1932

Abstract

Obesity is a chronic and progressive process affecting whole-body energy balance and is associated with comorbidity development. In addition to increased fat mass, obesity induces white adipose tissue (WAT) inflammation and fibrosis, leading to local and systemic metabolic dysfunctions, such as insulin resistance (IR). Accordingly, limiting inflammation or fibrosis deposition may improve IR and glucose homeostasis. Although no targeted therapy yet exists to slow or reverse adipose tissue fibrosis, a number of findings have clarified the underlying cellular and molecular mechanisms. In this review, we highlight adipose tissue remodeling events shown to be associated with fibrosis deposition, with a focus on adipose progenitors involved in obesity-induced healthy as well as unhealthy WAT expansion.

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2022-02-10
2024-05-04
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Literature Cited

  1. 1. 
    NCD Risk Factor Collab 2016. Trends in adult body-mass index in 200 countries from 1975 to 2014: a pooled analysis of 1698 population-based measurement studies with 19⋅2 million participants. Lancet 387:100261377–96
    [Google Scholar]
  2. 2. 
    Kita S, Maeda N, Shimomura I. 2019. Interorgan communication by exosomes, adipose tissue, and adiponectin in metabolic syndrome. J. Clin. Investig. 129:104041–49
    [Google Scholar]
  3. 3. 
    Sun K, Tordjman J, Clément K, Scherer PE. 2013. Fibrosis and adipose tissue dysfunction. Cell Metab. 18:4470–77
    [Google Scholar]
  4. 4. 
    Cannon B, Nedergaard J. 2004. Brown adipose tissue: function and physiological significance. Physiol. Rev. 84:1277–59
    [Google Scholar]
  5. 5. 
    Wu J, Cohen P, Spiegelman BM. 2013. Adaptive thermogenesis in adipocytes: Is beige the new brown?. Genes Dev 27:3234–50
    [Google Scholar]
  6. 6. 
    Vishvanath L, MacPherson KA, Hepler C, Wang QA, Shao M et al. 2016. Pdgfrβ+ mural preadipocytes contribute to adipocyte hyperplasia induced by high-fat-diet feeding and prolonged cold exposure in adult mice. Cell Metab 23:2350–59
    [Google Scholar]
  7. 7. 
    Wang QA, Tao C, Gupta RK, Scherer PE. 2013. Tracking adipogenesis during white adipose tissue development, expansion and regeneration. Nat. Med. 19:101338–44
    [Google Scholar]
  8. 8. 
    Lee Y-H, Petkova AP, Mottillo EP, Granneman JG. 2012. In vivo identification of bipotential adipocyte progenitors recruited by β3-adrenoceptor activation and high-fat feeding. Cell Metab 15:4480–91
    [Google Scholar]
  9. 9. 
    Lee Y-H, Petkova AP, Granneman JG. 2013. Identification of an adipogenic niche for adipose tissue remodeling and restoration. Cell Metab 18:3355–67
    [Google Scholar]
  10. 10. 
    Burl RB, Ramseyer VD, Rondini EA, Pique-Regi R, Lee Y-H, Granneman JG. 2018. Deconstructing adipogenesis induced by β3-adrenergic receptor activation with single-cell expression profiling. Cell Metab. 28:2300–9.e4
    [Google Scholar]
  11. 11. 
    Carrière A, Jeanson Y, Berger-Müller S, André M, Chenouard V et al. 2014. Browning of white adipose cells by intermediate metabolites: an adaptive mechanism to alleviate redox pressure. Diabetes 63:103253–65
    [Google Scholar]
  12. 12. 
    Wang W, Ishibashi J, Trefely S, Shao M, Cowan AJ et al. 2019. A PRDM16-driven metabolic signal from adipocytes regulates precursor cell fate. Cell Metab. 30:1174–89.e5
    [Google Scholar]
  13. 13. 
    Kajimura S, Spiegelman BM, Seale P. 2015. Brown and beige fat: physiological roles beyond heat-generation. Cell Metab. 22:4546–59
    [Google Scholar]
  14. 14. 
    Wang W, Seale P 2016. Control of brown and beige fat development. Nat. Rev. Mol. Cell Biol. 17:11691–702
    [Google Scholar]
  15. 15. 
    Leitner BP, Huang S, Brychta RJ, Duckworth CJ, Baskin AS et al. 2017. Mapping of human brown adipose tissue in lean and obese young men. PNAS 114:328649–54
    [Google Scholar]
  16. 16. 
    Chau Y-Y, Bandiera R, Serrels A, Martínez-Estrada OM, Qing W et al. 2014. Visceral and subcutaneous fat have different origins and evidence supports a mesothelial source. Nat. Cell Biol. 16:4367–75
    [Google Scholar]
  17. 17. 
    Sebo ZL, Jeffery E, Holtrup B, Rodeheffer MS 2018. A mesodermal fate map for adipose tissue. Development 145:17dev166801
    [Google Scholar]
  18. 18. 
    Lancerotto L, Stecco C, Macchi V, Porzionato A, Stecco A et al. 2011. Layers of the abdominal wall: anatomical investigation of subcutaneous tissue and superficial fascia. Surg. Radiol. Anat. 33:10835–42
    [Google Scholar]
  19. 19. 
