Milestones in Molecular Mechanisms of Adipogenesis and Adipose Tissue Plasticity

Olga P. Shatova, Anastasia A. Zabolotneva, Mikhail B. Potievskiy, Aleksandr V. Shestopalov, Sergei A. Roumiantsev

 
International Journal of Biomedicine. 2021;11(3):323-332.
DOI: 10.21103/Article11(3)_RA3
Originally published September 9, 2021

Abstract: 

This review focuses on the problem of adipogenesis mechanisms and the biological role of adipose tissue (AT) in the human body. Over the past decades, various types of adipocytes have been identified and characterized—white, brown, beige, yellow, and pink. An important feature of AT is a high plasticity and the ability to transdifferentiate and de-differentiate into another cell type. In this case, the pathway of transformation mostly depends on adipocytes’ cellular and metabolic microenvironment. The mechanisms of adipogenesis and the ways of its regulation remain not fully understood. The principal role in the terminal differentiation of preadipocytes is assigned to PPARγ and receptors activated by bone morphogenetic proteins, insulin, and cortisol. However, in chronic inflammation, adipogenesis is suppressed and old adipocytes increase the production of proinflammatory cytokines, which leads to the death of inflamed cells and hypertrophy of neighboring adipocytes. Thus, disruption of adipogenesis, premature aging of white adipocytes, perturbations in the metabolic and cellular microenvironment of preadipocytes, and early apoptosis of fat cells cause the development of insulin resistance and metabolically unhealthy obesity.

Keywords: 
adipose tissue • adipocytes • adipogenesis • transdifferentiation
References: 
  1. Bahmad HF, Daouk R, Azar J, Sapudom J, Teo JCM, Abou-Kheir W, et al. Modeling Adipogenesis: Current and Future Perspective. Cells. 2020 Oct 20;9(10):2326. doi: 10.3390/cells9102326.
  2. Kahn CR, Wang G, Lee KY. Altered adipose tissue and adipocyte function in the pathogenesis of metabolic syndrome. J Clin Invest. 2019 Oct 1;129(10):3990-4000. doi: 10.1172/JCI129187.
  3. Suchacki KJ, Tavares AAS, Mattiucci D, Scheller EL, Papanastasiou G, Gray C, et al. Bone marrow adipose tissue is a unique adipose subtype with distinct roles in glucose homeostasis. Nat Commun. 2020 Jun 18;11(1):3097. doi: 10.1038/s41467-020-16878-2.
  4. Driskell RR, Jahoda CA, Chuong CM, Watt FM, Horsley V. Defining dermal adipose tissue. Exp Dermatol. 2014 Sep;23(9):629-31. doi: 10.1111/exd.12450.
  5. Debette S, Beiser A, Hoffmann U, Decarli C, O'Donnell CJ, Massaro JM, et al. Visceral fat is associated with lower brain volume in healthy middle-aged adults. Ann Neurol. 2010 Aug;68(2):136-44. doi: 10.1002/ana.22062.
  6. Fox CS, Massaro JM, Hoffmann U, Pou KM, Maurovich-Horvat P, Liu CY, et al. Abdominal visceral and subcutaneous adipose tissue compartments: association with metabolic risk factors in the Framingham Heart Study. Circulation. 2007 Jul 3;116(1):39-48. doi: 10.1161/CIRCULATIONAHA.106.675355.
  7. Speliotes EK, Massaro JM, Hoffmann U, Vasan RS, Meigs JB, Sahani DV, et al. Fatty liver is associated with dyslipidemia and dysglycemia independent of visceral fat: the Framingham Heart Study. Hepatology. 2010 Jun;51(6):1979-87. doi: 10.1002/hep.23593.
  8. Enzi G, Busetto L, Sergi G, Coin A, Inelmen EM, Vindigni V, et al. Multiple symmetric lipomatosis: a rare disease and its possible links to brown adipose tissue. Nutr Metab Cardiovasc Dis. 2015 Apr;25(4):347-53. doi: 10.1016/j.numecd.2015.01.010.
