title: Time-course microarrays reveal modulation of developmental, lipid metabolism and immune gene networks in intrascapular brown adipose tissue during the development of diet-induced obesity.
abstract: OBJECTIVE
  The aim of this study was to establish the time-course of molecular events in intrascapular brown adipose tissue (iBAT) during the development of diet-induced obesity using microarrays and molecular network analysis.
  
  
  METHODS
  C57BL/6J male inbred mice were fed a high-fat diet (HFD) or normal diet (ND) and killed at multiple time-points over 24 weeks.
  
  
  METHODS
  Global transcriptional changes in iBAT were determined by time-course microarrays of pooled RNA (n=6, pools per time-point) at 2, 4, 8, 20 and 24 weeks using Illumina MouseWG-6 v2.0 Beadchips. Molecular networks were constructed using the Ingenuity knowledgebase based on differentially expressed genes at each time-point.
  
  
  RESULTS
  Body weight and subcutaneous adipose were progressively increased over 24 weeks, whereas iBAT was significantly increased between 6 and 12 weeks in HFD-fed C57BL/6J mice compared with controls. Blood glucose and insulin levels were increased between 16 and 24 weeks. Time-course microarrays, revealed 155 differentially expressed genes at one or more time-points over 24 weeks in the iBAT of HFD-fed mice compared with controls. Time-course network analysis revealed a network of skeletal muscle development genes that was activated between 2 and 4 weeks, subsequently a network of immune trafficking genes was activated at 8 weeks. After 20 and 24 weeks, multiple lipid metabolism and immune response networks were activated. Several target genes identified by time-course microarrays were independently validated using RT-qPCR. Tnnc1 was upregulated early between 2 and 4 weeks, later Cd68 and Col1a1 were upregulated between 20 and 24 weeks, whereas 11β-hydroxysteroid dehydrogenase (Hsd11b1) was consistently downregulated during the development of diet-induced obesity.
  
  
  CONCLUSIONS
  Molecular networks in iBAT are modulated in a time-dependent manner in response to a HFD. A broad range of gene targets exists to alter molecular changes within iBAT during the development of diet-induced obesity.
authors.affiliation: 1] Center for Food and Nutritional Genomics Research, Department of Food Science and Nutrition, Kyungpook National University, Daegu, Republic of Korea [2] Institute for Innovation in Biology, School of Biological Sciences, University of Auckland, Auckland, New Zealand.
authors.forename: R A
authors.initials: RA
authors.lastname: McGregor
authors.forename: E-Y
authors.initials: EY
authors.lastname: Kwon
authors.forename: S-K
authors.initials: SK
authors.lastname: Shin
authors.forename: U J
authors.initials: UJ
authors.lastname: Jung
authors.forename: E
authors.initials: E
authors.lastname: Kim
authors.forename: J H Y
authors.initials: JH
authors.lastname: Park
authors.forename: R
authors.initials: R
authors.lastname: Yu
authors.forename: J W
authors.initials: JW
authors.lastname: Yun
authors.forename: M-S
authors.initials: MS
authors.lastname: Choi
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000378:metabolism; D056704:Adaptive Immunity / Q000235:genetics*; D002001:Adipose Tissue, Brown / Q000276:immunology / Q000473:pathology*; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism*; D024042:Collagen Type I / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D059305:Diet, High-Fat; D015536:Down-Regulation; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D007333:Insulin Resistance / Q000276:immunology; D050356:Lipid Metabolism / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000209:etiology / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D019063:Tenascin / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation; D000097382:CD68 Molecule
chemical_list: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D019063:Tenascin; C539355:CD68 protein, rat; D000097382:CD68 Molecule; C477504:tenascin-N protein, mouse