    Yung S, Chan TM. 2007. Mesothelial cells. Perit. Dial. Int. 27:Suppl. 2S110–15
    [Google Scholar]
  20. 20. 
    Hepler C, Shan B, Zhang Q, Henry GH, Shao M et al. 2018. Identification of functionally distinct fibro-inflammatory and adipogenic stromal subpopulations in visceral adipose tissue of adult mice. eLife 7:e39636
    [Google Scholar]
  21. 21. 
    Westcott GP, Emont MP, Li J, Jacobs C, Tsai L et al. 2021. Mesothelial cells are not a source of adipocytes in mice. Cell Rep. 36:2109388
    [Google Scholar]
  22. 22. 
    Kissebah AH, Krakower GR. 1994. Regional adiposity and morbidity. Physiol. Rev. 74:4761–811
    [Google Scholar]
  23. 23. 
    Wajchenberg BL. 2000. Subcutaneous and visceral adipose tissue: their relation to the metabolic syndrome. Endocr. Rev. 21:6697–738
    [Google Scholar]
  24. 24. 
    Ibrahim MM. 2010. Subcutaneous and visceral adipose tissue: structural and functional differences. Obes. Rev. 11:111–18
    [Google Scholar]
  25. 25. 
    Björntorp P. 1990.. “ Portal” adipose tissue as a generator of risk factors for cardiovascular disease and diabetes. Arteriosclerosis 10:4493–96
    [Google Scholar]
  26. 26. 
    Rytka JM, Wueest S, Schoenle EJ, Konrad D 2011. The portal theory supported by venous drainage-selective fat transplantation. Diabetes 60:156–63
    [Google Scholar]
  27. 27. 
    Bouchard C. 1997. Genetic determinants of regional fat distribution. Hum. Reprod. 12:Suppl. 11–5
    [Google Scholar]
  28. 28. 
    Shungin D, Winkler TW, Croteau-Chonka DC, Ferreira T, Locke AE et al. 2015. New genetic loci link adipose and insulin biology to body fat distribution. Nature 518:7538187–96
    [Google Scholar]
  29. 29. 
    Jeffery E, Wing A, Holtrup B, Sebo Z, Kaplan JL et al. 2016. The adipose tissue microenvironment regulates depot-specific adipogenesis in obesity. Cell Metab 24:1142–50
    [Google Scholar]
  30. 30. 
    Rouault C, Marcelin G, Adriouch S, Rose C, Genser L et al. 2021. Senescence-associated β-galactosidase in subcutaneous adipose tissue associates with altered glycaemic status and truncal fat in severe obesity. Diabetologia 64:1240–54
    [Google Scholar]
  31. 31. 
    Alba DL, Farooq JA, Lin MYC, Schafer AL, Shepherd JS et al. 2018. Subcutaneous fat fibrosis links obesity to insulin resistance in Chinese Americans. J. Clin. Endocrinol. Metab. 103:93194–204
    [Google Scholar]
  32. 32. 
    Giordano A, Murano I, Mondini E, Perugini J, Smorlesi A et al. 2013. Obese adipocytes show ultrastructural features of stressed cells and die of pyroptosis. J. Lipid Res. 54:92423–36
    [Google Scholar]
  33. 33. 
    Jernås M, Palming J, Sjöholm K, Jennische E, Svensson PA et al. 2006. Separation of human adipocytes by size: hypertrophic fat cells display distinct gene expression. FASEB J. 20:91540–42
    [Google Scholar]
  34. 34. 
    Berger JJ, Barnard RJ. 1999. Effect of diet on fat cell size and hormone-sensitive lipase activity. J. Appl. Physiol. 87:1227–32
    [Google Scholar]
  35. 35. 
    Wueest S, Rapold RA, Rytka JM, Schoenle EJ, Konrad D. 2009. Basal lipolysis, not the degree of insulin resistance, differentiates large from small isolated adipocytes in high-fat fed mice. Diabetologia 52:3541–46
    [Google Scholar]
  36. 36. 
    Rodeheffer MS, Birsoy K, Friedman JM. 2008. Identification of white adipocyte progenitor cells in vivo. Cell 135:2240–49
    [Google Scholar]
  37. 37. 
    Wang QA, Scherer PE. 2014. The AdipoChaser mouse. Adipocyte 3:2146–50
    [Google Scholar]
  38. 38. 
    Tang W, Zeve D, Suh JM, Bosnakovski D, Kyba M et al. 2008. White fat progenitor cells reside in the adipose vasculature. Science 322:5901583–86
    [Google Scholar]
  39. 39. 
    Santini MP, Malide D, Hoffman G, Pandey G, D'Escamard V et al. 2020. Tissue-resident PDGFRα+ progenitor cells contribute to fibrosis versus healing in a context- and spatiotemporally dependent manner. Cell Rep. 30:2555–70.e7
    [Google Scholar]
  40. 40. 
    Farahani RM, Xaymardan M. 2015. Platelet-derived growth factor receptor alpha as a marker of mesenchymal stem cells in development and stem cell biology. Stem Cells Int 2015:362753
    [Google Scholar]
  41. 41. 
