Metabolic adaptation and maladaptation in adipose tissue


Adipose tissue possesses the remarkable capacity to control its size and function in response to a variety of internal and external cues, such as nutritional status and temperature. The regulatory circuits of fuel storage and oxidation in white adipocytes and thermogenic adipocytes (brown and beige adipocytes) play a central role in systemic energy homeostasis, whereas dysregulation of the pathways is closely associated with metabolic disorders and adipose tissue malfunction, including obesity, insulin resistance, chronic inflammation, mitochondrial dysfunction, and fibrosis. Recent studies have uncovered new regulatory elements that control the above parameters and provide new mechanistic opportunities to reprogram fat cell fate and function. In this Review, we provide an overview of the current understanding of adipocyte metabolism in physiology and disease and also discuss possible strategies to alter fuel utilization in fat cells to improve metabolic health.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: Control of fatty acid storage and oxidation.
Fig. 2: Cellular metabolism in thermogenic fat cells.
Fig. 3: Adaptation and maladaptation in adipose tissue.


  1. 1.

    Guarente, L. Mitochondria—a nexus for aging, calorie restriction, and sirtuins? Cell 132, 171–176 (2008).

  2. 2.

    Anderson, R. M. & Weindruch, R. Metabolic reprogramming, caloric restriction and aging. Trends Endocrinol. Metab. 21, 134–141 (2010).

  3. 3.

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

  4. 4.

    Sepa-Kishi, D. M., Sotoudeh-Nia, Y., Iqbal, A., Bikopoulos, G. & Ceddia, R. B. Cold acclimation causes fiber type-specific responses in glucose and fat metabolism in rat skeletal muscles. Sci. Rep. 7, 15430 (2017).

  5. 5.

    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).

  6. 6.

    Kleemann, R. et al. Time-resolved and tissue-specific systems analysis of the pathogenesis of insulin resistance. PLoS One 5, e8817 (2010).

  7. 7.

    Rosenwald, M., Perdikari, A., Rülicke, T. & Wolfrum, C. Bi-directional interconversion of brite and white adipocytes. Nat. Cell Biol. 15, 659–667 (2013).

  8. 8.

    Altshuler-Keylin, S. et al. Beige adipocyte maintenance is regulated by autophagy-induced mitochondrial clearance. Cell Metab. 24, 402–419 (2016).

  9. 9.

    Schenk, S., Saberi, M. & Olefsky, J. M. Insulin sensitivity: modulation by nutrients and inflammation. J. Clin. Invest. 118, 2992–3002 (2008).

  10. 10.

    Czech, M. P. Insulin action and resistance in obesity and type 2 diabetes. Nat. Med. 23, 804–814 (2017).

  11. 11.

    Pepino, M. Y., Kuda, O., Samovski, D. & Abumrad, N. A. Structure-function of CD36 and importance of fatty acid signal transduction in fat metabolism. Annu. Rev. Nutr. 34, 281–303 (2014).

  12. 12.

    Herman, M. A. et al. A novel ChREBP isoform in adipose tissue regulates systemic glucose metabolism. Nature 484, 333–338 (2012).

  13. 13.

    Strable, M. S. & Ntambi, J. M. Genetic control of de novo lipogenesis: role in diet-induced obesity. Crit. Rev. Biochem. Mol. Biol. 45, 199–214 (2010).

  14. 14.

    Park, J. et al. Overexpression of glucose-6-phosphate dehydrogenase is associated with lipid dysregulation and insulin resistance in obesity. Mol. Cell. Biol. 25, 5146–5157 (2005).

  15. 15.

    Foster, D. W. Malonyl-CoA: the regulator of fatty acid synthesis and oxidation. J. Clin. Invest. 122, 1958–1959 (2012).

  16. 16.

    Martin, D. B. & Vagelos, P. R. The mechanism of tricarboxylic acid cycle regulation of fatty acid synthesis. J. Biol. Chem. 237, 1787–1792 (1962).

  17. 17.

    Reshef, L. et al. Glyceroneogenesis and the triglyceride/fatty acid cycle. J. Biol. Chem. 278, 30413–30416 (2003).

