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Extracellular Matrix (ECM) and Fibrosis in Adipose Tissue: Overview and Perspectives

Kai Sun, Xin Li, Philipp E. Scherer

10.1002/cphy.c220020

Source: Volume 13, Issue 1, January 2023

Published online: January 2023

Full Article on Wiley Online Library



Abstract

Fibrosis in adipose tissue is a major driver of obesity‐related metabolic dysregulation. It is characterized by an overaccumulation of extracellular matrix (ECM) during unhealthy expansion of adipose tissue in response to over nutrition. In obese adipose‐depots, hypoxia stimulates multiple pro‐fibrotic signaling pathways in different cell populations, thereby inducing the overproduction of the ECM components, including collagens, noncollagenous proteins, and additional enzymatic components of ECM synthesis. As a consequence, local fibrosis develops. The result of fibrosis‐induced mechanical stress not only triggers cell necrosis and inflammation locally in adipose tissue but also leads to system‐wide lipotoxicity and insulin resistance. A better understanding of the mechanisms underlying the obesity‐induced fibrosis will help design therapeutic approaches to reduce or reverse the pathological changes associated with obese adipose tissue. Here, we aim to summarize the major advances in the field, which include newly identified fibrotic factors, cell populations that contribute to the fibrosis in adipose tissue, as well as novel mechanisms underlying the development of fibrosis. We further discuss the potential therapeutic strategies to target fibrosis in adipose tissue for the treatment of obesity‐linked metabolic diseases and cancer. © 2023 American Physiological Society. Compr Physiol 13:4387‐4407, 2023.

Figure 1. Figure 1. Working model for the development of fibrosis and inflammation in obese adipose tissue. In lean adipose tissue, the adipocytes are small and healthy. Adequate blood vessels formed by proper angiogenesis provide oxygen, hormones, nutrients, and adipocyte precursors to support the healthy expansion of the tissue (A); during diet‐induced obesity, adipose tissue expands rapidly through hyperplasia and hypertrophy. Meanwhile, new blood vessel formation cannot keep up with the expansion, the adipocytes become larger, and local hypoxia thus develops (B); At the late phase of obesity, hypoxia stimulates massive fibrosis. The mechanical stress induced by the overdeveloped ECM leads to necrosis of the adipocytes. As a result, macrophages are accumulated and polarized to the M1 subtype in the tissue. They form “crown‐like” structures in obese adipose depots. The local fibrosis and inflammation further lead to the whole‐body insulin resistance (C). Of note, not all the adipose tissue expansion has “unhealthy” consequences. In addition to the calorie excess, genetic variants and environmental factors also have profound effects on the expansion.
Figure 2. Figure 2. MMP14 digests Col6 and produce endotrophin. During diet‐induced obesity, local hypoxia induces HIF1α in adipose tissue. As a direct target of HIF1α, MMP14 is upregulated. Meanwhile, HIF1α also upregulates Col6 expression. MMP14 digests Col6α3 chain and produces endotrophin. Accumulation of endotrophin further shapes unhealthy microenvironment locally in the adipose tissue via triggering massive fibrosis and inflammation. The local pathological changes ultimately lead to systemic insulin resistance and other metabolic disorders.
Figure 3. Figure 3. The divergent function of different cell populations on fibrosis in obese adipose tissue. The fibrotic program is coordinated by multiple cell types in adipose tissue, including adipocytes, macrophages, endothelial cells, ACS, Mast cells and fibroblasts, etc. The cells secrete collagens and non‐collagenous proteins, pro‐inflammatory factors, ECM enzymes, and multiple unidentified factors which work together to fine‐tune the level of fibrosis in response to different cell stimuli. Moreover, the cells interplay with each other and regulate their pro‐fibrotic function through the cell‐cell communication.


Figure 1. Working model for the development of fibrosis and inflammation in obese adipose tissue. In lean adipose tissue, the adipocytes are small and healthy. Adequate blood vessels formed by proper angiogenesis provide oxygen, hormones, nutrients, and adipocyte precursors to support the healthy expansion of the tissue (A); during diet‐induced obesity, adipose tissue expands rapidly through hyperplasia and hypertrophy. Meanwhile, new blood vessel formation cannot keep up with the expansion, the adipocytes become larger, and local hypoxia thus develops (B); At the late phase of obesity, hypoxia stimulates massive fibrosis. The mechanical stress induced by the overdeveloped ECM leads to necrosis of the adipocytes. As a result, macrophages are accumulated and polarized to the M1 subtype in the tissue. They form “crown‐like” structures in obese adipose depots. The local fibrosis and inflammation further lead to the whole‐body insulin resistance (C). Of note, not all the adipose tissue expansion has “unhealthy” consequences. In addition to the calorie excess, genetic variants and environmental factors also have profound effects on the expansion.


Figure 2. MMP14 digests Col6 and produce endotrophin. During diet‐induced obesity, local hypoxia induces HIF1α in adipose tissue. As a direct target of HIF1α, MMP14 is upregulated. Meanwhile, HIF1α also upregulates Col6 expression. MMP14 digests Col6α3 chain and produces endotrophin. Accumulation of endotrophin further shapes unhealthy microenvironment locally in the adipose tissue via triggering massive fibrosis and inflammation. The local pathological changes ultimately lead to systemic insulin resistance and other metabolic disorders.


Figure 3. The divergent function of different cell populations on fibrosis in obese adipose tissue. The fibrotic program is coordinated by multiple cell types in adipose tissue, including adipocytes, macrophages, endothelial cells, ACS, Mast cells and fibroblasts, etc. The cells secrete collagens and non‐collagenous proteins, pro‐inflammatory factors, ECM enzymes, and multiple unidentified factors which work together to fine‐tune the level of fibrosis in response to different cell stimuli. Moreover, the cells interplay with each other and regulate their pro‐fibrotic function through the cell‐cell communication.
References
 1.AbdelMassih A, Yacoub E, Husseiny RJ, Kamel A, Hozaien R, El Shershaby M, Rajab M, Yacoub S, Eid MA, Elahmady M, Gadalla M, Mokhtar S, Hassan AA, Abou‐Zeid AS, Hussein M, Aboushadi N, Emad N, Zahra N, Hassan A, Hussein E, Ibrahim N, El Nahhas N, Elahmady T, Khallaf M, Mustafa H, Anis N, Albehairy M, Hanna F, Moris L, Ye J. Hypoxia‐inducible factor (HIF): The link between obesity and COVID‐19. Obes Med 22: 100317, 2021.
 2.Akra S, Aksnes TA, Flaa A, Eggesbo HB, Opstad TB, Njerve IU, Seljeflot I. Markers of remodeling in subcutaneous adipose tissue are strongly associated with overweight and insulin sensitivity in healthy non‐obese men. Sci Rep 10: 14055, 2020.
 3.Alkhouli N, Mansfield J, Green E, Bell J, Knight B, Liversedge N, Tham JC, Welbourn R, Shore AC, Kos K, Winlove CP. The mechanical properties of human adipose tissues and their relationships to the structure and composition of the extracellular matrix. Am J Physiol Endocrinol Metab 305: E1427‐E1435, 2013.
 4.Anvari G, Bellas E. Hypoxia induces stress fiber formation in adipocytes in the early stage of obesity. Sci Rep 11: 21473, 2021.
 5.Aruffo A, Stamenkovic I, Melnick M, Underhill CB, Seed B. CD44 is the principal cell surface receptor for hyaluronate. Cell 61: 1303‐1313, 1990.
 6.Attur M, Lu C, Zhang X, Han T, Alexandre C, Valacca C, Zheng S, Meikle S, Dabovic BB, Tassone E, Yang Q, Kolupaeva V, Yakar S, Abramson S, Mignatti P. Membrane‐type 1 matrix metalloproteinase modulates tissue homeostasis by a non‐proteolytic mechanism. iScience 23: 101789, 2020.
 7.Bahrami SB, Tolg C, Peart T, Symonette C, Veiseh M, Umoh JU, Holdsworth DW, McCarthy JB, Luyt LG, Bissell MJ, Yazdani A, Turley EA. Receptor for hyaluronan mediated motility (RHAMM/HMMR) is a novel target for promoting subcutaneous adipogenesis. Integr Biol (Camb) 9: 223‐237, 2017.
 8.Baker RG, Hayden MS, Ghosh S. NF‐kappaB, inflammation, and metabolic disease. Cell Metab 13: 11‐22, 2011.
 9.Bauters D, Bedossa P, Lijnen HR, Hemmeryckx B. Functional role of ADAMTS5 in adiposity and metabolic health. PLoS One 13: e0190595, 2018.
 10.Bauters D, Cobbaut M, Geys L, Van Lint J, Hemmeryckx B, Lijnen HR. Loss of ADAMTS5 enhances brown adipose tissue mass and promotes browning of white adipose tissue via CREB signaling. Mol. Metab. 6: 715‐724, 2017.
 11.Bel Lassen P, Charlotte F, Liu Y, Bedossa P, Le Naour G, Tordjman J, Poitou C, Bouillot JL, Genser L, Zucker JD, Sokolovska N, Aron‐Wisnewsky J, Clement K. The FAT score, a fibrosis score of adipose tissue: Predicting weight‐loss outcome after gastric bypass. J Clin Endocrinol Metab 102: 2443‐2453, 2017.
 12.Berezin AE, Kremzer AA. Predictive value of circulating osteonectin in patients with ischemic symptomatic chronic heart failure. Biomed J 38: 523‐530, 2015.
 13.Berra E, Benizri E, Ginouves A, Volmat V, Roux D, Pouyssegur J. HIF prolyl‐hydroxylase 2 is the key oxygen sensor setting low steady‐state levels of HIF‐1alpha in normoxia. EMBO J 22: 4082‐4090, 2003.
 14.Blaise S, Romier B, Kawecki C, Ghirardi M, Rabenoelina F, Baud S, Duca L, Maurice P, Heinz A, Schmelzer CE, Tarpin M, Martiny L, Garbar C, Dauchez M, Debelle L, Durlach V. Elastin‐derived peptides are new regulators of insulin resistance development in mice. Diabetes 62: 3807‐3816, 2013.
 15.Bolinder J, Kerckhoffs DA, Moberg E, Hagstrom‐Toft E, Arner P. Rates of skeletal muscle and adipose tissue glycerol release in nonobese and obese subjects. Diabetes 49: 797‐802, 2000.
 16.Bornstein P, Sage EH. Matricellular proteins: Extracellular modulators of cell function. Curr Opin Cell Biol 14: 608‐616, 2002.
 17.Bortell R, Owen TA, Ignotz R, Stein GS, Stein JL. TGF beta 1 prevents the down‐regulation of type I procollagen, fibronectin, and TGF beta 1 gene expression associated with 3T3‐L1 pre‐adipocyte differentiation. J Cell Biochem 54: 256‐263, 1994.
