title: Time-course microarrays reveal early activation of the immune transcriptome and adipokine dysregulation leads to fibrosis in visceral adipose depots during diet-induced obesity.
abstract: BACKGROUND
  Visceral white adipose tissue (WAT) hypertrophy, adipokine production, inflammation and fibrosis are strongly associated with obesity, but the time-course of these changes in-vivo are not fully understood. Therefore, the aim of this study was to establish the time-course of changes in adipocyte morphology, adipokines and the global transcriptional landscape in visceral WAT during the development of diet-induced obesity.
  
  
  RESULTS
  C57BL/6 J mice were fed a high-fat diet (HFD) or normal diet (ND) and sacrificed at 8 time-points over 24 weeks. Excessive fat accumulation was evident in visceral WAT depots (Epidydimal, Perirenal, Retroperitoneum, Mesentery) after 2-4 weeks. Fibrillar collagen accumulation was evident in epidydimal adipocytes at 24 weeks. Plasma adipokines, leptin, resistin and adipsin, increased early and time-dependently, while adiponectin decreased late after 20 weeks. Only plasma leptin and adiponectin levels were associated with their respective mRNA levels in visceral WAT. Time-course microarrays revealed early and sustained activation of the immune transcriptome in epididymal and mesenteric depots. Up-regulated inflammatory genes included pro-inflammatory cytokines, chemokines (Tnf, Il1rn, Saa3, Emr1, Adam8, Itgam, Ccl2, 3, 4, 6, 7 and 9) and their upstream signalling pathway genes (multiple Toll-like receptors, Irf5 and Cd14). Early changes also occurred in fibrosis, extracellular matrix, collagen and cathepsin related-genes, but histological fibrosis was only visible in the later stages.
  
  
  CONCLUSIONS
  In diet-induced obesity, early activation of TLR-mediated inflammatory signalling cascades by CD antigen genes, leads to increased expression of pro-inflammatory cytokines and chemokines, resulting in chronic low-grade inflammation. Early changes in collagen genes may trigger the accumulation of ECM components, promoting fibrosis in the later stages of diet-induced obesity. New therapeutic approaches targeting visceral adipose tissue genes altered early by HFD feeding may help ameliorate the deleterious effects of diet-induced obesity.
authors.affiliation: Center for Food and Nutritional Genomics Research, Kyungpook National University, Daegu, Republic of Korea.
authors.forename: Eun-Young
authors.initials: EY
authors.lastname: Kwon
authors.forename: Su-Kyung
authors.initials: SK
authors.lastname: Shin
authors.forename: Yun-Young
authors.initials: YY
authors.lastname: Cho
authors.forename: Un Ju
authors.initials: UJ
authors.lastname: Jung
authors.forename: Eunjung
authors.initials: E
authors.lastname: Kim
authors.forename: Taesun
authors.initials: T
authors.lastname: Park
authors.forename: Jung Han Yoon
authors.initials: JH
authors.lastname: Park
authors.forename: Jong Won
authors.initials: JW
authors.lastname: Yun
authors.forename: Robin A
authors.initials: RA
authors.lastname: McGregor
authors.forename: Yong Bok
authors.initials: YB
authors.lastname: Park
authors.forename: Myung-Sook
authors.initials: MS
authors.lastname: Choi
mesh_terms: D054392:Adipokines / Q000378:metabolism*; D052242:Adiponectin / Q000097:blood / Q000235:genetics; D052436:Adipose Tissue, White / Q000378:metabolism; D000818:Animals; D002403:Cathepsins / Q000235:genetics / Q000378:metabolism; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D011416:Complement Factor D / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D059305:Diet, High-Fat; D005355:Fibrosis / Q000235:genetics* / Q000378:metabolism; D020738:Leptin / Q000097:blood / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D052243:Resistin / Q000097:blood / Q000235:genetics; D015398:Signal Transduction; D013997:Time Factors; D059467:Transcriptome / Q000235:genetics*
chemical_list: D054392:Adipokines; D052242:Adiponectin; D018925:Chemokines; D016207:Cytokines; D020738:Leptin; D052243:Resistin; D002403:Cathepsins; D011416:Complement Factor D