  18. 18.

    Postic, C. & Girard, J. Contribution of de novo fatty acid synthesis to hepatic steatosis and insulin resistance: lessons from genetically engineered mice. J. Clin. Invest. 118, 829–838 (2008).

  19. 19.

    Hung, C. M. et al. Rictor/mTORC2 loss in the Myf5 lineage reprograms brown fat metabolism and protects mice against obesity and metabolic disease. Cell Rep. 8, 256–271 (2014).

  20. 20.

    Tang, Y. et al. Adipose tissue mTORC2 regulates ChREBP-driven de novo lipogenesis and hepatic glucose metabolism. Nat. Commun. 7, 11365 (2016).

  21. 21.

    Arner, P. Human fat cell lipolysis: biochemistry, regulation and clinical role. Best. Pract. Res. Clin. Endocrinol. Metab. 19, 471–482 (2005).

  22. 22.

    Braun, K., Oeckl, J., Westermeier, J., Li, Y. & Klingenspor, M. Non-adrenergic control of lipolysis and thermogenesis in adipose tissues. J. Exp. Biol. 221(Suppl 1), jeb165381 (2018).

  23. 23.

    Nakamura, K. & Morrison, S. F. Central efferent pathways for cold-defensive and febrile shivering. J. Physiol. (Lond.) 589, 3641–3658 (2011).

  24. 24.

    Rayner, D. V. The sympathetic nervous system in white adipose tissue regulation. Proc. Nutr. Soc. 60, 357–364 (2001).

  25. 25.

    Duncan, R. E., Ahmadian, M., Jaworski, K., Sarkadi-Nagy, E. & Sul, H. S. Regulation of lipolysis in adipocytes. Annu. Rev. Nutr. 27, 79–101 (2007).

  26. 26.

    Camell, C. D. et al. Inflammasome-driven catecholamine catabolism in macrophages blunts lipolysis during ageing. Nature 550, 119–123 (2017).

  27. 27.

    Pirzgalska, R. M. et al. Sympathetic neuron–associated macrophages contribute to obesity by importing and metabolizing norepinephrine. Nat. Med. 23, 1309–1318 (2017).

  28. 28.

    Bachman, E. S. et al. βAR signaling required for diet-induced thermogenesis and obesity resistance. Science 297, 843–845 (2002).

  29. 29.

    Jung, R. T., Shetty, P. S., James, W. P., Barrand, M. A. & Callingham, B. A. Reduced thermogenesis in obesity. Nature 279, 322–323 (1979).

  30. 30.

    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, 480–495 (2016).

  31. 31.

    Harms, M. & Seale, P. Brown and beige fat: development, function and therapeutic potential. Nat. Med. 19, 1252–1263 (2013).

  32. 32.

    Bordicchia, M. et al. Cardiac natriuretic peptides act via p38 MAPK to induce the brown fat thermogenic program in mouse and human adipocytes. J. Clin. Invest. 122, 1022–1036 (2012).

  33. 33.

    Jun, H. et al. An immune–beige adipocyte communication via nicotinic acetylcholine receptor signaling. Nat. Med. 24, 814–822 (2018).

  34. 34.

    Collins, S. β-adrenoceptor signaling networks in adipocytes for recruiting stored fat and energy expenditure. Front. Endocrinol. 2, 102 (2012).

  35. 35.

    Fedorenko, A., Lishko, P. V. & Kirichok, Y. Mechanism of fatty-acid-dependent UCP1 uncoupling in brown fat mitochondria. Cell 151, 400–413 (2012).

  36. 36.

    Fromme, T. et al. Degradation of brown adipocyte purine nucleotides regulates uncoupling protein 1 activity. Mol. Metab. 8, 77–85 (2018).

  37. 37.

    Han, Y. H. et al. Adipocyte-specific deletion of manganese superoxide dismutase protects from diet-induced obesity through increased mitochondrial uncoupling and biogenesis. Diabetes 65, 2639–2651 (2016).

  38. 38.