 18.Bouazizi K, Zarai M, Marquet F, Aron‐Wisnewsky J, Clement K, Redheuil A, Kachenoura N. Adipose tissue fibrosis assessed by high resolution ex vivo MRI as a hallmark of tissue alteration in morbid obesity. Quant Imaging Med Surg 11: 2162‐2168, 2021.
 19.Bradshaw AD, Graves DC, Motamed K, Sage EH. SPARC‐null mice exhibit increased adiposity without significant differences in overall body weight. Proc Natl Acad Sci U S A 100: 6045‐6050, 2003.
 20.Bradshaw AD, Puolakkainen P, Dasgupta J, Davidson JM, Wight TN, Helene Sage E. SPARC‐null mice display abnormalities in the dermis characterized by decreased collagen fibril diameter and reduced tensile strength. J Invest Dermatol 120: 949‐955, 2003.
 21.Brahimi‐Horn MC, Pouyssegur J. Oxygen, a source of life and stress. FEBS Lett 581: 3582‐3591, 2007.
 22.Bu D, Crewe C, Kusminski CM, Gordillo R, Ghaben AL, Kim M, Park J, Deng H, Xiong W, Liu XZ, Lonning PE, Halberg N, Rios A, Chang Y, Gonzalez A, Zhang N, An Z, Scherer PE. Human endotrophin as a driver of malignant tumor growth. JCI Insight 5: e125094, 2019.
 23.Cabral‐Pacheco GA, Garza‐Veloz I, Castruita‐De la Rosa C, Ramirez‐Acuna JM, Perez‐Romero BA, Guerrero‐Rodriguez JF, Martinez‐Avila N, Martinez‐Fierro ML. The roles of matrix metalloproteinases and their inhibitors in human diseases. Int J Mol Sci 21: 9739, 2020.
 24.Cao Y. Angiogenesis modulates adipogenesis and obesity. J Clin Invest 117: 2362‐2368, 2007.
 25.Cao Y. Angiogenesis and vascular functions in modulation of obesity, adipose metabolism, and insulin sensitivity. Cell Metab 18 (4): 478‐489, 2013.
 26.Carmeliet P, Jain RK. Molecular mechanisms and clinical applications of angiogenesis. Nature 473: 298‐307, 2011.
 27.Carobbio S, Pellegrinelli V, Vidal‐Puig A. Adipose tissue function and expandability as determinants of lipotoxicity and the metabolic syndrome. Adv Exp Med Biol 960: 161‐196, 2017.
 28.Chavey C, Boucher J, Monthouel‐Kartmann MN, Sage EH, Castan‐Laurell I, Valet P, Tartare‐Deckert S, Van Obberghen E. Regulation of secreted protein acidic and rich in cysteine during adipose conversion and adipose tissue hyperplasia. Obesity (Silver Spring) 14: 1890‐1897, 2006.
 29.Chavey C, Mari B, Monthouel MN, Bonnafous S, Anglard P, Van Obberghen E, Tartare‐Deckert S. Matrix metalloproteinases are differentially expressed in adipose tissue during obesity and modulate adipocyte differentiation. J Biol Chem 278: 11888‐11896, 2003.
 30.Chen N, Qian J, Chen J, Yu X, Mei C, Hao C, Jiang G, Lin H, Zhang X, Zuo L, He Q, Fu P, Li X, Ni D, Hemmerich S, Liu C, Szczech L, Besarab A, Neff TB, Peony Yu KH, Valone FH. Phase 2 studies of oral hypoxia‐inducible factor prolyl hydroxylase inhibitor FG‐4592 for treatment of anemia in China. Nephrol Dial Transplant 32: 1373‐1386, 2017.
 31.Chen SZ, Ning LF, Xu X, Jiang WY, Xing C, Jia WP, Chen XL, Tang QQ, Huang HY. The miR‐181d‐regulated metalloproteinase Adamts1 enzymatically impairs adipogenesis via ECM remodeling. Cell Death Differ 23: 1778‐1791, 2016.
 32.Chmelar J, Chung KJ, Chavakis T. The role of innate immune cells in obese adipose tissue inflammation and development of insulin resistance. Thromb Haemost 109: 399‐406, 2013.
 33.Cho DS, Lee B, Doles JD. Refining the adipose progenitor cell landscape in healthy and obese visceral adipose tissue using single‐cell gene expression profiling. Life Sci Alliance 2: e201900561, 2019.
 34.Choe SS, Shin KC, Ka S, Lee YK, Chun JS, Kim JB. Macrophage HIF‐2alpha ameliorates adipose tissue inflammation and insulin resistance in obesity. Diabetes 63: 3359‐3371, 2014.
 35.Chun TH, Hotary KB, Sabeh F, Saltiel AR, Allen ED, Weiss SJ. A pericellular collagenase directs the 3‐dimensional development of white adipose tissue. Cell 125: 577‐591, 2006.
 36.Chun TH, Inoue M, Morisaki H, Yamanaka I, Miyamoto Y, Okamura T, Sato‐Kusubata K, Weiss SJ. Genetic link between obesity and MMP14‐dependent adipogenic collagen turnover. Diabetes 59: 2484‐2494, 2010.
 37.Cinti S, Mitchell G, Barbatelli G, Murano I, Ceresi E, Faloia E, Wang S, Fortier M, Greenberg AS, Obin MS. Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans. J Lipid Res 46: 2347‐2355, 2005.
 38.Croissandeau G, Chretien M, Mbikay M. Involvement of matrix metalloproteinases in the adipose conversion of 3T3‐L1 preadipocytes. Biochem J 364: 739‐746, 2002.
 39.Csiszar K. Lysyl oxidases: A novel multifunctional amine oxidase family. Prog Nucleic Acid Res Mol Biol 70: 1‐32, 2001.
 40.Dahl LB, Dahl IM, Engstrom‐Laurent A, Granath K. Concentration and molecular weight of sodium hyaluronate in synovial fluid from patients with rheumatoid arthritis and other arthropathies. Ann Rheum Dis 44: 817‐822, 1985.
 41.Dam V, Sikder T, Santosa S. From neutrophils to macrophages: Differences in regional adipose tissue depots. Obes Rev 17: 1‐17, 2016.
 42.Dankel SN, Grytten E, Bjune JI, Nielsen HJ, Dietrich A, Bluher M, Sagen JV, Mellgren G. COL6A3 expression in adipose tissue cells is associated with levels of the homeobox transcription factor PRRX1. Sci Rep 10: 20164, 2020.
 43.Daquinag AC, Gao Z, Fussell C, Sun K, Kolonin MG. Glycosaminoglycan modification of decorin depends on MMP14 activity and regulates collagen assembly. Cell 9: 2646, 2020.
 44.Dasdemir Ilkhan G, Demirci Ucsular F, Celikhisar H, Arman Y, Yalniz E, Tukek T. Original article: Clinical research. Sarcoidosis Vasc Diffuse Lung Dis 38: e2021020, 2021.
 45.de Heer EC, Jalving M, Harris AL. HIFs, angiogenesis, and metabolism: Elusive enemies in breast cancer. J Clin Invest 130: 5074‐5087, 2020.
 46.DeBari MK, Abbott RD. Adipose tissue fibrosis: Mechanisms, models, and importance. Int J Mol Sci 21: 6030, 2020.
 47.Diebold I, Petry A, Sabrane K, Djordjevic T, Hess J, Gorlach A. The HIF1 target gene NOX2 promotes angiogenesis through urotensin‐II. J Cell Sci 125: 956‐964, 2012.
 48.Divoux A, Moutel S, Poitou C, Lacasa D, Veyrie N, Aissat A, Arock M, Guerre‐Millo M, Clement K. Mast cells in human adipose tissue: Link with morbid obesity, inflammatory status, and diabetes. J Clin Endocrinol Metab 97: E1677‐E1685, 2012.
 49.Divoux A, Tordjman J, Lacasa D, Veyrie N, Hugol D, Aissat A, Basdevant A, Guerre‐Millo M, Poitou C, Zucker JD, Bedossa P, Clement K. Fibrosis in human adipose tissue: Composition, distribution, and link with lipid metabolism and fat mass loss. Diabetes 59: 2817‐2825, 2010.
 50.Eljaafari A, Pestel J, Le Magueresse‐Battistoni B, Chanon S, Watson J, Robert M, Disse E, Vidal H. Adipose‐tissue‐derived mesenchymal stem cells mediate PD‐L1 overexpression in the white adipose tissue of obese individuals, resulting in T cell dysfunction. Cell 10: 2645, 2021.
 51.Elpek GO. Angiogenesis and liver fibrosis. World J Hepatol 7: 377‐391, 2015.
 52.Emami Nejad A, Najafgholian S, Rostami A, Sistani A, Shojaeifar S, Esparvarinha M, Nedaeinia R, Haghjooy Javanmard S, Taherian M, Ahmadlou M, Salehi R, Sadeghi B, Manian M. The role of hypoxia in the tumor microenvironment and development of cancer stem cell: A novel approach to developing treatment. Cancer Cell Int 21: 62, 2021.
 53.Engin AB. Adipocyte‐macrophage cross‐talk in obesity. Adv Exp Med Biol 960: 327‐343, 2017.
 54.Eruzun H, Toprak ID, Arman Y, Yilmaz U, Ozcan M, Kutlu Y, Irmak S, Kutlu O, Yoldemir SA, Altun O, Cil EO, Tukek T. Serum endotrophin levels in patients with heart failure with reduced and mid‐range ejection fraction. Eur J Intern Med 64: 29‐32, 2019.
 55.Ezzati‐Mobaser S, Malekpour‐Dehkordi Z, Nourbakhsh M, Tavakoli‐Yaraki M, Ahmadpour F, Golpour P, Nourbakhsh M. The up‐regulation of markers of adipose tissue fibrosis by visfatin in pre‐adipocytes as well as obese children and adolescents. Cytokine 134: 155193, 2020.
 56.Fenton A, Jesky MD, Ferro CJ, Sorensen J, Karsdal MA, Cockwell P, Genovese F. Serum endotrophin, a type VI collagen cleavage product, is associated with increased mortality in chronic kidney disease. PLoS One 12: e0175200, 2017.
 57.Ferrante AW Jr. The immune cells in adipose tissue. Diabetes Obes Metab 15 (Suppl 3): 34‐38, 2013.
 58.Feuerer M, Herrero L, Cipolletta D, Naaz A, Wong J, Nayer A, Lee J, Goldfine AB, Benoist C, Shoelson S, Mathis D. Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat Med 15: 930‐939, 2009.
 59.Fischer‐Posovszky P, Wang QA, Asterholm IW, Rutkowski JM, Scherer PE. Targeted deletion of adipocytes by apoptosis leads to adipose tissue recruitment of alternatively activated M2 macrophages. Endocrinology 152: 3074‐3081, 2011.
