{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T22:26:26Z","timestamp":1791239186173,"version":"4.1.0"},"reference-count":45,"publisher":"American Diabetes Association","issue":"6","content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2007,6,1]]},"abstract":"<jats:p>OBJECTIVE\u2014The expansion of adipose tissue mass seen in obesity involves both hyperplasia and hypertrophy of adipocytes. However, little is known about how adipocytes, adipocyte precursors, blood vessels, and stromal cells interact with one another to achieve adipogenesis.<\/jats:p>\n               <jats:p>RESEARCH DESIGN AND METHODS\u2014We have developed a confocal microscopy-based method of three-dimensional visualization of intact living adipose tissue that enabled us to simultaneously evaluate angiogenesis and adipogenesis in db\/db mice.<\/jats:p>\n               <jats:p>RESULTS\u2014We found that adipocyte differentiation takes place within cell clusters (which we designated adipogenic\/angiogenic cell clusters) that contain multiple cell types, including endothelial cells and stromal cells that express CD34 and CD68 and bind lectin. There were close spatial and temporal interrelationships between blood vessel formation and adipogenesis, and the sprouting of new blood vessels from preexisting vasculature was coupled to adipocyte differentiation. CD34+ CD68+ lectin-binding cells could clearly be distinguished from CD34\u2212 CD68+ macrophages, which were scattered in the stroma and did not bind lectin. Adipogenic\/angiogenic cell clusters can morphologically and immunohistochemically be distinguished from crown-like structures frequently seen in the late stages of adipose tissue obesity. Administration of anti\u2013vascular endothelial growth factor (VEGF) antibodies inhibited not only angiogenesis but also the formation of adipogenic\/angiogenic cell clusters, indicating that the coupling of adipogenesis and angiogenesis is essential for differentiation of adipocytes in obesity and that VEGF is a key mediator of that process.<\/jats:p>\n               <jats:p>CONCLUSIONS\u2014Living tissue imaging techniques provide novel evidence of the dynamic interactions between differentiating adipocytes, stromal cells, and angiogenesis in living obese adipose tissue.<\/jats:p>","DOI":"10.2337\/db06-1749","type":"journal-article","created":{"date-parts":[[2007,5,26]],"date-time":"2007-05-26T03:53:57Z","timestamp":1180151637000},"page":"1517-1526","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":398,"title":["Adipogenesis in Obesity Requires Close Interplay Between Differentiating Adipocytes, Stromal Cells, and Blood Vessels"],"prefix":"10.2337","volume":"56","author":[{"given":"Satoshi","family":"Nishimura","sequence":"first","affiliation":[{"name":"Department of Cardiovascular Medicine, University of Tokyo, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ichiro","family":"Manabe","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, University of Tokyo, Tokyo, Japan"},{"name":"Nano-Bioengineering Education Program, Tokyo, Japan"},{"name":"PRESTO, Japan Science and Technology Agency, Kawaguchi City, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mika","family":"Nagasaki","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, University of Tokyo, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yumiko","family":"Hosoya","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, University of Tokyo, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Yamashita","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, University of