    Chouchani, E. T. et al. Mitochondrial ROS regulate thermogenic energy expenditure and sulfenylation of UCP1. Nature 532, 112–116 (2016).

  39. 39.

    Nedergaard, J. & Cannon, B. UCP1 mRNA does not produce heat. Biochim. Biophys. Acta 1831, 943–949 (2013).

  40. 40.

    Ikeda, K. et al. UCP1-independent signaling involving SERCA2b-mediated calcium cycling regulates beige fat thermogenesis and systemic glucose homeostasis. Nat. Med. 23, 1454–1465 (2017).

  41. 41.

    Kazak, L. et al. A creatine-driven substrate cycle enhances energy expenditure and thermogenesis in beige fat. Cell 163, 643–655 (2015).

  42. 42.

    Vitali, A. et al. The adipose organ of obesity-prone C57BL/6J mice is composed of mixed white and brown adipocytes. J. Lipid Res. 53, 619–629 (2012).

  43. 43.

    Denton, R. M. Regulation of mitochondrial dehydrogenases by calcium ions. Biochim. Biophys. Acta 1787, 1309–1316 (2009).

  44. 44.

    Guan, H. P. et al. A futile metabolic cycle activated in adipocytes by antidiabetic agents. Nat. Med. 8, 1122–1128 (2002).

  45. 45.

    Kiskinis, E. et al. RIP140 represses the “brown-in-white” adipocyte program including a futile cycle of triacylglycerol breakdown and synthesis. Mol. Endocrinol. 28, 344–356 (2014).

  46. 46.

    Tan, G. D. et al. A “futile cycle” induced by thiazolidinediones in human adipose tissue? Nat. Med. 9, 811–812; author reply 812 (2003).

  47. 47.

    Cannon, B. & Nedergaard, J. Brown adipose tissue: function and physiological significance. Physiol. Rev. 84, 277–359 (2004).

  48. 48.

    Schreiber, R. et al. Cold-induced thermogenesis depends on ATGL-mediated lipolysis in cardiac muscle, but not brown adipose tissue. Cell Metab. 26, 753–763.e757 (2017).

  49. 49.

    Shin, H. et al. Lipolysis in brown adipocytes is not essential for cold-induced thermogenesis in mice. Cell Metab. 26, 764–777.e765 (2017).

  50. 50.

    Lee, J., Ellis, J. M. & Wolfgang, M. J. Adipose fatty acid oxidation is required for thermogenesis and potentiates oxidative stress-induced inflammation. Cell Rep. 10, 266–279 (2015).

  51. 51.

    Anderson, C. M. et al. Dependence of brown adipose tissue function on CD36-mediated coenzyme Q uptake. Cell Rep. 10, 505–515 (2015).

  52. 52.

    Putri, M. et al. CD36 is indispensable for thermogenesis under conditions of fasting and cold stress. Biochem. Biophys. Res. Commun. 457, 520–525 (2015).

  53. 53.

    Arch, J. R. Challenges in β(3)-adrenoceptor agonist drug development. Ther. Adv. Endocrinol. Metab. 2, 59–64 (2011).

  54. 54.

    Cypess, A. M. et al. Activation of human brown adipose tissue by a β3-adrenergic receptor agonist. Cell Metab. 21, 33–38 (2015).

  55. 55.

    Razzoli, M. et al. Stress-induced activation of brown adipose tissue prevents obesity in conditions of low adaptive thermogenesis. Mol. Metab. 5, 19–33 (2015).

  56. 56.

    Gnad, T. et al. Adenosine activates brown adipose tissue and recruits beige adipocytes via A2A receptors. Nature 516, 395–399 (2014).

  57. 57.

    Chen, Y. et al. Thermal stress induces glycolytic beige fat formation via a myogenic state. Nature (2018).

  58. 58.

    Kazak, L. et al. Genetic depletion of adipocyte creatine metabolism inhibits diet-induced thermogenesis and drives obesity. Cell Metab. 26, 660–671.e3 (2017).

  59. 59.