 60.Flaherty SE 3rd, Grijalva A, Xu X, Ables E, Nomani A, Ferrante AW Jr. A lipase‐independent pathway of lipid release and immune modulation by adipocytes. Science 363: 989‐993, 2019.
 61.Fraisl P, Mazzone M, Schmidt T, Carmeliet P. Regulation of angiogenesis by oxygen and metabolism. Dev Cell 16: 167‐179, 2009.
 62.Fujisaka S, Usui I, Ikutani M, Aminuddin A, Takikawa A, Tsuneyama K, Mahmood A, Goda N, Nagai Y, Takatsu K, Tobe K. Adipose tissue hypoxia induces inflammatory M1 polarity of macrophages in an HIF‐1alpha‐dependent and HIF‐1alpha‐independent manner in obese mice. Diabetologia 56: 1403‐1412, 2013.
 63.Galli SJ, Borregaard N, Wynn TA. Phenotypic and functional plasticity of cells of innate immunity: Macrophages, mast cells and neutrophils. Nat Immunol 12: 1035‐1044, 2011.
 64.Garcia‐Martin R, Alexaki VI, Qin N, Rubin de Celis MF, Economopoulou M, Ziogas A, Gercken B, Kotlabova K, Phieler J, Ehrhart‐Bornstein M, Bornstein SR, Eisenhofer G, Breier G, Bluher M, Hampe J, El‐Armouche A, Chatzigeorgiou A, Chung KJ, Chavakis T. Adipocyte‐specific hypoxia‐inducible factor 2alpha deficiency exacerbates obesity‐induced brown adipose tissue dysfunction and metabolic dysregulation. Mol Cell Biol 36: 376‐393, 2016.
 65.Gaspar JM, Velloso LA. Hypoxia inducible factor as a central regulator of metabolism—implications for the development of obesity. Front Neurosci 12: 813, 2018.
 66.Genovese F, Akhgar A, Lim SS, Farris AB, Battle M, Cobb J, Sinibaldi D, Karsdal MA, White WI. Collagen type III and VI remodeling biomarkers are associated with kidney fibrosis in lupus nephritis. Kidney360 2: 1473‐1481, 2021.
 67.Gerin I, Louis GW, Zhang X, Prestwich TC, Kumar TR, Myers MG Jr, Macdougald OA, Nothnick WB. Hyperphagia and obesity in female mice lacking tissue inhibitor of metalloproteinase‐1. Endocrinology 150: 1697‐1704, 2009.
 68.Ghaben AL, Scherer PE. Adipogenesis and metabolic health. Nat Rev Mol Cell Biol 20: 242‐258, 2019.
 69.Giaccia AJ. HIF‐2: The missing link between obesity and cardiomyopathy. J Am Heart Assoc 2: e000710, 2013.
 70.Gliniak CM, Scherer PE. A new signal that shrinks fat. Nat Metab 4: 305‐307, 2022.
 71.Gregor MF, Hotamisligil GS. Inflammatory mechanisms in obesity. Annu Rev Immunol 29: 415‐445, 2011.
 72.Guney G, Taskin MI, Baykan O, Adali E, Gul Tezcan S, Sarikaya S, Kaya C, Tolu E. Endotrophin as a novel marker in PCOS and its relation with other adipokines and metabolic parameters: A pilot study. Ther Adv Endocrinol Metab 12: 20420188211049607, 2021.
 73.Gurung P, Moussa K, Adams‐Huet B, Devaraj S, Jialal I. Increased mast cell abundance in adipose tissue of metabolic syndrome: Relevance to the proinflammatory state and increased adipose tissue fibrosis. Am J Physiol Endocrinol Metab 316: E504‐E509, 2019.
 74.Gutierrez LS, Gutierrez J. Thrombospondin 1 in metabolic diseases. Front Endocrinol (Lausanne) 12: 638536, 2021.
 75.Haase J, Weyer U, Immig K, Kloting N, Bluher M, Eilers J, Bechmann I, Gericke M. Local proliferation of macrophages in adipose tissue during obesity‐induced inflammation. Diabetologia 57: 562‐571, 2014.
 76.Hagström H, Bu D, Nasr P, Ekstedt M, Hegmar H, Kechagias S, Zhang N, An Z, Stal P, Scherer PE. Serum levels of endotrophin are associated with nonalcoholic steatohepatitis. Scand J Gastroenterol 56: 437‐442, 2021.
 77.Hajri T, Hall AM, Jensen DR, Pietka TA, Drover VA, Tao H, Eckel R, Abumrad NA. CD36‐facilitated fatty acid uptake inhibits leptin production and signaling in adipose tissue. Diabetes 56: 1872‐1880, 2007.
 78.Hajri T, Han XX, Bonen A, Abumrad NA. Defective fatty acid uptake modulates insulin responsiveness and metabolic responses to diet in CD36‐null mice. J Clin Invest 109: 1381‐1389, 2002.
 79.Halberg N, Khan T, Trujillo ME, Wernstedt‐Asterholm I, Attie AD, Sherwani S, Wang ZV, Landskroner‐Eiger S, Dineen S, Magalang UJ, Brekken RA, Scherer PE. Hypoxia‐inducible factor 1alpha induces fibrosis and insulin resistance in white adipose tissue. Mol Cell Biol 29: 4467‐4483, 2009.
 80.Han MS, White A, Perry RJ, Camporez JP, Hidalgo J, Shulman GI, Davis RJ. Regulation of adipose tissue inflammation by interleukin 6. Proc Natl Acad Sci U S A 117: 2751‐2760, 2020.
 81.Hara Y, Wakino S, Tanabe Y, Saito M, Tokuyama H, Washida N, Tatematsu S, Yoshioka K, Homma K, Hasegawa K, Minakuchi H, Fujimura K, Hosoya K, Hayashi K, Nakayama K, Itoh H. Rho and Rho‐kinase activity in adipocytes contributes to a vicious cycle in obesity that may involve mechanical stretch. Sci Signal 4: ra3, 2011.
 82.Hasegawa Y, Ikeda K, Chen Y, Alba DL, Stifler D, Shinoda K, Hosono T, Maretich P, Yang Y, Ishigaki Y, Chi J, Cohen P, Koliwad SK, Kajimura S. Repression of adipose tissue fibrosis through a PRDM16‐GTF2IRD1 complex improves systemic glucose homeostasis. Cell Metab 27: 180‐194 e186, 2018.
 83.Hashimoto N, Phan SH, Imaizumi K, Matsuo M, Nakashima H, Kawabe T, Shimokata K, Hasegawa Y. Endothelial‐mesenchymal transition in bleomycin‐induced pulmonary fibrosis. Am J Respir Cell Mol Biol 43: 161‐172, 2010.
 84.He Q, Gao Z, Yin J, Zhang J, Yun Z, Ye J. Regulation of HIF‐1{alpha} activity in adipose tissue by obesity‐associated factors: Adipogenesis, insulin, and hypoxia. Am J Physiol Endocrinol Metab 300: E877‐E885, 2011.
 85.Henegar C, Tordjman J, Achard V, Lacasa D, Cremer I, Guerre‐Millo M, Poitou C, Basdevant A, Stich V, Viguerie N, Langin D, Bedossa P, Zucker JD, Clement K. Adipose tissue transcriptomic signature highlights the pathological relevance of extracellular matrix in human obesity. Genome Biol 9: R14, 2008.
 86.Hepler C, Shan B, Zhang Q, Henry GH, Shao M, Vishvanath L, Ghaben AL, Mobley AB, Strand D, Hon GC, Gupta RK. Identification of functionally distinct fibro‐inflammatory and adipogenic stromal subpopulations in visceral adipose tissue of adult mice. elife 7: e39636, 2018.
 87.Hepler C, Vishvanath L, Gupta RK. Sorting out adipocyte precursors and their role in physiology and disease. Genes Dev 31: 127‐140, 2017.
 88.Herchenhan A, Uhlenbrock F, Eliasson P, Weis M, Eyre D, Kadler KE, Magnusson SP, Kjaer M. Lysyl oxidase activity is required for ordered collagen fibrillogenesis by tendon cells. J Biol Chem 290: 16440‐16450, 2015.
 89.Heumuller SE, Talantikite M, Napoli M, Armengaud J, Morgelin M, Hartmann U, Sengle G, Paulsson M, Moali C, Wagener R. C‐terminal proteolysis of the collagen VI alpha3 chain by BMP‐1 and proprotein convertase(s) releases endotrophin in fragments of different sizes. J Biol Chem 294: 13769‐13780, 2019.
 90.Hirai S, Ohyane C, Kim YI, Lin S, Goto T, Takahashi N, Kim CS, Kang J, Yu R, Kawada T. Involvement of mast cells in adipose tissue fibrosis. Am J Physiol Endocrinol Metab 306: E247‐E255, 2014.
 91.Holm Nielsen S, Edsfeldt A, Tengryd C, Gustafsson H, Shore AC, Natali A, Khan F, Genovese F, Bengtsson E, Karsdal M, Leeming DJ, Nilsson J, Goncalves I. The novel collagen matrikine, endotrophin, is associated with mortality and cardiovascular events in patients with atherosclerosis. J Intern Med 290: 179‐189, 2021.
 92.Hosogai N, Fukuhara A, Oshima K, Miyata Y, Tanaka S, Segawa K, Furukawa S, Tochino Y, Komuro R, Matsuda M, Shimomura I. Adipose tissue hypoxia in obesity and its impact on adipocytokine dysregulation. Diabetes 56: 901‐911, 2007.
 93.Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor‐alpha: Direct role in obesity‐linked insulin resistance. Science 259: 87‐91, 1993.
 94.Huang A, Lin YS, Kao LZ, Chiou YW, Lee GH, Lin HH, Wu CH, Chang CS, Lee KT, Hsueh YY, Tsai PJ, Tang MJ, Tsai YS. Inflammation‐induced macrophage lysyl oxidase in adipose stiffening and dysfunction in obesity. Clin Transl Med 11: e543, 2021.
 95.Huber J, Loffler M, Bilban M, Reimers M, Kadl A, Todoric J, Zeyda M, Geyeregger R, Schreiner M, Weichhart T, Leitinger N, Waldhausl W, Stulnig TM. Prevention of high‐fat diet‐induced adipose tissue remodeling in obese diabetic mice by n‐3 polyunsaturated fatty acids. Int J Obes 31: 1004‐1013, 2007.
 96.Ilyas Z, Perna S, Al‐Thawadi S, Alalwan TA, Riva A, Petrangolini G, Gasparri C, Infantino V, Peroni G, Rondanelli M. The effect of Berberine on weight loss in order to prevent obesity: A systematic review. Biomed Pharmacother 127: 110137, 2020.