    Berry R, Jeffery E, Rodeheffer MS 2014. Weighing in on adipocyte precursors. Cell Metab 19:18–20
    [Google Scholar]
  42. 42. 
    Hudak CS, Gulyaeva O, Wang Y, Park S-M, Lee L et al. 2014. Pref-1 marks very early mesenchymal precursors required for adipose tissue development and expansion. Cell Rep. 8:3678–87
    [Google Scholar]
  43. 43. 
    Hudak CS, Sul HS. 2013. Pref-1, a gatekeeper of adipogenesis. Front. Endocrinol. 4:79
    [Google Scholar]
  44. 44. 
    Gupta RK, Mepani RJ, Kleiner S, Lo JC, Khandekar MJ et al. 2012. Zfp423 expression identifies committed preadipocytes and localizes to adipose endothelial and perivascular cells. Cell Metab 15:2230–39
    [Google Scholar]
  45. 45. 
    Marcelin G, Ferreira A, Liu Y, Atlan M, Aron-Wisnewsky J et al. 2017. A PDGFRα-mediated switch toward CD9high adipocyte progenitors controls obesity-induced adipose tissue fibrosis. Cell Metab 25:3673–85
    [Google Scholar]
  46. 46. 
    Merrick D, Sakers A, Irgebay Z, Okada C, Calvert C et al. 2019. Identification of a mesenchymal progenitor cell hierarchy in adipose tissue. Science 364:6438eaav2501
    [Google Scholar]
  47. 47. 
    Spalding KL, Arner E, Westermark PO, Bernard S, Buchholz BA et al. 2008. Dynamics of fat cell turnover in humans. Nature 453:7196783–87
    [Google Scholar]
  48. 48. 
    Gao H, Volat F, Sandhow L, Galitzky J, Nguyen T et al. 2017. CD36 is a marker of human adipocyte progenitors with pronounced adipogenic and triglyceride accumulation potential. Stem Cells 35:71799–814
    [Google Scholar]
  49. 49. 
    Estève D, Boulet N, Volat F, Zakaroff-Girard A, Ledoux S et al. 2015. Human white and brite adipogenesis is supported by MSCA1 and is impaired by immune cells. Stem Cells 33:41277–91
    [Google Scholar]
  50. 50. 
    Raajendiran A, Ooi G, Bayliss J, O'Brien PE, Schittenhelm RB et al. 2019. Identification of metabolically distinct adipocyte progenitor cells in human adipose tissues. Cell Rep. 27:51528–40.e7
    [Google Scholar]
  51. 51. 
    Vijay J, Gauthier M-F, Biswell RL, Louiselle DA, Johnston JJ et al. 2020. Single-cell analysis of human adipose tissue identifies depot- and disease-specific cell types. Nat. Metab. 2:197–109
    [Google Scholar]
  52. 52. 
    Cho DS, Lee B, Doles JD 2019. Refining the adipose progenitor cell landscape in healthy and obese visceral adipose tissue using single-cell gene expression profiling. Life Sci. Alliance 2:6e201900561
    [Google Scholar]
  53. 53. 
    Estève D, Boulet N, Belles C, Zakaroff-Girard A, Decaunes P et al. 2019. Lobular architecture of human adipose tissue defines the niche and fate of progenitor cells. Nat. Commun. 10:12549
    [Google Scholar]
  54. 54. 
    Cao Y. 2007. Angiogenesis modulates adipogenesis and obesity. J. Clin. Investig. 117:92362–68
    [Google Scholar]
  55. 55. 
    Cao Y. 2013. Angiogenesis and vascular functions in modulation of obesity, adipose metabolism, and insulin sensitivity. Cell Metab 18:4478–89
    [Google Scholar]
  56. 56. 
    Pasarica M, Sereda OR, Redman LM, Albarado DC, Hymel DT et al. 2009. Reduced adipose tissue oxygenation in human obesity: evidence for rarefaction, macrophage chemotaxis, and inflammation without an angiogenic response. Diabetes 58:3718–25
    [Google Scholar]
  57. 57. 
    Goossens GH, Bizzarri A, Venteclef N, Essers Y, Cleutjens JP et al. 2011. Increased adipose tissue oxygen tension in obese compared with lean men is accompanied by insulin resistance, impaired adipose tissue capillarization, and inflammation. Circulation 124:167–76
    [Google Scholar]
  58. 58. 
    Pellegrinelli V, Rouault C, Veyrie N, Clément K, Lacasa D 2014. Endothelial cells from visceral adipose tissue disrupt adipocyte functions in a three-dimensional setting: partial rescue by angiopoietin-1. Diabetes 63:2535–49
    [Google Scholar]
  59. 59. 
    Villaret A, Galitzky J, Decaunes P, Estève D, Marques M-A et al. 2010. Adipose tissue endothelial cells from obese human subjects: differences among depots in angiogenic, metabolic, and inflammatory gene expression and cellular senescence. Diabetes 59:112755–63
    [Google Scholar]
  60. 60. 