    Mills, E. L. et al. Accumulation of succinate controls activation of adipose tissue thermogenesis. Nature 560, 102–106 (2018).

  60. 60.

    Chouchani, E. T., Kazak, L. & Spiegelman, B. M. Mitochondrial reactive oxygen species and adipose tissue thermogenesis: bridging physiology and mechanisms. J. Biol. Chem. 292, 16810–16816 (2017).

  61. 61.

    Lu, X. et al. The early metabolomic response of adipose tissue during acute cold exposure in mice. Sci. Rep. 7, 3455 (2017).

  62. 62.

    van Marken Lichtenbelt, W. D. et al. Cold-activated brown adipose tissue in healthy men. N. Engl. J. Med. 360, 1500–1508 (2009).

  63. 63.

    Cypess, A. M. et al. Identification and importance of brown adipose tissue in adult humans. N. Engl. J. Med. 360, 1509–1517 (2009).

  64. 64.

    Ouellet, V. et al. Brown adipose tissue oxidative metabolism contributes to energy expenditure during acute cold exposure in humans. J. Clin. Invest. 122, 545–552 (2012).

  65. 65.

    Virtanen, K. A. et al. Functional brown adipose tissue in healthy adults. N. Engl. J. Med. 360, 1518–1525 (2009).

  66. 66.

    Nedergaard, J., Bengtsson, T. & Cannon, B. Unexpected evidence for active brown adipose tissue in adult humans. Am. J. Physiol. Endocrinol. Metab. 293, E444–E452 (2007).

  67. 67.

    Saito, M. et al. High incidence of metabolically active brown adipose tissue in healthy adult humans: effects of cold exposure and adiposity. Diabetes 58, 1526–1531 (2009).

  68. 68.

    Labbé, S. M. et al. In vivo measurement of energy substrate contribution to cold-induced brown adipose tissue thermogenesis. FASEB J. 29, 2046–2058 (2015).

  69. 69.

    Bartelt, A. et al. Brown adipose tissue activity controls triglyceride clearance. Nat. Med. 17, 200–205 (2011).

  70. 70.

    Chondronikola, M. et al. Brown adipose tissue activation is linked to distinct systemic effects on lipid metabolism in humans. Cell Metab. 23, 1200–1206 (2016).

  71. 71.

    Lee, P. et al. Temperature-acclimated brown adipose tissue modulates insulin sensitivity in humans. Diabetes 63, 3686–3698 (2014).

  72. 72.

    Hanssen, M. J. et al. Short-term cold acclimation improves insulin sensitivity in patients with type 2 diabetes mellitus. Nat. Med. 21, 863–865 (2015).

  73. 73.

    Chondronikola, M. et al. Brown adipose tissue improves whole-body glucose homeostasis and insulin sensitivity in humans. Diabetes 63, 4089–4099 (2014).

  74. 74.

    Blondin, D. P. et al. Contributions of white and brown adipose tissues and skeletal muscles to acute cold-induced metabolic responses in healthy men. J. Physiol. (Lond.) 593, 701–714 (2015).

  75. 75.

    Olsen, J. M. et al. β3-Adrenergically induced glucose uptake in brown adipose tissue is independent of UCP1 presence or activity: mediation through the mTOR pathway. Mol. Metab. 6, 611–619 (2017).

  76. 76.

    Gerngross, C., Schretter, J., Klingenspor, M., Schwaiger, M. & Fromme, T. Active brown fat during 18F-FDG PET/CT imaging defines a patient group with characteristic traits and an increased probability of brown fat redetection. J. Nucl. Med. 58, 1104–1110 (2017).

  77. 77.

    Kozak, L. P. Brown fat and the myth of diet-induced thermogenesis. Cell Metab. 11, 263–267 (2010).

  78. 78.

    Weir, G. et al. Substantial metabolic activity of human brown adipose tissue during warm conditions and cold-induced lipolysis of local triglycerides. Cell Metab. 27, 1348–1355.e1344 (2018).

  79. 79.