 97.Itoh Y, Seiki M. MT1‐MMP: A potent modifier of pericellular microenvironment. J Cell Physiol 206: 1‐8, 2006.
 98.Iwayama T, Steele C, Yao L, Dozmorov MG, Karamichos D, Wren JD, Olson LE. PDGFRalpha signaling drives adipose tissue fibrosis by targeting progenitor cell plasticity. Genes Dev 29: 1106‐1119, 2015.
 99.Jablonska‐Trypuc A, Matejczyk M, Rosochacki S. Matrix metalloproteinases (MMPs), the main extracellular matrix (ECM) enzymes in collagen degradation, as a target for anticancer drugs. J Enzyme Inhib Med Chem 31: 177‐183, 2016.
 100.Janke K, Brockmeier U, Kuhlmann K, Eisenacher M, Nolde J, Meyer HE, Mairbaurl H, Metzen E. Factor inhibiting HIF‐1 (FIH‐1) modulates protein interactions of apoptosis‐stimulating p53 binding protein 2 (ASPP2). J Cell Sci 126: 2629‐2640, 2013.
 101.Ji Y, Cao M, Liu J, Chen Y, Li X, Zhao J, Qu C. Rock signaling control PPARgamma expression and actin polymerization during adipogenesis. Saudi J Biol Sci 24: 1866‐1870, 2017.
 102.Jiao B, An C, Du H, Tran M, Wang P, Zhou D, Wang Y. STAT6 deficiency attenuates myeloid fibroblast activation and macrophage polarization in experimental folic acid nephropathy. Cell 10: 3057, 2021.
 103.Jiao B, An C, Tran M, Du H, Wang P, Zhou D, Wang Y. Pharmacological inhibition of STAT6 ameliorates myeloid fibroblast activation and alternative macrophage polarization in renal fibrosis. Front Immunol 12: 735014, 2021.
 104.Jo W, Kim M, Oh J, Kim CS, Park C, Yoon S, Lee C, Kim S, Nam D, Park J. MicroRNA‐29 ameliorates fibro‐inflammation and insulin resistance in HIF1alpha‐deficient obese adipose tissue by inhibiting endotrophin generation. Diabetes 71: 1746‐1762, 2022.
 105.Jones JEC, Rabhi N, Orofino J, Gamini R, Perissi V, Vernochet C, Farmer SR. The adipocyte acquires a fibroblast‐like transcriptional signature in response to a high fat diet. Sci Rep 10: 2380, 2020.
 106.Kaartinen MT, Arora M, Heinonen S, Hang A, Barry A, Lundbom J, Hakkarainen A, Lundholm N, Rissanen A, Kaprio J, Pietilainen KH. F13A1 transglutaminase expression in human adipose tissue increases in acquired excess weight and associates with inflammatory status of adipocytes. Int J Obes 45: 577‐587, 2021.
 107.Kaartinen MT, Arora M, Heinonen S, Rissanen A, Kaprio J, Pietilainen KH. Transglutaminases and obesity in humans: Association of F13A1 to adipocyte hypertrophy and adipose tissue immune response. Int J Mol Sci 21: 8289, 2020.
 108.Kagan HM, Li W. Lysyl oxidase: Properties, specificity, and biological roles inside and outside of the cell. J Cell Biochem 88: 660‐672, 2003.
 109.Kane H, Lynch L. Innate immune control of adipose tissue homeostasis. Trends Immunol 40: 857‐872, 2019.
 110.Kang L, Lantier L, Kennedy A, Bonner JS, Mayes WH, Bracy DP, Bookbinder LH, Hasty AH, Thompson CB, Wasserman DH. Hyaluronan accumulates with high‐fat feeding and contributes to insulin resistance. Diabetes 62: 1888‐1896, 2013.
 111.Karastergiou K, Mohamed‐Ali V. The autocrine and paracrine roles of adipokines. Mol Cell Endocrinol 318: 69‐78, 2010.
 112.Karsdal MA, Henriksen K, Genovese F, Leeming DJ, Nielsen MJ, Riis BJ, Christiansen C, Byrjalsen I, Schuppan D. Serum endotrophin identifies optimal responders to PPARgamma agonists in type 2 diabetes. Diabetologia 60: 50‐59, 2017.
 113.Keith B, Johnson RS, Simon MC. HIF1alpha and HIF2alpha: Sibling rivalry in hypoxic tumour growth and progression. Nat Rev Cancer 12: 9‐22, 2011.
 114.Kendall RT, Feghali‐Bostwick CA. Fibroblasts in fibrosis: Novel roles and mediators. Front Pharmacol 5: 123, 2014.
 115.Kerbert AJC, Gupta S, Alabsawy E, Dobler I, Lonsmann I, Hall A, Nielsen SH, Nielsen MJ, Gronbaek H, Amoros A, Yeung D, Macnaughtan J, Mookerjee RP, Macdonald S, Andreola F, Moreau R, Arroyo V, Angeli P, Leeming DJ, Treem W, Karsdal MA, Jalan R. Biomarkers of extracellular matrix formation are associated with acute‐on‐chronic liver failure. JHEP Rep 3: 100355, 2021.
 116.Khan T, Muise ES, Iyengar P, Wang ZV, Chandalia M, Abate N, Zhang BB, Bonaldo P, Chua S, Scherer PE. Metabolic dysregulation and adipose tissue fibrosis: Role of collagen VI. Mol Cell Biol 29: 1575‐1591, 2009.
 117.Kim M, Lee C, Seo DY, Lee H, Horton JD, Park J, Scherer PE. The impact of endotrophin on the progression of chronic liver disease. Exp Mol Med 52: 1766‐1776, 2020.
 118.Kim M, Neinast MD, Frank AP, Sun K, Park J, Zehr JA, Vishvanath L, Morselli E, Amelotte M, Palmer BF, Gupta RK, Scherer PE, Clegg DJ. ERalpha upregulates Phd3 to ameliorate HIF‐1 induced fibrosis and inflammation in adipose tissue. Mol. Metab. 3: 642‐651, 2014.
 119.Kinsey R, Williamson MR, Chaudhry S, Mellody KT, McGovern A, Takahashi S, Shuttleworth CA, Kielty CM. Fibrillin‐1 microfibril deposition is dependent on fibronectin assembly. J Cell Sci 121: 2696‐2704, 2008.
 120.Kiran S, Kumar V, Murphy EA, Enos RT, Singh UP. High fat diet‐induced CD8(+) T cells in adipose tissue mediate macrophages to sustain low‐grade chronic inflammation. Front Immunol 12: 680944, 2021.
 121.Kodama K, Horikoshi M, Toda K, Yamada S, Hara K, Irie J, Sirota M, Morgan AA, Chen R, Ohtsu H, Maeda S, Kadowaki T, Butte AJ. Expression‐based genome‐wide association study links the receptor CD44 in adipose tissue with type 2 diabetes. Proc Natl Acad Sci U S A 109: 7049‐7054, 2012.
 122.Kong P, Gonzalez‐Quesada C, Li N, Cavalera M, Lee DW, Frangogiannis NG. Thrombospondin‐1 regulates adiposity and metabolic dysfunction in diet‐induced obesity enhancing adipose inflammation and stimulating adipocyte proliferation. Am J Physiol Endocrinol Metab 305: E439‐E450, 2013.
 123.Kos K, Wilding JP. SPARC: A key player in the pathologies associated with obesity and diabetes. Nat Rev Endocrinol 6: 225‐235, 2010.
 124.Kos K, Wong S, Tan B, Gummesson A, Jernas M, Franck N, Kerrigan D, Nystrom FH, Carlsson LM, Randeva HS, Pinkney JH, Wilding JP. Regulation of the fibrosis and angiogenesis promoter SPARC/osteonectin in human adipose tissue by weight change, leptin, insulin, and glucose. Diabetes 58: 1780‐1788, 2009.
 125.Koumenis C, Bi M, Ye J, Feldman D, Koong AC. Hypoxia and the unfolded protein response. Methods Enzymol 435: 275‐293, 2007.
 126.Kralisch S, Bluher M, Tonjes A, Lossner U, Paschke R, Stumvoll M, Fasshauer M. Tissue inhibitor of metalloproteinase‐1 predicts adiposity in humans. Eur J Endocrinol 156: 257‐261, 2007.
 127.Kruglikov IL, Joffin N, Scherer PE. The MMP14‐caveolin axis and its potential relevance for lipoedema. Nat Rev Endocrinol 16: 669‐674, 2020.
 128.Kruglikov IL, Zhang Z, Scherer PE. Phenotypical conversions of dermal adipocytes as pathophysiological steps in inflammatory cutaneous disorders. Int J Mol Sci 23: 3828, 2022.
 129.Kruglikov IL, Zhang Z, Scherer PE. Skin aging: Dermal adipocytes metabolically reprogram dermal fibroblasts. Bioessays 44: e2100207, 2022.
 130.Krystel‐Whittemore M, Dileepan KN, Wood JG. Mast cell: A multi‐functional master cell. Front Immunol 6: 620, 2015.
 131.Kusminski CM, Shetty S, Orci L, Unger RH, Scherer PE. Diabetes and apoptosis: Lipotoxicity. Apoptosis 14: 1484‐1495, 2009.
 132.Kusunoki H, Taniyama Y, Otsu R, Rakugi H, Morishita R. Anti‐inflammatory effects of hepatocyte growth factor on the vicious cycle of macrophages and adipocytes. Hypertens Res 37: 500‐506, 2014.
 133.Lackey DE, Olefsky JM. Regulation of metabolism by the innate immune system. Nat Rev Endocrinol 12: 15‐28, 2016.
 134.Lando D, Peet DJ, Gorman JJ, Whelan DA, Whitelaw ML, Bruick RK. FIH‐1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia‐inducible factor. Genes Dev 16: 1466‐1471, 2002.
 135.Lauterbach MA, Wunderlich FT. Macrophage function in obesity‐induced inflammation and insulin resistance. Pflugers Arch 469: 385‐396, 2017.
 136.Lawler HM, Underkofler CM, Kern PA, Erickson C, Bredbeck B, Rasouli N. Adipose tissue hypoxia, inflammation, and fibrosis in obese insulin‐sensitive and obese insulin‐resistant subjects. J Clin Endocrinol Metab 101: 1422‐1428, 2016.
 137.Leach HG, Chrobak I, Han R, Trojanowska M. Endothelial cells recruit macrophages and contribute to a fibrotic milieu in bleomycin lung injury. Am J Respir Cell Mol Biol 49: 1093‐1101, 2013.
 138.Lee C, Kim M, Lee JH, Oh J, Shin HH, Lee SM, Scherer PE, Kwon HM, Choi JH, Park J. COL6A3‐derived endotrophin links reciprocal interactions among hepatic cells in the pathology of chronic liver disease. J Pathol 247: 99‐109, 2019.