  9. Ortega-Molina A, Efeyan A, Lopez-Guadamillas E, Muñoz-Martin M, Gómez-López G, Cañamero M, et al. Pten positively regulates brown adipose function, energy expenditure, and longevity. Cell Metab. 2012 Mar 7;15(3):382-94. doi: 10.1016/j.cmet.2012.02.001.
  10. Cereijo R, Gallego-Escuredo JM, Moure R, Villarroya J, Domingo JC, Fontdevila J, et al. The Molecular Signature of HIV-1-Associated Lipomatosis Reveals Differential Involvement of Brown and Beige/Brite Adipocyte Cell Lineages. PLoS One. 2015 Aug 25;10(8):e0136571. doi: 10.1371/journal.pone.0136571.
  11. Grundy SM. Adipose tissue and metabolic syndrome: too much, too little or neither. Eur J Clin Invest. 2015 Nov;45(11):1209-17. doi: 10.1111/eci.12519. Epub 2015 Sep 13.
  12. Huang-Doran I, Sleigh A, Rochford JJ, O'Rahilly S, Savage DB. Lipodystrophy: metabolic insights from a rare disorder. J Endocrinol. 2010 Dec;207(3):245-55. doi: 10.1677/JOE-10-0272.
  13. Rui L. Brown and Beige Adipose Tissues in Health and Disease. Compr Physiol. 2017 Sep 12;7(4):1281-1306. doi: 10.1002/cphy.c170001.
  14. Pinckard KM, Shettigar VK, Wright KR, Abay E, Baer LA, Vidal P, et al. A Novel Endocrine Role for the BAT-Released Lipokine 12,13-diHOME to Mediate Cardiac Function. Circulation. 2021 Jan 12;143(2):145-159. doi: 10.1161/CIRCULATIONAHA.120.049813.
  15. Sbarbati A, Morroni M, Zancanaro C, Cinti S. Rat interscapular brown adipose tissue at different ages: a morphometric study. Int J Obes. 1991 Sep;15(9):581-7.
  16. Rossato M. Aging and brown adipose tissue activity decline in human: does the brain extinguish the fire? Aging Clin Exp Res. 2016 Jun;28(3):579-81. doi: 10.1007/s40520-016-0572-z.
  17. Vijgen GH, Bouvy ND, Teule GJ, Brans B, Schrauwen P, van Marken Lichtenbelt WD. Brown adipose tissue in morbidly obese subjects. PLoS One. 2011 Feb 24;6(2):e17247. doi: 10.1371/journal.pone.0017247.
  18. Chen Y, Ikeda K, Yoneshiro T, Scaramozza A, Tajima K, Wang Q, et al. Thermal stress induces glycolytic beige fat formation via a myogenic state. Nature. 2019 Jan;565(7738):180-185. doi: 10.1038/s41586-018-0801-z.
  19. Craft CS, Robles H, Lorenz MR, Hilker ED, Magee KL, Andersen TL, et al. Bone marrow adipose tissue does not express UCP1 during development or adrenergic-induced remodeling. Sci Rep. 2019 Nov 22;9(1):17427. doi: 10.1038/s41598-019-54036-x.
  20. Cawthorn WP, Scheller EL, Learman BS, Parlee SD, Simon BR, Mori H, et al. Bone marrow adipose tissue is an endocrine organ that contributes to increased circulating adiponectin during caloric restriction. Cell Metab. 2014 Aug 5;20(2):368-375. doi: 10.1016/j.cmet.2014.06.003.
  21. Scheller EL, Khandaker S, Learman BS, Cawthorn WP, Anderson LM, Pham HA, et al. Bone marrow adipocytes resist lipolysis and remodeling in response to β-adrenergic stimulation. Bone. 2019 Jan;118:32-41. doi: 10.1016/j.bone.2018.01.016.