    Hibi, M. et al. Brown adipose tissue is involved in diet-induced thermogenesis and whole-body fat utilization in healthy humans. Int. J. Obes. (Lond.) 40, 1655–1661 (2016).

  80. 80.

    Mueez, U. D. et al. Postprandial oxidative metabolism of human brown fat indicates thermogenesis.Cell Metab. 28, 207–216 (2018).

  81. 81.

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

  82. 82.

    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).

  83. 83.

    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).

  84. 84.

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

  85. 85.

    Lackey, D. E. et al. Contributions of adipose tissue architectural and tensile properties toward defining healthy and unhealthy obesity. Am. J. Physiol. Endocrinol. Metab. 306, E233–E246 (2014).

  86. 86.

    Muir, L. A. et al. Adipose tissue fibrosis, hypertrophy, and hyperplasia: ccorrelations with diabetes in humanobesity. Obes. (Silver Spring). 24, 597–605 (2016).

  87. 87.

    Divoux, A. et al. Fibrosis in human adipose tissue: composition, distribution, and link with lipid metabolism and fat mass loss. Diabetes 59, 2817–2825 (2010).

  88. 88.

    Reggio, S. et al. Increased basement membrane components in adipose tissue during obesity: links with TGFβ and metabolic phenotypes. J. Clin. Endocrinol. Metab. 101, 2578–2587 (2016).

  89. 89.

    Henegar, C. et al. Adipose tissue transcriptomic signature highlights the pathological relevance of extracellular matrix in human obesity. Genome Biol. 9, R14 (2008).

  90. 90.

    Sun, K., Tordjman, J., Clément, K. & Scherer, P. E. Fibrosis and adipose tissue dysfunction. Cell Metab. 18, 470–477 (2013).

  91. 91.

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

  92. 92.

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

  93. 93.

    Keophiphath, M. et al. Macrophage-secreted factors promote a profibrotic phenotype in human preadipocytes. Mol. Endocrinol. 23, 11–24 (2009).

  94. 94.

    Hasegawa, Y. et al. Repression of adipose tissue fibrosis through aprdm16–gtf2ird1 complex improves systemic glucose homeostasis. Cell Metab. 27, 180–194.e6 (2018).

  95. 95.

    Yadav, H. et al. Protection from obesity and diabetes by blockade of TGF-β/Smad3 signaling. Cell Metab. 14, 67–79 (2011).

  96. 96.

    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).

  97. 97.

    Rausch, M. E., Weisberg, S., Vardhana, P. & Tortoriello, D. V. Obesity in C57BL/6J mice is characterized by adipose tissue hypoxia and cytotoxic T-cell infiltration. Int. J. Obes. (Lond.) 32, 451–463 (2008).

  98. 98.

    Ye, J., Gao, Z., Yin, J. & He, Q. Hypoxia is a potential risk factor for chronic inflammation and adiponectin reduction in adipose tissue of ob/ob and dietary obese mice. Am. J. Physiol. Endocrinol. Metab. 293, E1118–E1128 (2007).

  99. 99.

    Hosogai, N. et al. Adipose tissue hypoxia in obesity and its impact on adipocytokine dysregulation. Diabetes 56, 901–911 (2007).

  100. 100.

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

  101. 101.

    Sun, K., Halberg, N., Khan, M., Magalang, U. J. & Scherer, P. E. Selective inhibition of hypoxia-inducible factor 1α ameliorates adipose tissue dysfunction. Mol. Cell. Biol. 33, 904–917 (2013).

  102. 102.

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

  103. 103.

    Sun, K. et al. Endotrophin triggers adipose tissue fibrosis and metabolic dysfunction. Nat. Commun. 5, 3485 (2014).

  104. 104.

    Choo, H. J. et al. Mitochondria are impaired in the adipocytes of type 2 diabetic mice. Diabetologia 49, 784–791 (2006).

  105. 105.

    Yin, X. et al. Adipocyte mitochondrial function is reduced in human obesity independent of fat cell size. J. Clin. Endocrinol. Metab. 99, E209–E216 (2014).

  106. 106.