Tokyo, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideo","family":"Fujita","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, University of Tokyo, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitsuru","family":"Ohsugi","sequence":"additional","affiliation":[{"name":"Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuyuki","family":"Tobe","sequence":"additional","affiliation":[{"name":"Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Kadowaki","sequence":"additional","affiliation":[{"name":"Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryozo","family":"Nagai","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, University of Tokyo, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seiryo","family":"Sugiura","sequence":"additional","affiliation":[{"name":"Department of Human and Engineered Environmental Studies, Graduate School of Frontier Sciences, University of Tokyo, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","reference":[{"key":"2022051610221457500_R1","doi-asserted-by":"crossref","unstructured":"Matsuzawa Y: Therapy Insight: adipocytokines in metabolic syndrome and related cardiovascular disease. Nat Clin Pract Cardiovasc Med\u20083: 35\u201342,2006","DOI":"10.1038\/ncpcardio0380"},{"key":"2022051610221457500_R2","doi-asserted-by":"crossref","unstructured":"Koerner A, Kratzsch J, Kiess W: Adipocytokines: leptin\u2013the classical, resistin\u2013the controversical, adiponectin\u2013the promising, and more to come. Best Pract Res Clin Endocrinol Metab\u200819: 525\u2013546,2005","DOI":"10.1016\/j.beem.2005.07.008"},{"key":"2022051610221457500_R3","doi-asserted-by":"crossref","unstructured":"Rosen ED, Spiegelman BM: Molecular regulation of adipogenesis. Annu Rev Cell Dev Biol\u200816: 145\u2013171,2000","DOI":"10.1146\/annurev.cellbio.16.1.145"},{"key":"2022051610221457500_R4","doi-asserted-by":"crossref","unstructured":"Morrison RF, Farmer SR: Hormonal signaling and transcriptional control of adipocyte differentiation. J Nutr\u2008130: 3116S\u20133121S,2000","DOI":"10.1093\/jn\/130.12.3116S"},{"key":"2022051610221457500_R5","doi-asserted-by":"crossref","unstructured":"Hausman DB, DiGirolamo M, Bartness TJ, Hausman GJ, Martin RJ: The biology of white adipocyte proliferation. Obes Rev\u20082: 239\u2013254,2001","DOI":"10.1046\/j.1467-789X.2001.00042.x"},{"key":"2022051610221457500_R6","doi-asserted-by":"crossref","unstructured":"DiGirolamo M, Fine JB, Tagra K, Rossmanith R: Qualitative regional differences in adipose tissue growth and cellularity in male Wistar rats fed ad libitum. Am J Physiol\u2008274: R1460\u20131467,1998","DOI":"10.1152\/ajpregu.1998.274.5.R1460"},{"key":"2022051610221457500_R7","doi-asserted-by":"crossref","unstructured":"Tchoukalova YD, Sarr MG, Jensen MD: Measuring committed preadipocytes in human adipose tissue from severely obese patients by using adipocyte fatty acid binding protein. Am J Physiol Regul Integr Comp Physiol\u2008287: R1132\u20131R140,2004","DOI":"10.1152\/ajpregu.00337.2004"},{"key":"2022051610221457500_R8","doi-asserted-by":"crossref","unstructured":"Zuk PA, Zhu M, Ashjian P, De Ugarte DA, Huang JI, Mizuno H, Alfonso ZC, Fraser JK, Benhaim P, Hedrick MH: Human adipose tissue is a source of multipotent stem cells. Mol Biol Cell\u200813: 4279\u20134295,2002","DOI":"10.1091\/mbc.e02-02-0105"},{"key":"2022051610221457500_R9","doi-asserted-by":"crossref","unstructured":"Nakagami H, Morishita R, Maeda K, Kikuchi Y, Ogihara T, Kaneda Y: Adipose tissue-derived stromal cells as a novel option for regenerative cell therapy. J Atheroscler Thromb\u200813: 