  22. Marcelin G, Ferreira A, Liu Y, Atlan M, Aron-Wisnewsky J, Pelloux V, et al. A PDGFRα-Mediated Switch toward CD9high Adipocyte Progenitors Controls Obesity-Induced Adipose Tissue Fibrosis. Cell Metab. 2017 Mar 7;25(3):673-685. doi: 10.1016/j.cmet.2017.01.010.
  23. Rojas-Rodriguez R, Lujan-Hernandez J, Min SY, DeSouza T, Teebagy P, Desai A, et al. 2019 Jun;25(11-12):842-854. doi: 10.1089/ten.TEA.2018.0067.
  24. Song A, Dai W, Jang MJ, Medrano L, Li Z, Zhao H, et al. Low- and high-thermogenic brown adipocyte subpopulations coexist in murine adipose tissue. J Clin Invest. 2020 Jan 2;130(1):247-257. doi: 10.1172/JCI129167.
  25. Esteve Ràfols M. Adipose tissue: cell heterogeneity and functional diversity. Endocrinol Nutr. 2014 Feb;61(2):100-12. English, Spanish. doi: 10.1016/j.endonu.2013.03.011.
  26. Ibrahim MM. Subcutaneous and visceral adipose tissue: structural and functional differences. Obes Rev. 2010 Jan;11(1):11-8. doi: 10.1111/j.1467-789X.2009.00623.x.
  27. Pellegrinelli V, Carobbio S, Vidal-Puig A. Adipose tissue plasticity: how fat depots respond differently to pathophysiological cues. Diabetologia. 2016 Jun;59(6):1075-88. doi: 10.1007/s00125-016-3933-4.
  28. Leiva M, Matesanz N, Pulgarín-Alfaro M, Nikolic I, Sabio G. Uncovering the Role of p38 Family Members in Adipose Tissue Physiology. Front Endocrinol (Lausanne). 2020 Dec 23;11:572089. doi: 10.3389/fendo.2020.572089.
  29. Bozec A, Hannemann N. Mechanism of Regulation of Adipocyte Numbers in Adult Organisms Through Differentiation and Apoptosis Homeostasis. J Vis Exp. 2016 Jun 3;(112):53822. doi: 10.3791/53822.
  30. Cinti S. Adipose Organ Development and Remodeling. Compr Physiol. 2018 Sep 14;8(4):1357-1431. doi: 10.1002/cphy.c170042.
  31. Morroni M, Barbatelli G, Zingaretti MC, Cinti S. Immunohistochemical, ultrastructural and morphometric evidence for brown adipose tissue recruitment due to cold acclimation in old rats. Int J Obes Relat Metab Disord. 1995 Feb;19(2):126-31.
  32. Lee YH, Petkova AP, Konkar AA, Granneman JG. Cellular origins of cold-induced brown adipocytes in adult mice. FASEB J. 2015 Jan;29(1):286-99. doi: 10.1096/fj.14-263038.
  33. Jeffery E, Wing A, Holtrup B, Sebo Z, Kaplan JL, Saavedra-Peña R, et al. The Adipose Tissue Microenvironment Regulates Depot-Specific Adipogenesis in Obesity. Cell Metab. 2016 Jul 12;24(1):142-50. doi: 10.1016/j.cmet.2016.05.012.
  34. Lee YH, Petkova AP, Mottillo EP, Granneman JG. In vivo identification of bipotential adipocyte progenitors recruited by β3-adrenoceptor activation and high-fat feeding. Cell Metab. 2012 Apr 4;15(4):480-91. doi: 10.1016/j.cmet.2012.03.009..
  35. Burl RB, Ramseyer VD, Rondini EA, Pique-Regi R, Lee YH, Granneman JG. Deconstructing Adipogenesis Induced by β3-Adrenergic Receptor Activation with Single-Cell Expression Profiling. Cell Metab. 2018 Aug 7;28(2):300-309.e4. doi: 10.1016/j.cmet.2018.05.025.
