Integrative systems analysis of diet-induced obesity identified a critical transition in the transcriptomes of the murine liver and epididymal white adipose tissue.
BACKGROUND
It is well known that high-fat diet (HFD) can cause immune system-related pathological alterations after a significant body weight gain. The mechanisms of the delayed pathological alterations during the development of diet-induced obesity (DIO) are not fully understood.


METHODS
To elucidate the mechanisms underlying DIO development, we analyzed time-course microarray data obtained from a previous study. First, differentially expressed genes (DEGs) were identified at each time point by comparing the hepatic transcriptome of mice fed HFD with that of mice fed normal diet. Next, we clustered the union of DEGs and identified annotations related to each cluster. Finally, we constructed an 'integrated obesity-associated gene regulatory network (GRN) in murine liver'. We analyzed the epididymal white adipose tissue (eWAT) transcriptome usig the same procedure.


RESULTS
Based on time-course microarray data, we found that the genes associated with immune responses were upregulated with an oscillating expression pattern between weeks 2 and 8, relatively downregulated between weeks 12 and 16, and eventually upregulated after week 20 in the liver of the mice fed HFD. The genes associated with immune responses were also upregulated at late stage, in the eWAT of the mice fed HFD. These results suggested that a critical transition occurred in the immune system-related transcriptomes of the liver and eWAT around week 16 of the DIO development, and this may be associated with the delayed pathological alterations. The GRN analysis suggested that Maff may be a key transcription factor for the immune system-related critical transition thatoccurred at week 16. We found that transcription factors associated with immune responses were centrally located in the integrated obesity-associated GRN in the liver.


CONCLUSIONS
In this study, systems analysis identified regulatory network modules underlying the delayed immune system-related pathological changes during the development of DIO and could suggest possible therapeutic targets.
CHA Cancer Institute, CHA University, Seongnam City, Kyunggi-do, Republic of Korea.
J
J
Kim
Center for Food and Nutritional Genomics Research, Department of Food Science and Nutrition, Kyungpook National University, Daegu, Republic of Korea.
E-Y
EY
Kwon
CHA Cancer Institute, CHA University, Seongnam City, Kyunggi-do, Republic of Korea.
S
S
Park
Department of Mathematics, University of Seoul, Seoul, Republic of Korea.
J-R
JR
Kim
CHA Cancer Institute, CHA University, Seongnam City, Kyunggi-do, Republic of Korea.|Chaum Life Center, CHA University, School of Medicine, Seoul, Republic of Korea.
S-W
SW
Choi
Center for Food and Nutritional Genomics Research, Department of Food Science and Nutrition, Kyungpook National University, Daegu, Republic of Korea.
M-S
MS
Choi
CHA Cancer Institute, CHA University, Seongnam City, Kyunggi-do, Republic of Korea.|Department of Biomedical Sciences, College of Life Sciences, CHA University, Seongnam City, Kyunggi-do, Republic of Korea.
S-J
SJ
Kim
D056704:Adaptive Immunity / Q000235:genetics*; D052436:Adipose Tissue, White / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D007333:Insulin Resistance; D050356:Lipid Metabolism / Q000276:immunology; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000276:immunology / Q000378:metabolism*; D059467:Transcriptome; D015854:Up-Regulation