77\u201381,2006","DOI":"10.5551\/jat.13.77"},{"key":"2022051610221457500_R10","doi-asserted-by":"crossref","unstructured":"Dicker A, Le Blanc K, Astrom G, van Harmelen V, Gotherstrom C, Blomqvist L, Arner P, Ryden M: Functional studies of mesenchymal stem cells derived from adult human adipose tissue. Exp Cell Res\u2008308: 283\u2013290,2005","DOI":"10.1016\/j.yexcr.2005.04.029"},{"key":"2022051610221457500_R11","doi-asserted-by":"crossref","unstructured":"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\u2008112: 1796\u20131808,2003","DOI":"10.1172\/JCI200319246"},{"key":"2022051610221457500_R12","doi-asserted-by":"crossref","unstructured":"Wellen KE, Hotamisligil GS: Obesity-induced inflammatory changes in adipose tissue. J Clin Invest\u2008112: 1785\u20131788,2003","DOI":"10.1172\/JCI20514"},{"key":"2022051610221457500_R13","doi-asserted-by":"crossref","unstructured":"Liu L, Meydani M: Angiogenesis inhibitors may regulate adiposity. Nutr Rev\u200861: 384\u2013387,2003","DOI":"10.1301\/nr.2003.nov.384-387"},{"key":"2022051610221457500_R14","doi-asserted-by":"crossref","unstructured":"Kolonin MG, Saha PK, Chan L, Pasqualini R, Arap W: Reversal of obesity by targeted ablation of adipose tissue. Nat Med\u200810: 625\u2013632,2004","DOI":"10.1038\/nm1048"},{"key":"2022051610221457500_R15","doi-asserted-by":"crossref","unstructured":"Rupnick MA, Panigrahy D, Zhang CY, Dallabrida SM, Lowell BB, Langer R, Folkman MJ: Adipose tissue mass can be regulated through the vasculature. Proc Natl Acad Sci U S A\u200899: 10730\u201310735,2002","DOI":"10.1073\/pnas.162349799"},{"key":"2022051610221457500_R16","doi-asserted-by":"crossref","unstructured":"Fukumura D, Ushiyama A, Duda DG, Xu L, Tam J, Krishna V, Chatterjee K, Garkavtsev I, Jain RK: Paracrine regulation of angiogenesis and adipocyte differentiation during in vivo adipogenesis. Circ Res\u200893: e88\u2013e97,2003","DOI":"10.1161\/01.RES.0000099243.20096.FA"},{"key":"2022051610221457500_R17","doi-asserted-by":"crossref","unstructured":"McDonald DM, Choyke PL: Imaging of angiogenesis: from microscope to clinic. Nat Med\u20089: 713\u2013725,2003","DOI":"10.1038\/nm0603-713"},{"key":"2022051610221457500_R18","doi-asserted-by":"crossref","unstructured":"Rosen ED: The molecular control of adipogenesis, with special reference to lymphatic pathology. Ann N Y Acad Sci\u2008979: 143\u2013158,2002","DOI":"10.1111\/j.1749-6632.2002.tb04875.x"},{"key":"2022051610221457500_R19","doi-asserted-by":"crossref","unstructured":"Laitinen L: Griffonia simplicifolia lectins bind specifically to endothelial cells and some epithelial cells in mouse tissues. Histochem J\u200819: 225\u2013234,1987","DOI":"10.1007\/BF01680633"},{"key":"2022051610221457500_R20","doi-asserted-by":"crossref","unstructured":"Hamid SA, Daly C, Campbell S: Visualization of live endothelial cells ex vivo and in vitro. Microvasc Res\u200866: 159\u2013163,2003","DOI":"10.1016\/S0026-2862(03)00054-2"},{"key":"2022051610221457500_R21","doi-asserted-by":"crossref","unstructured":"Wang SM, Hwang RD, Greenberg AS, Yeo HL: Temporal and spatial assembly of lipid droplet-associated proteins in 3T3\u2013L1 preadipocytes. Histochem Cell Biol\u2008120: 285\u2013292,2003","DOI":"10.1007\/s00418-003-0575-7"},{"key":"2022051610221457500_R22","doi-asserted-by":"crossref","unstructured":"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\u200846: 2347\u20132355,2005","DOI":"10.1194\/jlr.M500294-JLR200"},{"key":"2022051610221457500_R23","doi-asserted-by":"crossref","unstructured":"Casey R, Rogers PA, Vollenhoven BJ: An immunohistochemical