    Hosogai N, Fukuhara A, Oshima K, Miyata Y, Tanaka S et al. 2007. Adipose tissue hypoxia in obesity and its impact on adipocytokine dysregulation. Diabetes 56:4901–11
    [Google Scholar]
  61. 61. 
    Rausch ME, Weisberg S, Vardhana P, Tortoriello DV. 2008. Obesity in C57BL/6J mice is characterized by adipose tissue hypoxia and cytotoxic T-cell infiltration. Int. J. Obes. 32:3451–63
    [Google Scholar]
  62. 62. 
    Ye J, Gao Z, Yin J, He Q 2007. 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. 293:4E1118–28
    [Google Scholar]
  63. 63. 
    Halberg N, Khan T, Trujillo ME, Wernstedt-Asterholm I, Attie AD et al. 2009. Hypoxia-inducible factor 1α induces fibrosis and insulin resistance in white adipose tissue. Mol. Cell. Biol. 29:164467–83
    [Google Scholar]
  64. 64. 
    Majmundar AJ, Wong WJ, Simon MC. 2010. Hypoxia inducible factors and the response to hypoxic stress. Mol. Cell 40:2294–309
    [Google Scholar]
  65. 65. 
    Semenza GL. 2014. Oxygen sensing, hypoxia-inducible factors, and disease pathophysiology. Annu. Rev. Pathol. Mech. Dis. 9:47–71
    [Google Scholar]
  66. 66. 
    Trayhurn P. 2013. Hypoxia and adipose tissue function and dysfunction in obesity. Physiol. Rev. 93:11–21
    [Google Scholar]
  67. 67. 
    Cinti S, Mitchell G, Barbatelli G, Murano I, Ceresi E et al. 2005. Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans. J. Lipid Res. 46:112347–55
    [Google Scholar]
  68. 68. 
    Wynn TA, Ramalingam TR. 2012. Mechanisms of fibrosis: therapeutic translation for fibrotic disease. Nat. Med. 18:71028–40
    [Google Scholar]
  69. 69. 
    Park J, Kim M, Sun K, An YA, Gu X, Scherer PE. 2017. VEGF-A-expressing adipose tissue shows rapid beiging and enhanced survival after transplantation and confers IL-4-independent metabolic improvements. Diabetes 66:61479–90
    [Google Scholar]
  70. 70. 
    Robciuc MR, Kivelä R, Williams IM, de Boer JF, van Dijk TH et al. 2016. VEGFB/VEGFR1-induced expansion of adipose vasculature counteracts obesity and related metabolic complications. Cell Metab 23:4712–24
    [Google Scholar]
  71. 71. 
    Sun K, Asterholm IW, Kusminski CM, Bueno AC, Wang ZV et al. 2012. Dichotomous effects of VEGF-A on adipose tissue dysfunction. PNAS 109:155874–79
    [Google Scholar]
  72. 72. 
    Gautier EL, Yvan-Charvet L. 2014. Understanding macrophage diversity at the ontogenic and transcriptomic levels. Immunol. Rev. 262:185–95
    [Google Scholar]
  73. 73. 
    Hassnain Waqas SF, Noble A, Hoang AC, Ampem G, Popp M et al. 2017. Adipose tissue macrophages develop from bone marrow-independent progenitors in Xenopus laevis and mouse. J. Leukoc. Biol. 102:3845–55
    [Google Scholar]
  74. 74. 
    Cox N, Crozet L, Holtman IR, Loyher P-L, Lazarov T et al. 2021. Diet-regulated production of PDGFcc by macrophages controls energy storage. Science 373:6550eabe9383
    [Google Scholar]
  75. 75. 
    Weisberg SP, Hunter D, Huber R, Lemieux J, Slaymaker S et al. 2006. CCR2 modulates inflammatory and metabolic effects of high-fat feeding. J. Clin. Investig. 116:1115–24
    [Google Scholar]
  76. 76. 
    Randolph GJ, Gautier EL. 2013. Emerging roles of neural guidance molecules in atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 33:5882–83
    [Google Scholar]
  77. 77. 
    Kanda H, Tateya S, Tamori Y, Kotani K, Hiasa K et al. 2006. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J. Clin. Investig. 116:61494–505
    [Google Scholar]
  78. 78. 
    Lumeng CN, Bodzin JL, Saltiel AR. 2007. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J. Clin. Investig. 117:1175–84
    [Google Scholar]
  79. 79. 
    Patsouris D, Li P-P, Thapar D, Chapman J, Olefsky JM, Neels JG. 2008. Ablation of CD11c-positive cells normalizes insulin sensitivity in obese insulin resistant animals. Cell Metab. 8:4301–9
    [Google Scholar]
  80. 80. 
    Zheng C, Yang Q, Xu C, Shou P, Cao J et al. 2015. CD11b regulates obesity-induced insulin resistance via limiting alternative activation and proliferation of adipose tissue macrophages. PNAS 112:52E7239–48
    [Google Scholar]
  81. 81. 
    Amano SU, Cohen JL, Vangala P, Tencerova M, Nicoloro SM et al. 2014. Local proliferation of macrophages contributes to obesity-associated adipose tissue inflammation. Cell Metab. 19:1162–71
    [Google Scholar]
  82. 82. 