 139.Lee K, Kim HM. A novel approach to cancer therapy using PX‐478 as a HIF‐1alpha inhibitor. Arch Pharm Res 34: 1583‐1585, 2011.
 140.Lee MH, Goralczyk AG, Kriszt R, Ang XM, Badowski C, Li Y, Summers SA, Toh SA, Yassin MS, Shabbir A, Sheppard A, Raghunath M. ECM microenvironment unlocks brown adipogenic potential of adult human bone marrow‐derived MSCs. Sci Rep 6: 21173, 2016.
 141.Lee SH, Park HS, Lee JA, Song YS, Jang YJ, Kim JH, Lee YJ, Heo Y. Fibronectin gene expression in human adipose tissue and its associations with obesity‐related genes and metabolic parameters. Obes Surg 23: 554‐560, 2013.
 142.Lee YH, Petkova AP, Granneman JG. Identification of an adipogenic niche for adipose tissue remodeling and restoration. Cell Metab 18: 355‐367, 2013.
 143.Lee YS, Kim JW, Osborne O, Oh DY, Sasik R, Schenk S, Chen A, Chung H, Murphy A, Watkins SM, Quehenberger O, Johnson RS, Olefsky JM. Increased adipocyte O2 consumption triggers HIF‐1alpha, causing inflammation and insulin resistance in obesity. Cell 157: 1339‐1352, 2014.
 144.Lee YS, Wollam J, Olefsky JM. An integrated view of immunometabolism. Cell 172: 22‐40, 2018.
 145.Leeming DJ, Nielsen SH, Vongsuvanh R, Uchila P, Nielsen MJ, Reese‐Petersen AL, van der Poorten D, Eslam M, Schuppan D, Karsdal MA, George J. Endotrophin, a pro‐peptide of Type VI collagen, is a biomarker of survival in cirrhotic patients with hepatocellular carcinoma. Hepat Oncol 8: HEP32, 2020.
 146.Li G, Jin F, Du J, He Q, Yang B, Luo P. Macrophage‐secreted TSLP and MMP9 promote bleomycin‐induced pulmonary fibrosis. Toxicol Appl Pharmacol 366: 10‐16, 2019.
 147.Li G, Li X, Yang L, Wang S, Dai Y, Fekry B, Veillon L, Tan L, Berdeaux R, Eckel‐Mahan K, Lorenzi PL, Zhao Z, Lehner R, Sun K. Adipose tissue‐specific ablation of Ces1d causes metabolic dysregulation in mice. Life Sci Alliance 5: e202101209, 2022.
 148.Li Q, Hata A, Kosugi C, Kataoka N, Funaki M. The density of extracellular matrix proteins regulates inflammation and insulin signaling in adipocytes. FEBS Lett 584: 4145‐4150, 2010.
 149.Li X, Yang L, Mao Z, Pan X, Zhao Y, Gu X, Eckel‐Mahan K, Zuo Z, Tong Q, Hartig SM, Cheng X, Du G, Moore DD, Bellen HJ, Sesaki H, Sun K. Novel role of dynamin‐related‐protein 1 in dynamics of ER‐lipid droplets in adipose tissue. FASEB J 34: 8265‐8282, 2020.
 150.Li X, Zhao Y, Chen C, Yang L, Lee HH, Wang Z, Zhang N, Kolonin MG, An Z, Ge X, Scherer PE, Sun K. Critical role of matrix metalloproteinase 14 in adipose tissue remodeling during obesity. Mol Cell Biol 40: e00564‐19, 2020.
 151.Li Y, Tong X, Rumala C, Clemons K, Wang S. Thrombospondin1 deficiency reduces obesity‐associated inflammation and improves insulin sensitivity in a diet‐induced obese mouse model. PLoS One 6: e26656, 2011.
 152.Liang X, Kanjanabuch T, Mao SL, Hao CM, Tang YW, Declerck PJ, Hasty AH, Wasserman DH, Fogo AB, Ma LJ. Plasminogen activator inhibitor‐1 modulates adipocyte differentiation. Am J Physiol Endocrinol Metab 290: E103‐E113, 2006.
 153.Lin Q, Huang Y, Booth CJ, Haase VH, Johnson RS, Celeste Simon M, Giordano FJ, Yun Z. Activation of hypoxia‐inducible factor‐2 in adipocytes results in pathological cardiac hypertrophy. J Am Heart Assoc 2: e000548, 2013.
 154.Lindholm M, Godskesen LE, Manon‐Jensen T, Kjeldsen J, Krag A, Karsdal MA, Mortensen JH. Endotrophin and C6Ma3, serological biomarkers of type VI collagen remodelling, reflect endoscopic and clinical disease activity in IBD. Sci Rep 11: 14713, 2021.
 155.Liu J, Divoux A, Sun J, Zhang J, Clement K, Glickman JN, Sukhova GK, Wolters PJ, Du J, Gorgun CZ, Doria A, Libby P, Blumberg RS, Kahn BB, Hotamisligil GS, Shi GP. Genetic deficiency and pharmacological stabilization of mast cells reduce diet‐induced obesity and diabetes in mice. Nat Med 15: 940‐945, 2009.
 156.Liu Y, Aron‐Wisnewsky J, Marcelin G, Genser L, Le Naour G, Torcivia A, Bauvois B, Bouchet S, Pelloux V, Sasso M, Miette V, Tordjman J, Clement K. Accumulation and changes in composition of collagens in subcutaneous adipose tissue after bariatric surgery. J Clin Endocrinol Metab 101: 293‐304, 2016.
 157.Lizardo K, Ayyappan JP, Oswal N, Weiss LM, Scherer PE, Nagajyothi JF. Fat tissue regulates the pathogenesis and severity of cardiomyopathy in murine chagas disease. PLoS Negl Trop Dis 15: e0008964, 2021.
 158.Mack M. Inflammation and fibrosis. Matrix Biol 68‐69: 106‐121, 2018.
 159.Mahon PC, Hirota K, Semenza GL. FIH‐1: A novel protein that interacts with HIF‐1alpha and VHL to mediate repression of HIF‐1 transcriptional activity. Genes Dev 15: 2675‐2686, 2001.
 160.Maki JM, Sormunen R, Lippo S, Kaarteenaho‐Wiik R, Soininen R, Myllyharju J. Lysyl oxidase is essential for normal development and function of the respiratory system and for the integrity of elastic and collagen fibers in various tissues. Am J Pathol 167: 927‐936, 2005.
 161.Maquoi E, Munaut C, Colige A, Collen D, Lijnen HR. Modulation of adipose tissue expression of murine matrix metalloproteinases and their tissue inhibitors with obesity. Diabetes 51: 1093‐1101, 2002.
 162.Marcelin G, Ferreira A, Liu Y, Atlan M, Aron‐Wisnewsky J, Pelloux V, Botbol Y, Ambrosini M, Fradet M, Rouault C, Henegar C, Hulot JS, Poitou C, Torcivia A, Nail‐Barthelemy R, Bichet JC, Gautier EL, Clement K. A PDGFRalpha‐mediated switch toward CD9(high) adipocyte progenitors controls obesity‐induced adipose tissue fibrosis. Cell Metab 25: 673‐685, 2017.
 163.Marcelin G, Gautier EL, Clement K. Adipose tissue fibrosis in obesity: Etiology and challenges. Annu Rev Physiol 84: 135‐155, 2022.
 164.Marcelin G, Silveira ALM, Martins LB, Ferreira AV, Clement K. Deciphering the cellular interplays underlying obesity‐induced adipose tissue fibrosis. J Clin Invest 129: 4032‐4040, 2019.
 165.Mariman EC, Wang P. Adipocyte extracellular matrix composition, dynamics and role in obesity. Cell Mol Life Sci 67: 1277‐1292, 2010.
 166.Martinez FO, Helming L, Gordon S. Alternative activation of macrophages: An immunologic functional perspective. Annu Rev Immunol 27: 451‐483, 2009.
 167.Martinez‐Santibanez G, Singer K, Cho KW, DelProposto JL, Mergian T, Lumeng CN. Obesity‐induced remodeling of the adipose tissue elastin network is independent of the metalloelastase MMP‐12. Adipocyte 4: 264‐272, 2015.
 168.McBeath R, Pirone DM, Nelson CM, Bhadriraju K, Chen CS. Cell shape, cytoskeletal tension, and RhoA regulate stem cell lineage commitment. Dev Cell 6: 483‐495, 2004.
 169.McLaughlin T, Ackerman SE, Shen L, Engleman E. Role of innate and adaptive immunity in obesity‐associated metabolic disease. J Clin Invest 127: 5‐13, 2017.
 170.Meissburger B, Stachorski L, Roder E, Rudofsky G, Wolfrum C. Tissue inhibitor of matrix metalloproteinase 1 (TIMP1) controls adipogenesis in obesity in mice and in humans. Diabetologia 54: 1468‐1479, 2011.
 171.Memetimin H, Li D, Tan K, Zhou C, Liang Y, Wu Y, Wang S. Myeloid‐specific deletion of thrombospondin 1 protects against inflammation and insulin resistance in long‐term diet‐induced obese male mice. Am J Physiol Endocrinol Metab 315: E1194‐E1203, 2018.
 172.Merrick D, Sakers A, Irgebay Z, Okada C, Calvert C, Morley MP, Percec I, Seale P. Identification of a mesenchymal progenitor cell hierarchy in adipose tissue. Science 364: eaav2501, 2019.
 173.Michailidou Z, Gomez‐Salazar M, Alexaki VI. Innate immune cells in the adipose tissue in health and metabolic disease. J Innate Immun 14: 4‐30, 2022.
 174.Michailidou Z, Morton NM, Moreno Navarrete JM, West CC, Stewart KJ, Fernandez‐Real JM, Schofield CJ, Seckl JR, Ratcliffe PJ. Adipocyte pseudohypoxia suppresses lipolysis and facilitates benign adipose tissue expansion. Diabetes 64: 733‐745, 2015.
 175.Miossec P, Dinarello CA, Ziff M. Interleukin‐1 lymphocyte chemotactic activity in rheumatoid arthritis synovial fluid. Arthritis Rheum 29: 461‐470, 1986.
 176.Misumi I, Starmer J, Uchimura T, Beck MA, Magnuson T, Whitmire JK. Obesity expands a distinct population of T cells in adipose tissue and increases vulnerability to infection. Cell Rep 27: 514‐524 e515, 2019.
 177.Mori S, Kiuchi S, Ouchi A, Hase T, Murase T. Characteristic expression of extracellular matrix in subcutaneous adipose tissue development and adipogenesis; comparison with visceral adipose tissue. Int J Biol Sci 10: 825‐833, 2014.
 178.Mosher DF, Schad PE. Cross‐linking of fibronectin to collagen by blood coagulation factor XIIIa. J Clin Invest 64: 781‐787, 1979.