    Schöttl, T., Kappler, L., Fromme, T. & Klingenspor, M. Limited OXPHOS capacity in white adipocytes is a hallmark of obesity in laboratory mice irrespective of the glucose tolerance status. Mol. Metab. 4, 631–642 (2015).

  107. 107.

    Heinonen, S. et al. impaired mitochondrial biogenesis in adipose tissue in acquired obesity. Diabetes 64, 3135–3145 (2015).

  108. 108.

    Heinonen, S. et al. Mitochondria-related transcriptional signature is downregulated in adipocytes in obesity: a study of young healthy MZ twins. Diabetologia 60, 169–181 (2017).

  109. 109.

    Ohno, H., Shinoda, K., Spiegelman, B. M. & Kajimura, S. PPARγ agonists induce a white-to-brown fat conversion through stabilization of PRDM16 protein. Cell Metab. 15, 395–404 (2012).

  110. 110.

    Trevellin, E. et al. Exercise training induces mitochondrial biogenesis and glucose uptake in subcutaneous adipose tissue through eNOS-dependent mechanisms. Diabetes 63, 2800–2811 (2014).

  111. 111.

    Bogacka, I., Xie, H., Bray, G. A. & Smith, S. R. Pioglitazone induces mitochondrial biogenesis in human subcutaneous adipose tissue in vivo. Diabetes 54, 1392–1399 (2005).

  112. 112.

    Wilson-Fritch, L. et al. Mitochondrial remodeling in adipose tissue associated with obesity and treatment with rosiglitazone. J. Clin. Invest. 114, 1281–1289 (2004).

  113. 113.

    Rong, J. X. et al. Adipose mitochondrial biogenesis is suppressed in db/db and high-fat diet-fed mice and improved by rosiglitazone. Diabetes 56, 1751–1760 (2007).

  114. 114.

    Jokinen, R. et al. Adipose tissue mitochondrial capacity associates with long-term weight loss success. Int. J. Obes. (Lond.) 42, 817–825 (2018).

  115. 115.

    Vernochet, C. et al. Adipose tissue mitochondrial dysfunction triggers a lipodystrophic syndrome with insulin resistance, hepatosteatosis, and cardiovascular complications. FASEB J. 28, 4408–4419 (2014).

  116. 116.

    Kleiner, S. et al. Development of insulin resistance in mice lacking PGC-1α in adipose tissues. Proc. Natl. Acad. Sci. USA 109, 9635–9640 (2012).

  117. 117.

    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).

  118. 118.

    Kusminski, C. M., Park, J. & Scherer, P. E. MitoNEET-mediated effects on browning of white adipose tissue. Nat. Commun. 5, 3962 (2014).

  119. 119.

    Morton, N. M. et al. Genetic identification of thiosulfate sulfurtransferase as an adipocyte-expressed antidiabetic target in mice selected for leanness. Nat. Med. 22, 771–779 (2016).

  120. 120.

    Ouchi, N., Parker, J. L., Lugus, J. J. & Walsh, K. Adipokines in inflammation and metabolic disease. Nat. Rev. Immunol. 11, 85–97 (2011).

  121. 121.

    Kadowaki, T. et al. Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. J. Clin. Invest. 116, 1784–1792 (2006).

  122. 122.

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

  123. 123.

    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).

  124. 124.

    Syed, I. et al. Palmitic acid hydroxystearic acids activate GPR40, which is involved in their beneficial effects on glucose homeostasis. Cell Metab. 27, 419–427.e4 (2018).

  125. 125.

    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.e3 (2018).

  126. 126.

    Lynes, M. D. et al. The cold-induced lipokine 12,13-diHOME promotes fatty acid transport into brown adipose tissue. Nat. Med. 23, 631–637 (2017).

  127. 127.

    Zimmer, B. et al. The oxidized linoleic acid metabolite 12,13-DiHOME mediates thermal hyperalgesia during inflammatory pain. Biochim. Biophys. Acta Mol. Cell Biol. Lipids 1863, 669–678 (2018).

  128. 128.