    Braune J, Weyer U, Hobusch C, Mauer J, Brüning JC et al. 2017. IL-6 regulates M2 polarization and local proliferation of adipose tissue macrophages in obesity. J. Immunol. 198:72927–34
    [Google Scholar]
  83. 83. 
    Hill DA, Lim H-W, Kim YH, Ho WY, Foong YH et al. 2018. Distinct macrophage populations direct inflammatory versus physiological changes in adipose tissue. PNAS 115:22E5096–105
    [Google Scholar]
  84. 84. 
    Cancello R, Tordjman J, Poitou C, Guilhem G, Bouillot JL et al. 2006. Increased infiltration of macrophages in omental adipose tissue is associated with marked hepatic lesions in morbid human obesity. Diabetes 55:61554–61
    [Google Scholar]
  85. 85. 
    Vila IK, Badin P-M, Marques M-A, Monbrun L, Lefort C et al. 2014. Immune cell Toll-like receptor 4 mediates the development of obesity- and endotoxemia-associated adipose tissue fibrosis. Cell Rep. 7:41116–29
    [Google Scholar]
  86. 86. 
    Strissel KJ, Stancheva Z, Miyoshi H, Perfield JW, DeFuria J et al. 2007. Adipocyte death, adipose tissue remodeling, and obesity complications. Diabetes 56:122910–18
    [Google Scholar]
  87. 87. 
    Pajvani UB, Trujillo ME, Combs TP, Iyengar P, Jelicks L et al. 2005. Fat apoptosis through targeted activation of caspase 8: a new mouse model of inducible and reversible lipoatrophy. Nat. Med. 11:7797–803
    [Google Scholar]
  88. 88. 
    Surmi BK, Hasty AH. 2008. Macrophage infiltration into adipose tissue. Future Lipidol 3:5545–56
    [Google Scholar]
  89. 89. 
    Hotamisligil GS, Shargill NS, Spiegelman BM. 1993. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 259:509187–91
    [Google Scholar]
  90. 90. 
    Di Gregorio GB, Yao-Borengasser A, Rasouli N, Varma V, Lu T et al. 2005. Expression of CD68 and macrophage chemoattractant protein-1 genes in human adipose and muscle tissues: association with cytokine expression, insulin resistance, and reduction by pioglitazone. Diabetes 54:82305–13
    [Google Scholar]
  91. 91. 
    Harman-Boehm I, Blüher M, Redel H, Sion-Vardy N, Ovadia S et al. 2007. Macrophage infiltration into omental versus subcutaneous fat across different populations: effect of regional adiposity and the comorbidities of obesity. J. Clin. Endocrinol. Metab. 92:62240–47
    [Google Scholar]
  92. 92. 
    McLaughlin T, Deng A, Gonzales O, Aillaud M, Yee G et al. 2008. Insulin resistance is associated with a modest increase in inflammation in subcutaneous adipose tissue of moderately obese women. Diabetologia 51:122303–8
    [Google Scholar]
  93. 93. 
    Murray PJ, Allen JE, Biswas SK, Fisher EA, Gilroy DW et al. 2014. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity 41:114–20
    [Google Scholar]
  94. 94. 
    Kratz M, Coats BR, Hisert KB, Hagman D, Mutskov V et al. 2014. Metabolic dysfunction drives a mechanistically distinct proinflammatory phenotype in adipose tissue macrophages. Cell Metab. 20:4614–25
    [Google Scholar]
  95. 95. 
    Xue J, Schmidt SV, Sander J, Draffehn A, Krebs W et al. 2014. Transcriptome-based network analysis reveals a spectrum model of human macrophage activation. Immunity 40:2274–88
    [Google Scholar]
  96. 96. 
    Jaitin DA, Adlung L, Thaiss CA, Weiner A, Li B et al. 2019. Lipid-associated macrophages control metabolic homeostasis in a Trem2-dependent manner. Cell 178:3686–98.e1
    [Google Scholar]
  97. 97. 
    Weinstock A, Brown EJ, Garabedian ML, Pena S, Sharma M et al. 2019. Single-cell RNA sequencing of visceral adipose tissue leukocytes reveals that caloric restriction following obesity promotes the accumulation of a distinct macrophage population with features of phagocytic cells. Immunometabolism 1:e190008
    [Google Scholar]
  98. 98. 
    Sharif O, Brunner JS, Korosec A, Martins R, Jais A et al. 2021. Beneficial metabolic effects of TREM2 in obesity are uncoupled from its expression on macrophages. Diabetes 70:92042–57
    [Google Scholar]
  99. 99. 
    Lancaster GI, Langley KG, Berglund NA, Kammoun HL, Reibe S et al. 2018. Evidence that TLR4 is not a receptor for saturated fatty acids but mediates lipid-induced inflammation by reprogramming macrophage metabolism. Cell Metab. 27:51096–110.e5
    [Google Scholar]
  100. 100. 
    Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C et al. 2007. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 56:71761–72
    [Google Scholar]
  101. 101. 