  36. Schwalie PC, Dong H, Zachara M, Russeil J, Alpern D, Akchiche N, et al. A stromal cell population that inhibits adipogenesis in mammalian fat depots. Nature. 2018 Jul;559(7712):103-108. doi: 10.1038/s41586-018-0226-8.
  37. Mota de Sá P, Richard AJ, Hang H, Stephens JM. Transcriptional Regulation of Adipogenesis. Compr Physiol. 2017 Mar 16;7(2):635-674. doi: 10.1002/cphy.c160022.
  38. Ghaben AL, Scherer PE. Adipogenesis and metabolic health. Nat Rev Mol Cell Biol. 2019 Apr;20(4):242-258. doi: 10.1038/s41580-018-0093-z.
  39. Sarjeant K, Stephens JM. Adipogenesis. Cold Spring Harb Perspect Biol. 2012 Sep 1;4(9):a008417. doi: 10.1101/cshperspect.a008417.
  40. Berry R, Rodeheffer MS. Characterization of the adipocyte cellular lineage in vivo. Nat Cell Biol. 2013 Mar;15(3):302-8. doi: 10.1038/ncb2696.
  41. Min SY, Kady J, Nam M, Rojas-Rodriguez R, Berkenwald A, Kim JH, Noh HL, et al. Human 'brite/beige' adipocytes develop from capillary networks, and their implantation improves metabolic homeostasis in mice. Nat Med. 2016 Mar;22(3):312-8. doi: 10.1038/nm.4031.
  42. Planat-Benard V, Silvestre JS, Cousin B, André M, Nibbelink M, Tamarat R, et al. Plasticity of human adipose lineage cells toward endothelial cells: physiological and therapeutic perspectives. Circulation. 2004 Feb 10;109(5):656-63. doi: 10.1161/01.CIR.0000114522.38265.61.
  43. Medici D, Shore EM, Lounev VY, Kaplan FS, Kalluri R, Olsen BR. Conversion of vascular endothelial cells into multipotent stem-like cells. Nat Med. 2010 Dec;16(12):1400-6. doi: 10.1038/nm.2252.
  44. Maddaluno L, Rudini N, Cuttano R, Bravi L, Giampietro C, Corada M, et al. EndMT contributes to the onset and progression of cerebral cavernous malformations. Nature. 2013 Jun 27;498(7455):492-6. doi: 10.1038/nature12207.
  45. Horowitz MC, Berry R, Holtrup B, Sebo Z, Nelson T, Fretz JA, et al. Bone marrow adipocytes. Adipocyte. 2017 Jul 3;6(3):193-204. doi: 10.1080/21623945.2017.1367881.
  46. Chau YY, Bandiera R, Serrels A, Martínez-Estrada OM, Qing W, Lee M, et al. Visceral and subcutaneous fat have different origins and evidence supports a mesothelial source. Nat Cell Biol. 2014 Apr;16(4):367-75. doi: 10.1038/ncb2922.
  47. Tang W, Zeve D, Suh JM, Bosnakovski D, Kyba M, Hammer RE, et al. White fat progenitor cells reside in the adipose vasculature. Science. 2008 Oct 24;322(5901):583-6. doi: 10.1126/science.1156232.
  48. Vishvanath L, MacPherson KA, Hepler C, Wang QA, Shao M, Spurgin SB, et al. Pdgfrβ+ Mural Preadipocytes Contribute to Adipocyte Hyperplasia Induced by High-Fat-Diet Feeding and Prolonged Cold Exposure in Adult Mice. Cell Metab. 2016 Feb 9;23(2):350-9. doi: 10.1016/j.cmet.2015.10.018.