analysis of fibroid vasculature. Hum Reprod\u200815: 1469\u20131475,2000","DOI":"10.1093\/humrep\/15.7.1469"},{"key":"2022051610221457500_R24","doi-asserted-by":"crossref","unstructured":"Mattsson G, Carlsson PO, Olausson K, Jansson L: Histological markers for endothelial cells in endogenous and transplanted rodent pancreatic islets. Pancreatology\u20082: 155\u2013162,2002","DOI":"10.1159\/000055906"},{"key":"2022051610221457500_R25","doi-asserted-by":"crossref","unstructured":"Hristov M, Weber C: Endothelial progenitor cells: characterization, pathophysiology, and possible clinical relevance. J Cell Mol Med\u20088: 498\u2013508,2004","DOI":"10.1111\/j.1582-4934.2004.tb00474.x"},{"key":"2022051610221457500_R26","doi-asserted-by":"crossref","unstructured":"Modarai B, Burnand KG, Sawyer B, Smith A: Endothelial progenitor cells are recruited into resolving venous thrombi. Circulation\u2008111: 2645\u20132653,2005","DOI":"10.1161\/CIRCULATIONAHA.104.492678"},{"key":"2022051610221457500_R27","doi-asserted-by":"crossref","unstructured":"Rumpold H, Wolf D, Koeck R, Gunsilius E: Endothelial progenitor cells: a source for therapeutic vasculogenesis?J Cell Mol Med\u20088: 509\u2013518,2004","DOI":"10.1111\/j.1582-4934.2004.tb00475.x"},{"key":"2022051610221457500_R28","doi-asserted-by":"crossref","unstructured":"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\u2008112: 1821\u20131830,2003","DOI":"10.1172\/JCI200319451"},{"key":"2022051610221457500_R29","doi-asserted-by":"crossref","unstructured":"Rehman J, Li J, Orschell CM, March KL: Peripheral blood \u201cendothelial progenitor cells\u201d are derived from monocyte\/macrophages and secrete angiogenic growth factors. Circulation\u2008107: 1164\u20131169,2003","DOI":"10.1161\/01.CIR.0000058702.69484.A0"},{"key":"2022051610221457500_R30","doi-asserted-by":"crossref","unstructured":"Fain JN: Release of interleukins and other inflammatory cytokines by human adipose tissue is enhanced in obesity and primarily due to the nonfat cells. Vitam Horm\u200874: 443\u2013477,2006","DOI":"10.1016\/S0083-6729(06)74018-3"},{"key":"2022051610221457500_R31","doi-asserted-by":"crossref","unstructured":"Rehman J, Traktuev D, Li J, Merfeld-Clauss S, Temm-Grove CJ, Bovenkerk JE, Pell CL, Johnstone BH, Considine RV, March KL: Secretion of angiogenic and antiapoptotic factors by human adipose stromal cells. Circulation\u2008109: 1292\u20131298,2004","DOI":"10.1161\/01.CIR.0000121425.42966.F1"},{"key":"2022051610221457500_R32","doi-asserted-by":"crossref","unstructured":"Carmeliet P, Jain RK: Angiogenesis in cancer and other diseases. Nature\u2008407: 249\u2013257,2000","DOI":"10.1038\/35025220"},{"key":"2022051610221457500_R33","doi-asserted-by":"crossref","unstructured":"Kraemer FB, Shen WJ: Hormone-sensitive lipase knockouts. Nutr Metab (Lond)\u20083: 12,2006","DOI":"10.1186\/1743-7075-3-12"},{"key":"2022051610221457500_R34","doi-asserted-by":"crossref","unstructured":"Silha JV, Krsek M, Sucharda P, Murphy LJ: Angiogenic factors are elevated in overweight and obese individuals. Int J Obes (Lond)\u200829: 1308\u20131314,2005","DOI":"10.1038\/sj.ijo.0802987"},{"key":"2022051610221457500_R35","doi-asserted-by":"crossref","unstructured":"Neels JG, Thinnes T, Loskutoff DJ: Angiogenesis in an in vivo model of adipose tissue development. Faseb J\u200818: 983\u2013985,2004","DOI":"10.1096\/fj.03-1101fje"},{"key":"2022051610221457500_R36","doi-asserted-by":"crossref","unstructured":"Miyazawa-Hoshimoto S, Takahashi K, Bujo H, Hashimoto N, Yagui K, Saito Y: Roles of degree of fat deposition and its localization on