    Catalán V, Gómez-Ambrosi J, Rodríguez A, Ramírez B, Rotellar F et al. 2012. Increased tenascin C and Toll-like receptor 4 levels in visceral adipose tissue as a link between inflammation and extracellular matrix remodeling in obesity. J. Clin. Endocrinol. Metab. 97:10E1880–89
    [Google Scholar]
  102. 102. 
    Gunasekaran MK, Viranaicken W, Girard A-C, Festy F, Cesari M et al. 2013. Inflammation triggers high mobility group box 1 (HMGB1) secretion in adipose tissue, a potential link to obesity. Cytokine 64:1103–11
    [Google Scholar]
  103. 103. 
    Nativel B, Marimoutou M, Thon-Hon VG, Gunasekaran MK, Andries J et al. 2013. Soluble HMGB1 is a novel adipokine stimulating IL-6 secretion through RAGE receptor in SW872 preadipocyte cell line: contribution to chronic inflammation in fat tissue. PLOS ONE 8:9e76039
    [Google Scholar]
  104. 104. 
    Trepanowski JF, Mey J, Varady KA. 2015. Fetuin-A: a novel link between obesity and related complications. Int. J. Obes. 39:5734–41
    [Google Scholar]
  105. 105. 
    Han MS, Jung DY, Morel C, Lakhani SA, Kim JK et al. 2013. JNK expression by macrophages promotes obesity-induced insulin resistance and inflammation. Science 339:6116218–22
    [Google Scholar]
  106. 106. 
    Brestoff JR, Wilen CB, Moley JR, Li Y, Zou W et al. 2021. Intercellular mitochondria transfer to macrophages regulates white adipose tissue homeostasis and is impaired in obesity. Cell Metab. 33:2270–82.e8
    [Google Scholar]
  107. 107. 
    Tanaka M, Ikeda K, Suganami T, Komiya C, Ochi K et al. 2014. Macrophage-inducible C-type lectin underlies obesity-induced adipose tissue fibrosis. Nat. Commun. 5:4982
    [Google Scholar]
  108. 108. 
    Madsen DH, Leonard D, Masedunskas A, Moyer A, Jürgensen HJ et al. 2013. M2-like macrophages are responsible for collagen degradation through a mannose receptor-mediated pathway. J. Cell Biol. 202:6951–66
    [Google Scholar]
  109. 109. 
    Atabai K, Jame S, Azhar N, Kuo A, Lam M et al. 2009. Mfge8 diminishes the severity of tissue fibrosis in mice by binding and targeting collagen for uptake by macrophages. J. Clin. Investig. 119:123713–22
    [Google Scholar]
  110. 110. 
    Henegar C, Tordjman J, Achard V, Lacasa D, Cremer I et al. 2008. Adipose tissue transcriptomic signature highlights the pathological relevance of extracellular matrix in human obesity. Genome Biol 9:1R14
    [Google Scholar]
  111. 111. 
    Divoux A, Tordjman J, Lacasa D, Veyrie N, Hugol D et al. 2010. Fibrosis in human adipose tissue: composition, distribution, and link with lipid metabolism and fat mass loss. Diabetes 59:112817–25
    [Google Scholar]
  112. 112. 
    Datta R, Podolsky MJ, Atabai K. 2018. Fat fibrosis: friend or foe?. JCI Insight 3:19e122289
    [Google Scholar]
  113. 113. 
    O'Connor KC, Song H, Rosenzweig N, Jansen DA 2003. Extracellular matrix substrata alter adipocyte yield and lipogenesis in primary cultures of stromal-vascular cells from human adipose. Biotechnol. Lett. 25:231967–72
    [Google Scholar]
  114. 114. 
    Spiegelman BM, Ginty CA. 1983. Fibronectin modulation of cell shape and lipogenic gene expression in 3t3-adipocytes. Cell 35:3 Part 2657–66
    [Google Scholar]
  115. 115. 
    Grandl G, Müller S, Moest H, Moser C, Wollscheid B, Wolfrum C 2016. Depot specific differences in the adipogenic potential of precursors are mediated by collagenous extracellular matrix and Flotillin 2 dependent signaling. Mol. Metab. 5:10937–47
    [Google Scholar]
  116. 116. 
    Bel Lassen P, Charlotte F, Liu Y, Bedossa P, Le Naour G et al. 2017. The FAT score, a fibrosis score of adipose tissue: predicting weight-loss outcome after gastric bypass. J. Clin. Endocrinol. Metab. 102:72443–53
    [Google Scholar]
  117. 117. 
    Khan T, Muise ES, Iyengar P, Wang ZV, Chandalia M et al. 2009. Metabolic dysregulation and adipose tissue fibrosis: role of collagen VI. Mol. Cell. Biol. 29:61575–91
    [Google Scholar]
  118. 118. 
    Chun T-H, Hotary KB, Sabeh F, Saltiel AR, Allen ED, Weiss SJ 2006. A pericellular collagenase directs the 3-dimensional development of white adipose tissue. Cell 125:3577–91
    [Google Scholar]
  119. 119. 