  49. Hepler C, Shao M, Xia JY, Ghaben AL, Pearson MJ, Vishvanath L, et al. Directing visceral white adipocyte precursors to a thermogenic adipocyte fate improves insulin sensitivity in obese mice. Elife. 2017 Jul 19;6:e27669. doi: 10.7554/eLife.27669.
  50. Huang H, Song TJ, Li X, Hu L, He Q, Liu M, et al. BMP signaling pathway is required for commitment of C3H10T1/2 pluripotent stem cells to the adipocyte lineage. Proc Natl Acad Sci U S A. 2009 Aug 4;106(31):12670-5. doi: 10.1073/pnas.0906266106.
  51. Gupta RK, Arany Z, Seale P, Mepani RJ, Ye L, Conroe HM, et al. Transcriptional control of preadipocyte determination by Zfp423. Nature. 2010 Mar 25;464(7288):619-23. doi: 10.1038/nature08816.
  52. Shao M, Hepler C, Vishvanath L, MacPherson KA, Busbuso NC, Gupta RK. Fetal development of subcutaneous white adipose tissue is dependent on Zfp423. Mol Metab. 2016 Nov 21;6(1):111-124. doi: 10.1016/j.molmet.2016.11.009.
  53. Barak Y, Nelson MC, Ong ES, Jones YZ, Ruiz-Lozano P, Chien KR, et al. PPAR gamma is required for placental, cardiac, and adipose tissue development. Mol Cell. 1999 Oct;4(4):585-95. doi: 10.1016/s1097-2765(00)80209-9.
  54. Rosen ED, Sarraf P, Troy AE, Bradwin G, Moore K, Milstone DS, et al. PPAR gamma is required for the differentiation of adipose tissue in vivo and in vitro. Mol Cell. 1999 Oct;4(4):611-7. doi: 10.1016/s1097-2765(00)80211-7.
  55. Schupp M, Lazar MA. Endogenous ligands for nuclear receptors: digging deeper. J Biol Chem. 2010 Dec 24;285(52):40409-15. doi: 10.1074/jbc.R110.182451.
  56. Wu Z, Rosen ED, Brun R, Hauser S, Adelmant G, Troy AE, et al. Cross-regulation of C/EBP alpha and PPAR gamma controls the transcriptional pathway of adipogenesis and insulin sensitivity. Mol Cell. 1999 Feb;3(2):151-8. doi: 10.1016/s1097-2765(00)80306-8.
  57. Freytag SO, Paielli DL, Gilbert JD. Ectopic expression of the CCAAT/enhancer-binding protein alpha promotes the adipogenic program in a variety of mouse fibroblastic cells. Genes Dev. 1994 Jul 15;8(14):1654-63. doi: 10.1101/gad.8.14.1654.
  58. Lefterova MI, Zhang Y, Steger DJ, Schupp M, Schug J, Cristancho A, et al. PPARgamma and C/EBP factors orchestrate adipocyte biology via adjacent binding on a genome-wide scale. Genes Dev. 2008 Nov 1;22(21):2941-52. doi: 10.1101/gad.1709008.
  59. Wang QA, Tao C, Jiang L, Shao M, Ye R, Zhu Y, et al. Distinct regulatory mechanisms governing embryonic versus adult adipocyte maturation. Nat Cell Biol. 2015 Sep;17(9):1099-111. doi: 10.1038/ncb3217.
  60. Lowe CE, O'Rahilly S, Rochford JJ. Adipogenesis at a glance. J Cell Sci. 2011 Aug 15;124(Pt 16):2681-6. doi: 10.1242/jcs.079699.
  61. Plikus MV, Guerrero-Juarez CF, Ito M, Li YR, Dedhia PH, Zheng Y, et al. Regeneration of fat cells from myofibroblasts during wound healing. Science. 2017 Feb 17;355(6326):748-752. doi: 10.1126/science.aai8792.