VEGF expression in adipocytes. Am J Physiol Endocrinol Metab\u2008288: E1128\u2013E1136,2005","DOI":"10.1152\/ajpendo.00003.2004"},{"key":"2022051610221457500_R37","doi-asserted-by":"crossref","unstructured":"Ferrara N, Gerber HP, LeCouter J: The biology of VEGF and its receptors. Nat Med\u20089: 669\u2013676,2003","DOI":"10.1038\/nm0603-669"},{"key":"2022051610221457500_R38","doi-asserted-by":"crossref","unstructured":"Olsson AK, Dimberg A, Kreuger J, Claesson-Welsh L: VEGF receptor signalling: in control of vascular function. Nat Rev Mol Cell Biol\u20087: 359\u2013371,2006","DOI":"10.1038\/nrm1911"},{"key":"2022051610221457500_R39","doi-asserted-by":"crossref","unstructured":"Yancopoulos GD, Davis S, Gale NW, Rudge JS, Wiegand SJ, Holash J: Vascular-specific growth factors and blood vessel formation. Nature\u2008407: 242\u2013248,2000","DOI":"10.1038\/35025215"},{"key":"2022051610221457500_R40","doi-asserted-by":"crossref","unstructured":"Zachary I, Mathur A, Yla-Herttuala S, Martin J: Vascular protection: a novel nonangiogenic cardiovascular role for vascular endothelial growth factor. Arterioscler Thromb Vasc Biol\u200820: 1512\u20131520,2000","DOI":"10.1161\/01.ATV.20.6.1512"},{"key":"2022051610221457500_R41","doi-asserted-by":"crossref","unstructured":"Liu Y, Yang H, Otaka K, Takatsuki H, Sakanishi A: Effects of vascular endothelial growth factor (VEGF) and chondroitin sulfate A on human monocytic THP-1 cell migration. Colloids Surf B Biointerfaces\u200843: 216\u2013220,2005","DOI":"10.1016\/j.colsurfb.2005.04.011"},{"key":"2022051610221457500_R42","doi-asserted-by":"crossref","unstructured":"Cummins EP, Taylor CT: Hypoxia-responsive transcription factors. Pflugers Arch\u2008450: 363\u2013371,2005","DOI":"10.1007\/s00424-005-1413-7"},{"key":"2022051610221457500_R43","doi-asserted-by":"crossref","unstructured":"Asahara T, Takahashi T, Masuda H, Kalka C, Chen D, Iwaguro H, Inai Y, Silver M, Isner JM: VEGF contributes to postnatal neovascularization by mobilizing bone marrow-derived endothelial progenitor cells. Embo J\u200818: 3964\u20133972,1999","DOI":"10.1093\/emboj\/18.14.3964"},{"key":"2022051610221457500_R44","doi-asserted-by":"crossref","unstructured":"Celletti FL, Waugh JM, Amabile PG, Brendolan A, Hilfiker PR, Dake MD: Vascular endothelial growth factor enhances atherosclerotic plaque progression. Nat Med\u20087: 425\u2013429,2001","DOI":"10.1038\/86490"},{"key":"2022051610221457500_R45","doi-asserted-by":"crossref","unstructured":"Haddad JJ, Harb HL: Cytokines and the regulation of hypoxia-inducible factor (HIF)-1alpha. Int Immunopharmacol\u20085: 461\u2013483,2005 o:p","DOI":"10.1016\/j.intimp.2004.11.009"}],"container-title":["Diabetes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.org\/diabetes\/diabetes\/article-pdf\/56\/6\/1517\/248294\/zdb00607001517.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article-pdf\/56\/6\/1517\/248294\/zdb00607001517.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,2]],"date-time":"2022-11-02T16:10:31Z","timestamp":1667405431000},"score":1,"resource":{"primary":{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article\/56\/6\/1517\/12901\/Adipogenesis-in-Obesity-Requires-Close-Interplay"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2007,6,1]]},"references-count":45,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2007,6,1]]}},"URL":"https:\/\/doi.org\/10.2337\/db06-1749","relation":{},"ISSN":["0012-1797","1939-327X"],"issn-type":[{"value":"0012-1797","type":"print"},{"value":"1939-327X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2007,6,1]]}}}