 179.Muir LA, Neeley CK, Meyer KA, Baker NA, Brosius AM, Washabaugh AR, Varban OA, Finks JF, Zamarron BF, Flesher CG, Chang JS, DelProposto JB, Geletka L, Martinez‐Santibanez G, Kaciroti N, Lumeng CN, O'Rourke RW. Adipose tissue fibrosis, hypertrophy, and hyperplasia: Correlations with diabetes in human obesity. Obesity (Silver Spring) 24: 597‐605, 2016.
 180.Murano I, Barbatelli G, Parisani V, Latini C, Muzzonigro G, Castellucci M, Cinti S. Dead adipocytes, detected as crown‐like structures, are prevalent in visceral fat depots of genetically obese mice. J Lipid Res 49: 1562‐1568, 2008.
 181.Muscogiuri G, Bettini S, Boschetti M, Barrea L, Savastano S, Colao A. Obesity programs of nutrition ER, and assessment g. Low‐grade inflammation, CoVID‐19, and obesity: Clinical aspect and molecular insights in childhood and adulthood. Int J Obes 46 (7): 1254‐1261, 2022.
 182.Myneni VD, Hitomi K, Kaartinen MT. Factor XIII‐A transglutaminase acts as a switch between preadipocyte proliferation and differentiation. Blood 124: 1344‐1353, 2014.
 183.Nagase H, Visse R, Murphy G. Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res 69: 562‐573, 2006.
 184.Nakayama Y, Komuro R, Yamamoto A, Miyata Y, Tanaka M, Matsuda M, Fukuhara A, Shimomura I. RhoA induces expression of inflammatory cytokine in adipocytes. Biochem Biophys Res Commun 379: 288‐292, 2009.
 185.Nishimura S, Manabe I, Nagasaki M, Eto K, Yamashita H, Ohsugi M, Otsu M, Hara K, Ueki K, Sugiura S, Yoshimura K, Kadowaki T, Nagai R. CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat Med 15: 914‐920, 2009.
 186.Ogawa T, Shichino S, Ueha S, Matsushima K. Macrophages in lung fibrosis. Int Immunol 33: 665‐671, 2021.
 187.Ogawa T, Shichino S, Ueha S, Ogawa S, Matsushima K. Complement protein C1q activates lung fibroblasts and exacerbates silica‐induced pulmonary fibrosis in mice. Biochem Biophys Res Commun 603: 88‐93, 2022.
 188.Oja AE, van Lier RAW, Hombrink P. Two sides of the same coin: Protective versus pathogenic CD4(+) resident memory T cells. Sci Immunol 7: eabf9393, 2022.
 189.Olefsky JM, Glass CK. Macrophages, inflammation, and insulin resistance. Annu Rev Physiol 72: 219‐246, 2010.
 190.Olson E, Demopoulos L, Haws TF, Hu E, Fang Z, Mahar KM, Qin P, Lepore J, Bauer TA, Hiatt WR. Short‐term treatment with a novel HIF‐prolyl hydroxylase inhibitor (GSK1278863) failed to improve measures of performance in subjects with claudication‐limited peripheral artery disease. Vasc Med 19: 473‐482, 2014.
 191.Osborn O, Olefsky JM. The cellular and signaling networks linking the immune system and metabolism in disease. Nat Med 18: 363‐374, 2012.
 192.Ouchi N, Parker JL, Lugus JJ, Walsh K. Adipokines in inflammation and metabolic disease. Nat Rev Immunol 11: 85‐97, 2011.
 193.Pajvani UB, Trujillo ME, Combs TP, Iyengar P, Jelicks L, Roth KA, Kitsis RN, Scherer PE. Fat apoptosis through targeted activation of caspase 8: A new mouse model of inducible and reversible lipoatrophy. Nat Med 11: 797‐803, 2005.
 194.Pan Y, Hui X, Hoo RLC, Ye D, Chan CYC, Feng T, Wang Y, Lam KSL, Xu A. Adipocyte‐secreted exosomal microRNA‐34a inhibits M2 macrophage polarization to promote obesity‐induced adipose inflammation. J Clin Invest 129: 834‐849, 2019.
 195.Park J, Kim M, Sun K, An YA, Gu X, Scherer PE. VEGF‐A‐expressing adipose tissue shows rapid beiging and enhanced survival after transplantation and confers IL‐4‐independent metabolic improvements. Diabetes 66: 1479‐1490, 2017.
 196.Park J, Morley TS, Scherer PE. Inhibition of endotrophin, a cleavage product of collagen VI, confers cisplatin sensitivity to tumours. EMBO Mol Med 5: 935‐948, 2013.
 197.Park J, Scherer PE. Adipocyte‐derived endotrophin promotes malignant tumor progression. J Clin Invest 122: 4243‐4256, 2012.
 198.Park J, Scherer PE. Endotrophin—a novel factor linking obesity with aggressive tumor growth. Oncotarget 3: 1487‐1488, 2012.
 199.Park J, Scherer PE. Endotrophin in the tumor stroma: A new therapeutic target for breast cancer? Expert Rev Anticancer Ther 13: 111‐113, 2013.
 200.Pasarica M, Gowronska‐Kozak B, Burk D, Remedios I, Hymel D, Gimble J, Ravussin E, Bray GA, Smith SR. Adipose tissue collagen VI in obesity. J Clin Endocrinol Metab 94: 5155‐5162, 2009.
 201.Pasarica M, Sereda OR, Redman LM, Albarado DC, Hymel DT, Roan LE, Rood JC, Burk DH, Smith SR. Reduced adipose tissue oxygenation in human obesity: Evidence for rarefaction, macrophage chemotaxis, and inflammation without an angiogenic response. Diabetes 58: 718‐725, 2009.
 202.Pastel E, Price E, Sjoholm K, McCulloch LJ, Rittig N, Liversedge N, Knight B, Moller N, Svensson PA, Kos K. Lysyl oxidase and adipose tissue dysfunction. Metabolism 78: 118‐127, 2018.
 203.Peics J, Vishvanath L, Zhang Q, Shan B, Pedersen TA, Gupta RK. Isolation of adipogenic and fibro‐inflammatory stromal cell subpopulations from murine intra‐abdominal adipose depots. J Vis Exp, 2020. DOI: 10.3791/61610.
 204.Peng H, Hamanaka RB, Katsnelson J, Hao LL, Yang W, Chandel NS, Lavker RM. MicroRNA‐31 targets FIH‐1 to positively regulate corneal epithelial glycogen metabolism. FASEB J 26: 3140‐3147, 2012.
 205.Peng H, Katsnelson J, Yang W, Brown MA, Lavker RM. FIH‐1/c‐kit signaling: A novel contributor to corneal epithelial glycogen metabolism. Invest Ophthalmol Vis Sci 54: 2781‐2786, 2013.
 206.Petrus P, Fernandez TL, Kwon MM, Huang JL, Lei V, Safikhan NS, Karunakaran S, O'Shannessy DJ, Zheng X, Catrina SB, Albone E, Laine J, Virtanen K, Clee SM, Kieffer TJ, Noll C, Carpentier AC, Johnson JD, Ryden M, Conway EM. Specific loss of adipocyte CD248 improves metabolic health via reduced white adipose tissue hypoxia, fibrosis and inflammation. EBioMedicine 44: 489‐501, 2019.
 207.Plotkin JD, Elias MG, Fereydouni M, Daniels‐Wells TR, Dellinger AL, Penichet ML, Kepley CL. Human mast cells from adipose tissue target and induce apoptosis of breast cancer cells. Front Immunol 10: 138, 2019.
 208.Poblete JMS, Ballinger MN, Bao S, Alghothani M, Nevado JB Jr, Eubank TD, Christman JW, Magalang UJ. Macrophage HIF‐1alpha mediates obesity‐related adipose tissue dysfunction via interleukin‐1 receptor‐associated kinase M. Am J Physiol Endocrinol Metab 318: E689‐E700, 2020.
 209.Porsche CE, Delproposto JB, Geletka L, O'Rourke R, Lumeng CN. Obesity results in adipose tissue T cell exhaustion. JCI Insight 6: e139793, 2021.
 210.Rabhi N, Desevin K, Belkina AC, Tilston‐Lunel A, Varelas X, Layne MD, Farmer SR. Obesity‐induced senescent macrophages activate a fibrotic transcriptional program in adipocyte progenitors. Life Sci Alliance 5: e202101286, 2022.
 211.Rasmussen DGK, Fenton A, Jesky M, Ferro C, Boor P, Tepel M, Karsdal MA, Genovese F, Cockwell P. Urinary endotrophin predicts disease progression in patients with chronic kidney disease. Sci Rep 7: 17328, 2017.
 212.Rausch ME, Weisberg S, Vardhana P, Tortoriello DV. Obesity in C57BL/6J mice is characterized by adipose tissue hypoxia and cytotoxic T‐cell infiltration. Int J Obes 32: 451‐463, 2008.
 213.Reilly SM, Saltiel AR. Adapting to obesity with adipose tissue inflammation. Nat Rev Endocrinol 13: 633‐643, 2017.
 214.Remacle A, Murphy G, Roghi C. Membrane type I‐matrix metalloproteinase (MT1‐MMP) is internalised by two different pathways and is recycled to the cell surface. J Cell Sci 116: 3905‐3916, 2003.
 215.Rønnow SR, Langholm LL, Karsdal MA, Manon‐Jensen T, Tal‐Singer R, Miller BE, Vestbo J, Leeming DJ, Sand JMB. Endotrophin, an extracellular hormone, in combination with neoepitope markers of von Willebrand factor improves prediction of mortality in the ECLIPSE COPD cohort. Respir Res 21: 202, 2020.
 216.Rossow L, Veitl S, Vorlova S, Wax JK, Kuhn AE, Maltzahn V, Upcin B, Karl F, Hoffmann H, Gatzner S, Kallius M, Nandigama R, Scheld D, Irmak S, Herterich S, Zernecke A, Ergun S, Henke E. LOX‐catalyzed collagen stabilization is a proximal cause for intrinsic resistance to chemotherapy. Oncogene 37: 4921‐4940, 2018.
 217.Ruas JL, Poellinger L, Pereira T. Role of CBP in regulating HIF‐1‐mediated activation of transcription. J Cell Sci 118: 301‐311, 2005.
 218.Ruiz‐Ojeda FJ, Mendez‐Gutierrez A, Aguilera CM, Plaza‐Diaz J. Extracellular matrix remodeling of adipose tissue in obesity and metabolic diseases. Int J Mol Sci 20: 4888, 2019.
 219.Rutkowski JM, Stern JH, Scherer PE. The cell biology of fat expansion. J Cell Biol 208: 501‐512, 2015.