    Shulman, G. I. Ectopic fat in insulin resistance, dyslipidemia, and cardiometabolic disease. N. Engl. J. Med. 371, 1131–1141 (2014).

  129. 129.

    Summers, S. A. Could ceramides become the new cholesterol? Cell Metab. 27, 276–280 (2018).

  130. 130.

    Kurek, K. et al. Inhibition of ceramide de novo synthesis ameliorates diet induced skeletal muscles insulin resistance. J. Diabetes Res. 2015, 154762 (2015).

  131. 131.

    Ussher, J. R. et al. Inhibition of de novo ceramide synthesis reverses diet-induced insulin resistance and enhances whole-body oxygen consumption. Diabetes 59, 2453–2464 (2010).

  132. 132.

    Yang, G. et al. Central role of ceramide biosynthesis in body weight regulation, energy metabolism, and the metabolic syndrome. Am. J. Physiol. Endocrinol. Metab. 297, E211–E224 (2009).

  133. 133.

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

  134. 134.

    Blachnio-Zabielska, A. U., Chacinska, M., Vendelbo, M. H. & Zabielski, P. The crucial role of C18-Cer in fat-induced skeletal muscle insulin resistance. Cell. Physiol. Biochem. 40, 1207–1220 (2016).

  135. 135.

    Turpin, S. M. et al. Obesity-induced CerS6-dependent C16:0 ceramide production promotes weight gain and glucose intolerance. Cell Metab. 20, 678–686 (2014).

  136. 136.

    Chaurasia, B. et al. Adipocyte ceramides regulate subcutaneous adipose browning, inflammation, and metabolism. Cell Metab. 24, 820–834 (2016).

  137. 137.

    Holland, W. L. et al. Receptor-mediated activation of ceramidase activity initiates the pleiotropic actions of adiponectin. Nat. Med. 17, 55–63 (2011).

  138. 138.

    Vasiliauskaité-Brooks, I. et al. Structural insights into adiponectin receptors suggest ceramidase activity. Nature 544, 120–123 (2017).

  139. 139.

    Ryu, K. W. et al. Metabolic regulation of transcription through compartmentalized NAD+ biosynthesis. Science 360, eaan5780 (2018).

  140. 140.

    Tsukita, S. et al. Hepatic glucokinase modulates obesity predisposition by regulating BAT thermogenesis via neural signals. Cell Metab. 16, 825–832 (2012).

  141. 141.

    Camarda, R. et al. Inhibition of fatty acid oxidation as a therapy for MYC-overexpressing triple-negative breast cancer. Nat. Med. 22, 427–432 (2016).

  142. 142.

    Wang, H., Liu, L., Lin, J. Z., Aprahamian, T. R. & Farmer, S. R. Browning of white adipose tissue with roscovitine induces a distinct population of UCP1+ adipocytes. Cell Metab. 24, 835–847 (2016).

  143. 143.

    Burl, R. B. et al. Deconstructing adipogenesis induced by β3-adrenergic receptor activation with single-cell expression profiling. Cell Metab. 28, 300–309.e4 (2018).

  144. 144.

    Schwalie, P. C. et al. A stromal cell population that inhibits adipogenesis in mammalian fat depots. Nature 559, 103–108 (2018).

  145. 145.

    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).

  146. 146.

    Hagberg, C. E. et al. Flow cytometry of mouse and human adipocytes for the analysis of browning and cellular heterogeneity. Cell Rep. 24, 2746–2756.e5 (2018).

Download references


We apologize for being unable to cite papers that have contributed to the progress of this field owing to space limitations. This work was supported by the National Institutes of Health (DK97441, DK112268, and DK108822); the Edward Mallinckrodt, Jr. Foundation to S.K.; and the Claudia Adams Barr Program to E.T.C.

Author information




E.T.C and S.K. conceived the project and wrote the manuscript.

Corresponding authors

Correspondence to Edward T. Chouchani or Shingo Kajimura.

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.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Chouchani, E.T., Kajimura, S. Metabolic adaptation and maladaptation in adipose tissue. Nat Metab 1, 189–200 (2019).

Download citation

Further reading