  62. Bi P, Yue F, Karki A, Castro B, Wirbisky SE, Wang C, et al. Notch activation drives adipocyte dedifferentiation and tumorigenic transformation in mice. J Exp Med. 2016 Sep 19;213(10):2019-37. doi: 10.1084/jem.20160157.
  63. Wang QA, Song A, Chen W, Schwalie PC, Zhang F, Vishvanath L, et al. Reversible De-differentiation of Mature White Adipocytes into Preadipocyte-like Precursors during Lactation. Cell Metab. 2018 Aug 7;28(2):282-288.e3. doi: 10.1016/j.cmet.2018.05.022.
  64. Spalding KL, Arner E, Westermark PO, Bernard S, Buchholz BA, Bergmann O, et al. Dynamics of fat cell turnover in humans. Nature. 2008 Jun 5;453(7196):783-7. doi: 10.1038/nature06902.
  65. Wang QA, Tao C, Gupta RK, Scherer PE. Tracking adipogenesis during white adipose tissue development, expansion and regeneration. Nat Med. 2013 Oct;19(10):1338-44. doi: 10.1038/nm.3324.
  66. Jeffery E, Church CD, Holtrup B, Colman L, Rodeheffer MS. Rapid depot-specific activation of adipocyte precursor cells at the onset of obesity. Nat Cell Biol. 2015 Apr;17(4):376-85. doi: 10.1038/ncb3122.
  67. Smith U, Kahn BB. Adipose tissue regulates insulin sensitivity: role of adipogenesis, de novo lipogenesis and novel lipids. J Intern Med. 2016 Nov;280(5):465-475. doi: 10.1111/joim.12540.
  68. Mahadev K, Motoshima H, Wu X, Ruddy JM, Arnold RS, Cheng G, 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. 2004 Mar;24(5):1844-54. doi: 10.1128/MCB.24.5.1844-1854.2004.
  69. Furukawa S, Fujita T, Shimabukuro M, Iwaki M, Yamada Y, Nakajima Y, et al. Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest. 2004 Dec;114(12):1752-61. doi: 10.1172/JCI21625.
  70. Bäck K, Arnqvist HJ. Changes in insulin and IGF-I receptor expression during differentiation of human preadipocytes. Growth Horm IGF Res. 2009 Apr;19(2):101-11. doi: 10.1016/j.ghir.2008.06.004.
  71. Chapman AB, Knight DM, Ringold GM. Glucocorticoid regulation of adipocyte differentiation: hormonal triggering of the developmental program and induction of a differentiation-dependent gene. J Cell Biol. 1985 Oct;101(4):1227-35. doi: 10.1083/jcb.101.4.1227.
  72. Fontaine C, Cousin W, Plaisant M, Dani C, Peraldi P. Hedgehog signaling alters adipocyte maturation of human mesenchymal stem cells. Stem Cells. 2008 Apr;26(4):1037-46. doi: 10.1634/stemcells.2007-0974.
  73. Wang W, Seale P. Control of brown and beige fat development. Nat Rev Mol Cell Biol. 2016 Nov;17(11):691-702. doi: 10.1038/nrm.2016.96.
  74. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. 2003 Dec;112(12):1796-808. doi: 10.1172/JCI19246.
  75. Alessi MC, Bastelica D, Morange P, Berthet B, Leduc I, Verdier M, et al. Plasminogen activator inhibitor 1, transforming growth factor-beta1, and BMI are closely associated in human adipose tissue during morbid obesity. Diabetes. 2000 Aug;49(8):1374-80. doi: 10.2337/diabetes.49.8.1374.
  76. Sun M, Feng W, Wang F, Li P, Li Z, Li M, et al. Meta-analysis on shift work and risks of specific obesity types. Obes Rev. 2018 Jan;19(1):28-40. doi: 10.1111/obr.12621.
  77. Spalding KL, Bernard S, Näslund E, Salehpour M, Possnert G, Appelsved L, et al. Impact of fat mass and distribution on lipid turnover in human adipose tissue. Nat Commun. 2017 May 23;8:15253. doi: 10.1038/ncomms15253.