 220.Sabeh F, Li XY, Saunders TL, Rowe RG, Weiss SJ. Secreted versus membrane‐anchored collagenases: Relative roles in fibroblast‐dependent collagenolysis and invasion. J Biol Chem 284: 23001‐23011, 2009.
 221.Sakamoto T, Seiki M. A membrane protease regulates energy production in macrophages by activating hypoxia‐inducible factor‐1 via a non‐proteolytic mechanism. J Biol Chem 285: 29951‐29964, 2010.
 222.Sakamoto T, Seiki M. Integrated functions of membrane‐type 1 matrix metalloproteinase in regulating cancer malignancy: Beyond a proteinase. Cancer Sci 108: 1095‐1100, 2017.
 223.Sakamoto T, Weng JS, Hara T, Yoshino S, Kozuka‐Hata H, Oyama M, Seiki M. Hypoxia‐inducible factor 1 regulation through cross talk between mTOR and MT1‐MMP. Mol Cell Biol 34: 30‐42, 2014.
 224.Sakamuri S, Watts R, Takawale A, Wang X, Hernandez‐Anzaldo S, Bahitham W, Fernandez‐Patron C, Lehner R, Kassiri Z. Absence of tissue inhibitor of metalloproteinase‐4 (TIMP4) ameliorates high fat diet‐induced obesity in mice due to defective lipid absorption. Sci Rep 7: 6210, 2017.
 225.Scherer PE, Bickel PE, Kotler M, Lodish HF. Cloning of cell‐specific secreted and surface proteins by subtractive antibody screening. Nat Biotechnol 16: 581‐586, 1998.
 226.Scherer PE, Gupta OT. Endotrophin: Nominated for best supporting actor in the fibro‐inflammatory saga. EBioMedicine 69: 103447, 2021.
 227.Sebestyen A, Kopper L, Danko T, Timar J. Hypoxia signaling in cancer: From basics to clinical practice. Pathol Oncol Res 27: 1609802, 2021.
 228.Semenza GL. HIF‐1 and human disease: One highly involved factor. Genes Dev 14: 1983‐1991, 2000.
 229.Seo JB, Riopel M, Cabrales P, Huh JY, Bandyopadhyay GK, Andreyev AY, Murphy AN, Beeman SC, Smith GI, Klein S, Lee YS, Olefsky JM. Knockdown of Ant2 reduces adipocyte hypoxia and improves insulin resistance in obesity. Nat Metab 1: 86‐97, 2019.
 230.Shan B, Shao M, Zhang Q, Hepler C, Paschoal VA, Barnes SD, Vishvanath L, An YA, Jia L, Malladi VS, Strand DW, Gupta OT, Elmquist JK, Oh D, Gupta RK. Perivascular mesenchymal cells control adipose‐tissue macrophage accrual in obesity. Nat Metab 2: 1332‐1349, 2020.
 231.Shao M, Hepler C, Zhang Q, Shan B, Vishvanath L, Henry GH, Zhao S, An YA, Wu Y, Strand DW, Gupta RK. Pathologic HIF1alpha signaling drives adipose progenitor dysfunction in obesity. Cell Stem Cell 28: 685‐701 e687, 2021.
 232.Sharma M, Boytard L, Hadi T, Koelwyn G, Simon R, Ouimet M, Seifert L, Spiro W, Yan B, Hutchison S, Fisher EA, Ramasamy R, Ramkhelawon B, Moore KJ. Enhanced glycolysis and HIF‐1alpha activation in adipose tissue macrophages sustains local and systemic interleukin‐1beta production in obesity. Sci Rep 10: 5555, 2020.
 233.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.
 234.Sottile J, Hocking DC. Fibronectin polymerization regulates the composition and stability of extracellular matrix fibrils and cell‐matrix adhesions. Mol Biol Cell 13: 3546‐3559, 2002.
 235.Sparding N, Genovese F, Rasmussen DGK, Karsdal MA, Neprasova M, Maixnerova D, Satrapova V, Frausova D, Hornum M, Bartonova L, Honsova E, Kollar M, Koprivova H, Hruskova Z, Tesar V. Endotrophin, a collagen type VI‐derived matrikine, reflects the degree of renal fibrosis in patients with IgA nephropathy and in patients with ANCA‐associated vasculitis. Nephrol Dial Transplant 37 (6): 1099‐1108, 2021.
 236.Spencer M, Unal R, Zhu B, Rasouli N, McGehee RE Jr, Peterson CA, Kern PA. Adipose tissue extracellular matrix and vascular abnormalities in obesity and insulin resistance. J Clin Endocrinol Metab 96: E1990‐E1998, 2011.
 237.Spencer M, Yao‐Borengasser A, Unal R, Rasouli N, Gurley CM, Zhu B, Peterson CA, Kern PA. Adipose tissue macrophages in insulin‐resistant subjects are associated with collagen VI and fibrosis and demonstrate alternative activation. Am J Physiol Endocrinol Metab 299: E1016‐E1027, 2010.
 238.Staunstrup LM, Bager CL, Frederiksen P, Helge JW, Brunak S, Christiansen C, Karsdal M. Endotrophin is associated with chronic multimorbidity and all‐cause mortality in a cohort of elderly women. EBioMedicine 68: 103391, 2021.
 239.Strohmeyer N, Bharadwaj M, Costell M, Fassler R, Muller DJ. Fibronectin‐bound alpha5beta1 integrins sense load and signal to reinforce adhesion in less than a second. Nat Mater 16: 1262‐1270, 2017.
 240.Suganami T, Nishida J, Ogawa Y. A paracrine loop between adipocytes and macrophages aggravates inflammatory changes: Role of free fatty acids and tumor necrosis factor alpha. Arterioscler Thromb Vasc Biol 25: 2062‐2068, 2005.
 241.Sun K, Halberg N, Khan M, Magalang UJ, Scherer PE. Selective inhibition of hypoxia‐inducible factor 1alpha ameliorates adipose tissue dysfunction. Mol Cell Biol 33: 904‐917, 2013.
 242.Sun K, Kusminski CM, Scherer PE. Adipose tissue remodeling and obesity. J Clin Invest 121: 2094‐2101, 2011.
 243.Sun K, Park J, Gupta OT, Holland WL, Auerbach P, Zhang N, Goncalves Marangoni R, Nicoloro SM, Czech MP, Varga J, Ploug T, An Z, Scherer PE. Endotrophin triggers adipose tissue fibrosis and metabolic dysfunction. Nat Commun 5: 3485, 2014.
 244.Sun K, Park J, Kim M, Scherer PE. Endotrophin, a multifaceted player in metabolic dysregulation and cancer progression, is a predictive biomarker for the response to PPARgamma agonist treatment. Diabetologia 60: 24‐29, 2017.
 245.Sun K, Tordjman J, Clement K, Scherer PE. Fibrosis and adipose tissue dysfunction. Cell Metab 18: 470‐477, 2013.
 246.Sun K, Wernstedt Asterholm I, Kusminski CM, Bueno AC, Wang ZV, Pollard JW, Brekken RA, Scherer PE. Dichotomous effects of VEGF‐A on adipose tissue dysfunction. Proc Natl Acad Sci U S A 109: 5874‐5879, 2012.
 247.Takahashi M, Nagaretani H, Funahashi T, Nishizawa H, Maeda N, Kishida K, Kuriyama H, Shimomura I, Maeda K, Hotta K, Ouchi N, Kihara S, Nakamura T, Yamashita S, Matsuzawa Y. The expression of SPARC in adipose tissue and its increased plasma concentration in patients with coronary artery disease. Obes Res 9: 388‐393, 2001.
 248.Talukdar S, Oh DY, Bandyopadhyay G, Li D, Xu J, McNelis J, Lu M, Li P, Yan Q, Zhu Y, Ofrecio J, Lin M, Brenner MB, Olefsky JM. Neutrophils mediate insulin resistance in mice fed a high‐fat diet through secreted elastase. Nat Med 18: 1407‐1412, 2012.
 249.Tang PM, Nikolic‐Paterson DJ, Lan HY. Macrophages: Versatile players in renal inflammation and fibrosis. Nat Rev Nephrol 15: 144‐158, 2019.
 250.Tepel M, Alkaff FF, Kremer D, Bakker SJL, Thaunat O, Nagarajah S, Saleh Q, Berger SP, van den Born J, Krogstrup NV, Nielsen MB, Norregaard R, Jespersen B, Sparding N, Genovese F, Karsdal MA, Rasmussen DGK. Pretransplant endotrophin predicts delayed graft function after kidney transplantation. Sci Rep 12: 4079, 2022.
 251.Thompson RW, Pesce JT, Ramalingam T, Wilson MS, White S, Cheever AW, Ricklefs SM, Porcella SF, Li L, Ellies LG, Wynn TA. Cationic amino acid transporter‐2 regulates immunity by modulating arginase activity. PLoS Pathog 4: e1000023, 2008.
 252.Thrailkill KM, Clay Bunn R, Fowlkes JL. Matrix metalloproteinases: Their potential role in the pathogenesis of diabetic nephropathy. Endocrine 35: 1‐10, 2009.
 253.Todorcevic M, Manuel AR, Austen L, Michailidou Z, Hazlehurst JM, Neville M, Stradling JR, Karpe F. Markers of adipose tissue hypoxia are elevated in subcutaneous adipose tissue of severely obese patients with obesity hypoventilation syndrome but not in the moderately obese. Int J Obes 45: 1618‐1622, 2021.
 254.Tomasek JJ, Gabbiani G, Hinz B, Chaponnier C, Brown RA. Myofibroblasts and mechano‐regulation of connective tissue remodelling. Nat Rev Mol Cell Biol 3: 349‐363, 2002.
 255.Trayhurn P. Hypoxia and adipose tissue function and dysfunction in obesity. Physiol Rev 93: 1‐21, 2013.
 256.Trinh K, Julovi SM, Rogers NM. The role of matrix proteins in cardiac pathology. Int J Mol Sci 23: 1338, 2022.
 257.Trujillo ME, Pajvani UB, Scherer PE. Apoptosis through targeted activation of caspase 8 (“ATTAC‐mice”): Novel mouse models of inducible and reversible tissue ablation. Cell Cycle 4: 1141‐1145, 2005.
 258.Unger RH, Clark GO, Scherer PE, Orci L. Lipid homeostasis, lipotoxicity and the metabolic syndrome. Biochim Biophys Acta 1801: 209‐214, 2010.
 259.Varma V, Yao‐Borengasser A, Bodles AM, Rasouli N, Phanavanh B, Nolen GT, Kern EM, Nagarajan R, Spencer HJ 3rd, Lee MJ, Fried SK, McGehee RE Jr, Peterson CA, Kern PA. Thrombospondin‐1 is an adipokine associated with obesity, adipose inflammation, and insulin resistance. Diabetes 57: 432‐439, 2008.
