NIH) grants R01-DK55758, P01-DK088761, R01-DK099110 and P01-AG051459 and by an unrestricted grant from the Novo Nordisk Research Foundation. A.L.G. is supported by the NIH, National Institute of General Medical Sciences Training Grant T32-GM008203.

Reviewer information

Nature Reviews Molecular Cell Biology thanks K. Spalding and other anonymous reviewer(s) for their contribution to the peer review of this work.

Author information




Both authors contributed equally to all aspects of the article.

Corresponding author

Correspondence to Philipp E. Scherer.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information


Insulin resistance

A pathological condition in which the systemic and cellular response to insulin action is impaired. At the cellular level, insulin resistance can be defined as reduced signal transduction along the PI3K–AKT–mTOR pathway per unit of insulin, resulting in decreased glucose uptake per unit of insulin in adipocytes and skeletal muscle or decreased suppression of hepatic gluconeogenesis. Systemically, compared with healthy individuals, individuals with insulin resistance have elevated plasma insulin levels, elevated plasma glucose levels and impaired glucose clearance in response to the same bolus of insulin.


A cellular dysfunction arising from accumulation of lipid intermediates in cells other than adipocytes. In liver, accumulation of lipids contributes to the pathogenesis of non-alcoholic fatty liver disease and to insulin resistance. Lipid accumulation in skeletal muscle can contribute to insulin resistance, whereas in cardiac muscle, it can cause apoptotic cell death. Pancreatic lipid accumulation can lead to dysregulation of β-cell insulin secretion, and ultimately to apoptotic cell death.


Signalling molecules (proteins or lipids) secreted from adipose tissue.


A term referring to an animal that maintains a constant body temperature.

Interscapular depot

The brown adipose tissue depot found between the scapulae in rodents and infant humans.

Supraclavicular depot

The thermogenic adipose tissue depot found above the clavicles in adult humans and mice, which in humans contains the highest proportion, by volume, of total brown adipose tissue.

Sympathetic output

The sympathetic nervous system is a system of peripheral nerves that signal primarily with the neurotransmitter noradrenaline through activation of adrenergic receptors. Sympathetic output refers to central signals that increase the activity of these nerves.


The generation of glucose from non-carbohydrate carbon sources (glycerol, odd-chain fatty acids, lactate or certain amino acids). In mammals, the liver, kidney, intestine and skeletal muscle are the only organs capable of gluconeogenesis.


A class of sphingolipids extensively reported to contribute to insulin resistance. The anti-diabetic adipokine adiponectin exhibits effects partially through receptor-associated ceramidase activity.

Mesenchymal precursor

A stromal, fibroblast-like cell found throughout the body that is capable of differentiating to form an adipocyte, chondrocyte or osteoblast.

Nuclear hormone receptor

A class of nuclear receptors capable of directly binding to both DNA and a steroid or other endocrine hormone. Nuclear hormone receptors are able to directly regulate transcription upon ligand binding.


Straight-chain, 20-carbon polyunsaturated fatty acids that contain an oxygen moiety. Characteristically, eicosanoids are signalling lipids.


A subclass of eicosanoids derived from arachidonic acid with a characteristic five-carbon ring. The signalling actions of prostaglandins are highly tissue-specific.

Gluteofemoral depot

A representative, commonly studied human subcutaneous adipose depot. This depot is anatomically located subcutaneously, along the hips, buttocks and thighs.

Omental depot

One of the commonly studied human visceral adipose depots. The omental adipose depot is inside the peritoneum, starts near the stomach and spleen and extends deep into the abdomen.

Panniculus carnosus

Striated muscle anatomically located within or just beneath the superficial fascia of the dermis that controls local movement of the skin. It is present in many lower mammals but absent in humans.


The age-related loss of muscle mass.

Metabolic syndrome

A combination of five metabolic risk factors: high blood pressure, elevated fasting blood glucose, hypertriglyceridaemia, decreased serum high-density lipoprotein and increased abdominal adiposity, which collectively increase the risk of heart disease, diabetes and stroke.


Small, flask-like invaginations of plasma membrane that are abundant in many mammalian cell types including adipocytes. They have been implicated in various processes, including endocytosis, signalling, lipid regulation and mechanosensing.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Ghaben, A.L., Scherer, P.E. Adipogenesis and metabolic health. Nat Rev Mol Cell Biol 20, 242–258 (2019).

Download citation

Further reading