  78. Graja A, Schulz TJ. Mechanisms of aging-related impairment of brown adipocyte development and function. Gerontology. 2015;61(3):211-7. doi: 10.1159/000366557.
  79. Franceschi C. Healthy ageing in 2016: Obesity in geroscience - is cellular senescence the culprit? Nat Rev Endocrinol. 2017 Feb;13(2):76-78. doi: 10.1038/nrendo.2016.213.
  80. Franceschi C, Garagnani P, Vitale G, Capri M, Salvioli S. Inflammaging and 'Garb-aging'. Trends Endocrinol Metab. 2017 Mar;28(3):199-212. doi: 10.1016/j.tem.2016.09.005.
  81. Rouault C, Marcelin G, Adriouch S, Rose C, Genser L, Ambrosini M, et al. Senescence-associated β-galactosidase in subcutaneous adipose tissue associates with altered glycaemic status and truncal fat in severe obesity. Diabetologia. 2021 Jan;64(1):240-254. doi: 10.1007/s00125-020-05307-0..
  82. Halberg N, Khan T, Trujillo ME, Wernstedt-Asterholm I, Attie AD, Sherwani S, et al. Hypoxia-inducible factor 1alpha induces fibrosis and insulin resistance in white adipose tissue. Mol Cell Biol. 2009 Aug;29(16):4467-83. doi: 10.1128/MCB.00192-09.
  83. Murano I, Barbatelli G, Parisani V, Latini C, Muzzonigro G, Castellucci M, et al. Dead adipocytes, detected as crown-like structures, are prevalent in visceral fat depots of genetically obese mice. J Lipid Res. 2008 Jul;49(7):1562-8. doi: 10.1194/jlr.M800019-JLR200.
  84. Kanda H, Tateya S, Tamori Y, Kotani K, Hiasa K, Kitazawa R, et al. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Clin Invest. 2006 Jun;116(6):1494-505. doi: 10.1172/JCI26498.
  85. Sun K, Kusminski CM, Scherer PE. Adipose tissue remodeling and obesity. J Clin Invest. 2011 Jun;121(6):2094-101. doi: 10.1172/JCI45887.
  86. Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest. 2003 Dec;112(12):1821-30. doi: 10.1172/JCI19451.
  87. Duewell P, Kono H, Rayner KJ, Sirois CM, Vladimer G, Bauernfeind FG, et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature. 2010 Apr 29;464(7293):1357-61. doi: 10.1038/nature08938.
  88. Martinon F, Tschopp J. Inflammatory caspases and inflammasomes: master switches of inflammation. Cell Death Differ. 2007 Jan;14(1):10-22. doi: 10.1038/sj.cdd.4402038.
  89. Petrus P, Mejhert N, Corrales P, Lecoutre S, Li Q, Maldonado E, et al. Transforming Growth Factor-β3 Regulates Adipocyte Number in Subcutaneous White Adipose Tissue. Cell Rep. 2018 Oct 16;25(3):551-560.e5. doi: 10.1016/j.celrep.2018.09.069.
  90. Galic S, Oakhill JS, Steinberg GR. Adipose tissue as an endocrine organ. Mol Cell Endocrinol. 2010 Mar 25;316(2):129-39. doi: 10.1016/j.mce.2009.08.018.
  91. Kuda O. Bioactive metabolites of docosahexaenoic acid. Biochimie. 2017 May;136:12-20. doi: 10.1016/j.biochi.2017.01.002.
  92. Vidal P, Stanford KI. Exercise-Induced Adaptations to Adipose Tissue Thermogenesis. Front Endocrinol (Lausanne). 2020 Apr 29;11:270. doi: 10.3389/fendo.2020.00270.

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Received July 4, 2021.
Accepted August 25, 2021.
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