 260.Verkouter I, Noordam R, Loh NY, van Dijk KW, Zock PL, Mook‐Kanamori DO, le Cessie S, Rosendaal FR, Karpe F, Christodoulides C, de Mutsert R. The relation between adult weight gain, adipocyte volume, and the metabolic profile at middle age. J Clin Endocrinol Metab 106: e4438‐e4447, 2021.
 261.Vijay J, Gauthier MF, Biswell RL, Louiselle DA, Johnston JJ, Cheung WA, Belden B, Pramatarova A, Biertho L, Gibson M, Simon MM, Djambazian H, Staffa A, Bourque G, Laitinen A, Nystedt J, Vohl MC, Fraser JD, Pastinen T, Tchernof A, Grundberg E. Single‐cell analysis of human adipose tissue identifies depot and disease specific cell types. Nat Metab 2: 97‐109, 2020.
 262.Vila IK, Badin PM, Marques MA, Monbrun L, Lefort C, Mir L, Louche K, Bourlier V, Roussel B, Gui P, Grober J, Stich V, Rossmeislova L, Zakaroff‐Girard A, Bouloumie A, Viguerie N, Moro C, Tavernier G, Langin D. Immune cell Toll‐like receptor 4 mediates the development of obesity‐ and endotoxemia‐associated adipose tissue fibrosis. Cell Rep 7: 1116‐1129, 2014.
 263.Visscher TL, Seidell JC. The public health impact of obesity. Annu Rev Public Health 22: 355‐375, 2001.
 264.Wang E, Zhang C, Polavaram N, Liu F, Wu G, Schroeder MA, Lau JS, Mukhopadhyay D, Jiang SW, O'Neill BP, Datta K, Li J. The role of factor inhibiting HIF (FIH‐1) in inhibiting HIF‐1 transcriptional activity in glioblastoma multiforme. PLoS One 9: e86102, 2014.
 265.Wang L, Ye X, Hua Y, Song Y. Berberine alleviates adipose tissue fibrosis by inducing AMP‐activated kinase signaling in high‐fat diet‐induced obese mice. Biomed Pharmacother 105: 121‐129, 2018.
 266.Wang Y, Nishina PM, Naggert JK. Degradation of IRS1 leads to impaired glucose uptake in adipose tissue of the type 2 diabetes mouse model TALLYHO/Jng. J Endocrinol 203: 65‐74, 2009.
 267.Wang Y, Zhao L, Smas C, Sul HS. Pref‐1 interacts with fibronectin to inhibit adipocyte differentiation. Mol Cell Biol 30: 3480‐3492, 2010.
 268.Warnberg J, Moreno LA, Mesana MI, Marcos A, group A. Inflammatory mediators in overweight and obese Spanish adolescents. The AVENA Study. Int J Obes Relat Metab Disord 28 (Suppl 3): S59‐S63, 2004.
 269.Wei K, Piecewicz SM, McGinnis LM, Taniguchi CM, Wiegand SJ, Anderson K, Chan CW, Mulligan KX, Kuo D, Yuan J, Vallon M, Morton L, Lefai E, Simon MC, Maher JJ, Mithieux G, Rajas F, Annes J, McGuinness OP, Thurston G, Giaccia AJ, Kuo CJ. A liver Hif‐2alpha‐Irs2 pathway sensitizes hepatic insulin signaling and is modulated by Vegf inhibition. Nat Med 19: 1331‐1337, 2013.
 270.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 112: 1796‐1808, 2003.
 271.Weiss L, Slavin S, Reich S, Cohen P, Shuster S, Stern R, Kaganovsky E, Okon E, Rubinstein AM, Naor D. Induction of resistance to diabetes in non‐obese diabetic mice by targeting CD44 with a specific monoclonal antibody. Proc Natl Acad Sci U S A 97: 285‐290, 2000.
 272.Winer DA, Winer S, Shen L, Wadia PP, Yantha J, Paltser G, Tsui H, Wu P, Davidson MG, Alonso MN, Leong HX, Glassford A, Caimol M, Kenkel JA, Tedder TF, McLaughlin T, Miklos DB, Dosch HM, Engleman EG. B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies. Nat Med 17: 610‐617, 2011.
 273.Wu Y, Lee MJ, Ido Y, Fried SK. High‐fat diet‐induced obesity regulates MMP3 to modulate depot‐ and sex‐dependent adipose expansion in C57BL/6J mice. Am J Physiol Endocrinol Metab 312: E58‐E71, 2017.
 274.Wynn TA, Vannella KM. Macrophages in tissue repair, regeneration, and fibrosis. Immunity 44: 450‐462, 2016.
 275.Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA, Chen H. Chronic inflammation in fat plays a crucial role in the development of obesity‐related insulin resistance. J Clin Invest 112: 1821‐1830, 2003.
 276.Xu Y, Kong X, Li J, Cui T, Wei Y, Xu J, Zhu Y, Zhu X. Mild hypoxia enhances the expression of HIF and VEGF and triggers the response to injury in rat kidneys. Front Physiol 12: 690496, 2021.
 277.Yamazaki Y, Mikami Y, Yuguchi M, Namba Y, Isokawa K. Development of collagen fibres and lysyl oxidase expression in the presumptive dermis of chick limb bud. Anat Histol Embryol 41: 68‐74, 2012.
 278.Yang N, Cao DF, Yin XX, Zhou HH, Mao XY. Lysyl oxidases: Emerging biomarkers and therapeutic targets for various diseases. Biomed Pharmacother 131: 110791, 2020.
 279.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.
 280.Yin J, Gao Z, He Q, Zhou D, Guo Z, Ye J. Role of hypoxia in obesity‐induced disorders of glucose and lipid metabolism in adipose tissue. Am J Physiol Endocrinol Metab 296: E333‐E342, 2009.
 281.Yoldemir SA, Arman Y, Akarsu M, Altun O, Ozcan M, Tukek T. Correlation of glycemic regulation and endotrophin in patients with type 2 diabetes; pilot study. Diabetol Metab Syndr 13: 9, 2021.
 282.Yu M, Shen W, Shi X, Wang Q, Zhu L, Xu X, Yu J, Liu L. Upregulated LOX and increased collagen content associated with aggressive clinicopathological features and unfavorable outcome in oral squamous cell carcinoma. J Cell Biochem 120: 14348‐14359, 2019.
 283.Zelechowska P, Agier J, Kozlowska E, Brzezinska‐Blaszczyk E. Mast cells participate in chronic low‐grade inflammation within adipose tissue. Obes Rev 19: 686‐697, 2018.
 284.Zhang N, Fu Z, Linke S, Chicher J, Gorman JJ, Visk D, Haddad GG, Poellinger L, Peet DJ, Powell F, Johnson RS. The asparaginyl hydroxylase factor inhibiting HIF‐1alpha is an essential regulator of metabolism. Cell Metab 11: 364‐378, 2010.
 285.Zhang R, Gao Y, Zhao X, Gao M, Wu Y, Han Y, Qiao Y, Luo Z, Yang L, Chen J, Ge G. FSP1‐positive fibroblasts are adipogenic niche and regulate adipose homeostasis. PLoS Biol 16: e2001493, 2018.
 286.Zhang S, Li Y, Huang X, Liu K, Wang QD, Chen AF, Sun K, Lui KO, Zhou B. Seamless genetic recording of transiently activated mesenchymal gene expression in endothelial cells during cardiac fibrosis. Circulation 144: 2004‐2020, 2021.
 287.Zhang Z, Cai J, Li Y, He Y, Dong Z, Dai J, Lu F. External volume expansion adjusted adipose stem cell by shifting the ratio of fibronectin to laminin. Tissue Eng Part A 26: 66‐77, 2020.
 288.Zhang Z, Kruglikov I, Zhao S, Zi Z, Gliniak CM, Li N, Wang MY, Zhu Q, Kusminski CM, Scherer PE. Dermal adipocytes contribute to the metabolic regulation of dermal fibroblasts. Exp Dermatol 30: 102‐111, 2021.
 289.Zhang Z, Qu R, Fan T, Ouyang J, Lu F, Dai J. Stepwise adipogenesis of decellularized cellular extracellular matrix regulates adipose tissue‐derived stem cell migration and differentiation. Stem Cells Int 2019: 1845926, 2019.
 290.Zhao Y, Gu X, Zhang N, Kolonin MG, An Z, Sun K. Divergent functions of endotrophin on different cell populations in adipose tissue. Am J Physiol Endocrinol Metab 311: E952‐E963, 2016.
 291.Zhou HY, Sui H, Zhao YJ, Qian HJ, Yang N, Liu L, Guan Q, Zhou Y, Lin HL, Wang DP. The impact of inflammatory immune reactions of the vascular niche on organ fibrosis. Front Pharmacol 12: 750509, 2021.
 292.Zhou R, Tardivel A, Thorens B, Choi I, Tschopp J. Thioredoxin‐interacting protein links oxidative stress to inflammasome activation. Nat Immunol 11: 136‐140, 2010.
 293.Zhu R, Cheng M, Lu T, Yang N, Ye S, Pan YH, Hong T, Dang S, Zhang W. A disintegrin and metalloproteinase with thrombospondin motifs 18 deficiency leads to visceral adiposity and associated metabolic syndrome in mice. Am J Pathol 188: 461‐473, 2018.
 294.Zhu Y, Crewe C, Scherer PE. Hyaluronan in adipose tissue: Beyond dermal filler and therapeutic carrier. Sci Transl Med 8: 323ps324, 2016.
 295.Zhu Y, Kruglikov IL, Akgul Y, Scherer PE. Hyaluronan in adipogenesis, adipose tissue physiology and systemic metabolism. Matrix Biol 78‐79: 284‐291, 2019.
 296.Zhu Y, Li N, Huang M, Bartels M, Dogne S, Zhao S, Chen X, Crewe C, Straub L, Vishvanath L, Zhang Z, Shao M, Yang Y, Gliniak CM, Gordillo R, Smith GI, Holland WL, Gupta RK, Dong B, Caron N, Xu Y, Akgul Y, Klein S, Scherer PE. Adipose tissue hyaluronan production improves systemic glucose homeostasis and primes adipocytes for CL 316,243‐stimulated lipolysis. Nat Commun 12: 4829, 2021.
 297.Zucker S, Pei D, Cao J, Lopez‐Otin C. Membrane type‐matrix metalloproteinases (MT‐MMP). Curr Top Dev Biol 54: 1‐74, 2003.

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Article Title: Extracellular Matrix (ECM) and Fibrosis in Adipose Tissue: Overview and Perspectives
 

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Kai Sun, Xin Li, Philipp E. Scherer. Extracellular Matrix (ECM) and Fibrosis in Adipose Tissue: Overview and Perspectives. Compr Physiol 2023, 13: 4387-4407. doi: 10.1002/cphy.c220020