    Spencer M, Yao-Borengasser A, Unal R, Rasouli N, Gurley CM et al. 2010. Adipose tissue macrophages in insulin-resistant subjects are associated with collagen VI and fibrosis and demonstrate alternative activation. Am. J. Physiol. Endocrinol. Metab. 299:6E1016–27
    [Google Scholar]
  120. 120. 
    Li X, Zhao Y, Chen C, Yang L, Lee H-H et al. 2020. Critical role of matrix metalloproteinase 14 in adipose tissue remodeling during obesity. Mol. Cell. Biol. 40:8e00564-19
    [Google Scholar]
  121. 121. 
    Abdennour M, Reggio S, Le Naour G, Liu Y, Poitou C et al. 2014. Association of adipose tissue and liver fibrosis with tissue stiffness in morbid obesity: links with diabetes and BMI loss after gastric bypass. J. Clin. Endocrinol. Metab. 99:3898–907
    [Google Scholar]
  122. 122. 
    Li Q, Hosaka T, Jambaldorj B, Nakaya Y, Funaki M. 2009. Extracellular matrix with the rigidity of adipose tissue helps 3T3-L1 adipocytes maintain insulin responsiveness. J. Med. Investig. 56:3–4142–49
    [Google Scholar]
  123. 123. 
    Pellegrinelli V, Heuvingh J, du Roure O, Rouault C, Devulder A et al. 2014. Human adipocyte function is impacted by mechanical cues: human adipocytes as mechanosensitive cells. J. Pathol. 233:2183–95
    [Google Scholar]
  124. 124. 
    Sun K, Park J, Kim M, Scherer PE 2017. Endotrophin, a multifaceted player in metabolic dysregulation and cancer progression, is a predictive biomarker for the response to PPARγ agonist treatment. Diabetologia 60:124–29
    [Google Scholar]
  125. 125. 
    Kiefer FW, Zeyda M, Gollinger K, Pfau B, Neuhofer A et al. 2010. Neutralization of osteopontin inhibits obesity-induced inflammation and insulin resistance. Diabetes 59:4935–46
    [Google Scholar]
  126. 126. 
    Bhattacharyya S, Wang W, Morales-Nebreda L, Feng G, Wu M et al. 2016. Tenascin-C drives persistence of organ fibrosis. Nat. Commun. 7:111703
    [Google Scholar]
  127. 127. 
    Bertola A, Deveaux V, Bonnafous S, Rousseau D, Anty R et al. 2009. Elevated expression of osteopontin may be related to adipose tissue macrophage accumulation and liver steatosis in morbid obesity. Diabetes 58:1125–33
    [Google Scholar]
  128. 128. 
    Tomasek JJ, Gabbiani G, Hinz B, Chaponnier C, Brown RA 2002. Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat. Rev. Mol. Cell Biol. 3:5349–63
    [Google Scholar]
  129. 129. 
    Dulauroy S, Di Carlo SE, Langa F, Eberl G, Peduto L 2012. Lineage tracing and genetic ablation of ADAM12+ perivascular cells identify a major source of profibrotic cells during acute tissue injury. Nat. Med. 18:81262–70
    [Google Scholar]
  130. 130. 
    Kramann R, Schneider RK, DiRocco DP, Machado F, Fleig S et al. 2015. Perivascular Gli1+ progenitors are key contributors to injury-induced organ fibrosis. Cell Stem Cell 16:151–66
    [Google Scholar]
  131. 131. 
    Coles CA, Maksimovic J, Wadeson J, Fahri FT, Webster T et al. 2018. Knockdown of a disintegrin A metalloprotease 12 (ADAM12) during adipogenesis reduces cell numbers, delays differentiation, and increases lipid accumulation in 3T3-L1 cells. Mol. Biol. Cell 29:151839–55
    [Google Scholar]
  132. 132. 
    Masaki M, Kurisaki T, Shirakawa K, Sehara-Fujisawa A. 2005. Role of meltrin α (ADAM12) in obesity induced by high-fat diet. Endocrinology 146:41752–63
    [Google Scholar]
  133. 133. 
    Kaplan JL, Marshall MA, McSkimming C, Harmon DB, Garmey JC et al. 2015. Adipocyte progenitor cells initiate monocyte chemoattractant protein-1-mediated macrophage accumulation in visceral adipose tissue. Mol. Metab. 4:11779–94
    [Google Scholar]
  134. 134. 
    Shan B, Shao M, Zhang Q, Hepler C, Paschoal VA et al. 2020. Perivascular mesenchymal cells control adipose-tissue macrophage accrual in obesity. Nat. Metab. 2:1332–49
    [Google Scholar]
  135. 135. 
    Shao M, Vishvanath L, Busbuso NC, Hepler C, Shan B et al. 2018. De novo adipocyte differentiation from Pdgfrβ+ preadipocytes protects against pathologic visceral adipose expansion in obesity. Nat. Commun. 9:1890
    [Google Scholar]
  136. 136. 
    Iwayama T, Steele C, Yao L, Dozmorov MG, Karamichos D et al. 2015. PDGFRα signaling drives adipose tissue fibrosis by targeting progenitor cell plasticity. Genes Dev 29:111106–19
    [Google Scholar]
  137. 137. 
    Olson LE, Soriano P. 2009. Increased PDGFRα activation disrupts connective tissue development and drives systemic fibrosis. Dev. Cell 16:2303–13
    [Google Scholar]
  138. 138. 
    Sun C, Berry WL, Olson LE. 2017. PDGFRα controls the balance of stromal and adipogenic cells during adipose tissue organogenesis. Development 144:183–94
    [Google Scholar]
  139. 139. 
    McDonald ME, Li C, Bian H, Smith BD, Layne MD, Farmer SR 2015. Myocardin-related transcription factor A regulates conversion of progenitors to beige adipocytes. Cell 160:1105–18
    [Google Scholar]
  140. 140. 
    Marcelin G, Da Cunha C, Suffee N, Rouault C, Leclerc A et al. 2020. Autophagy inhibition blunts PDGFRA adipose progenitors’ cell-autonomous fibrogenic response to high-fat diet. Autophagy 16:122156–66
    [Google Scholar]
  141. 141. 
    Yamauchi T, Kamon J, Minokoshi Y, Ito Y, Waki H et al. 2002. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat. Med. 8:111288–95
    [Google Scholar]
  142. 142. 
    Yanagida K, Igarashi H, Yasuda D, Kobayashi D, Ohto-Nakanishi T et al. 2018. The Gα12/13-coupled receptor LPA4 limits proper adipose tissue expansion and remodeling in diet-induced obesity. JCI Insight 3:24e97293
    [Google Scholar]
  143. 143. 
    Okuno Y, Fukuhara A, Hashimoto E, Kobayashi H, Kobayashi S et al. 2018. Oxidative stress inhibits healthy adipose expansion through suppression of SREBF1-mediated lipogenic pathway. Diabetes 67:61113–27
    [Google Scholar]
  144. 144. 
    Tordjman J, Poitou C, Hugol D, Bouillot J-L, Basdevant A et al. 2009. Association between omental adipose tissue macrophages and liver histopathology in morbid obesity: influence of glycemic status. J. Hepatol. 51:2354–62
    [Google Scholar]
  145. 145. 
    Beals JW, Smith GI, Shankaran M, Fuchs A, Schweitzer GG et al. 2021. Increased adipose tissue fibrogenesis, not impaired expandability, is associated with nonalcoholic fatty liver disease. Hepatology 74:31287–99
    [Google Scholar]
  146. 146. 
    Walker RW, Allayee H, Inserra A, Fruhwirth R, Alisi A et al. 2014. Macrophage accumulation and fibrosis in adipose tissue is linked to liver damage and metabolic risk in obese children. Obesity 22:61512–19
    [Google Scholar]
  147. 147. 
    Kusminski CM, Bickel PE, Scherer PE. 2016. Targeting adipose tissue in the treatment of obesity-associated diabetes. Nat. Rev. Drug Discov. 15:9639–60
    [Google Scholar]
  148. 148. 
    Guglielmi V, Cardellini M, Cinti F, Corgosinho F, Cardolini I et al. 2015. Omental adipose tissue fibrosis and insulin resistance in severe obesity. Nutr. Diabetes 5:e175
    [Google Scholar]
  149. 149. 
    Johansen ML, Ibarrola J, Fernández-Celis A, Schou M, Sonne MP et al. 2021. The mineralocorticoid receptor antagonist eplerenone suppresses interstitial fibrosis in subcutaneous adipose tissue in patients with type 2 diabetes. Diabetes 70:1196–203
    [Google Scholar]
  150. 150. 
    Liu Y, Aron-Wisnewsky J, Marcelin G, Genser L, Le Naour G et al. 2016. Accumulation and changes in composition of collagens in subcutaneous adipose tissue after bariatric surgery. J. Clin. Endocrinol. Metab. 101:1293–304
    [Google Scholar]
  151. 151. 
    Zamarron BF, Mergian TA, Cho KW, Martinez-Santibanez G, Luan D et al. 2017. Macrophage proliferation sustains adipose tissue inflammation in formerly obese mice. Diabetes 66:2392–406
    [Google Scholar]
  152. 152. 
    McKleroy W, Lee T-H, Atabai K. 2013. Always cleave up your mess: targeting collagen degradation to treat tissue fibrosis. Am. J. Physiol. Lung Cell. Mol. Physiol. 304:11L709–21
    [Google Scholar]
  153. 153. 
    Schmitz J, Evers N, Awazawa M, Nicholls HT, Brönneke HS et al. 2016. Obesogenic memory can confer long-term increases in adipose tissue but not liver inflammation and insulin resistance after weight loss. Mol. Metab. 5:5328–39
    [Google Scholar]
  154. 154. 
    Li G, Xie C, Lu S, Nichols RG, Tian Y et al. 2017. Intermittent fasting promotes white adipose browning and decreases obesity by shaping the gut microbiota. Cell Metab. 26:4672–85.e4
    [Google Scholar]
  155. 155. 
    Kim K-H, Kim YH, Son JE, Lee JH, Kim S et al. 2017. Intermittent fasting promotes adipose thermogenesis and metabolic homeostasis via VEGF-mediated alternative activation of macrophage. Cell Res. 27:111309–26
    [Google Scholar]
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