title: DNA hypomethylation of inflammation-associated genes in adipose tissue of female mice after multigenerational high fat diet feeding.
abstract: OBJECTIVE
  Maternal obesity significantly increases the susceptibility of offspring to develop obesity and chronic diseases in adulthood. The offspring of obese mothers are shown to prefer high fat diet (HFD) due to their altered neural circuitry, creating a 'feed-forward cycle' across generations. We hypothesized that the 'feed-forward cycle' caused by multigenerational HFD feeding would have exacerbated effects in adipose tissue of the offspring.
  
  
  METHODS
  Three generations (F0, F1 and F2) of HFD (60% Kcal fat)-fed and corresponding normal chow (NC)-fed C57BL/6 mice were generated. Body weight (BW) and food intake were monitored weekly. Parametrial adipose tissue (pAT) weight and endocrine parameters were measured in 9-month-old female offspring. Gene expression microarray, quantitative RT-PCR and bisulfite sequencing were performed using pAT.
  
  
  RESULTS
  BW and pAT weight increased in female mice across generations under continuous HFD stress, with the most severe phenotype found in the F2 generation. Genes involved in inflammatory response showed increased expression across generations in the pAT, accompanied by increased macrophage infiltration. The promoters of Toll-like receptor 1 (Tlr1), Tlr2 and linker for activation of T cells (Lat) were hypomethylated in the HF groups compared with the NC group, with additional hypomethylation on some specific CpG sites in the F2 generation.
  
  
  CONCLUSIONS
  A feed-forward cycle exists in female mice after continuous HFD stress as demonstrated by increased adiposity and progressive inflammation in adipose tissue across generations. DNA hypomethylation over generations lead to epigenetically altered expression of Tlr1, Tlr2 and Lat, which may contribute to the inflammation in adipose tissue. Our study provides a potential mechanism for enhanced inflammation in adipose tissue under multigenerational HFD-fed stress.
authors.affiliation: 1] College of Life Sciences, Wuhan University, Wuhan, People's Republic of China [2] Diabetes Center, Wuhan University, Wuhan, People's Republic of China.
authors.forename: Y
authors.initials: Y
authors.lastname: Ding
authors.affiliation: 1] College of Life Sciences, Wuhan University, Wuhan, People's Republic of China [2] Diabetes Center, Wuhan University, Wuhan, People's Republic of China.
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.affiliation: College of Life Sciences, Wuhan University, Wuhan, People's Republic of China.
authors.forename: S
authors.initials: S
authors.lastname: Liu
authors.affiliation: College of Life Sciences, Wuhan University, Wuhan, People's Republic of China.
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.affiliation: College of Life Sciences, Wuhan University, Wuhan, People's Republic of China.
authors.forename: H
authors.initials: H
authors.lastname: Xiao
authors.affiliation: College of Life Sciences, Wuhan University, Wuhan, People's Republic of China.
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.affiliation: Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors.forename: H
authors.initials: H
authors.lastname: Chen
authors.affiliation: Departments of Pathology, Neuroscience and Neurology, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: R B
authors.initials: RB
authors.lastname: Petersen
authors.affiliation: 1] Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan, People's Republic of China [2] Centre for Biomedicine Research, Wuhan Institute of Biotechnology, Wuhan, People's Republic of China.
authors.forename: K
authors.initials: K
authors.lastname: Huang
authors.affiliation: 1] College of Life Sciences, Wuhan University, Wuhan, People's Republic of China [2] Diabetes Center, Wuhan University, Wuhan, People's Republic of China.
authors.forename: L
authors.initials: L
authors.lastname: Zheng
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D001724:Birth Weight; D019175:DNA Methylation / Q000235:genetics* / Q000502:physiology; D059305:Diet, High-Fat; D004435:Eating / Q000235:genetics; D044127:Epigenesis, Genetic; D005260:Female; D018507:Gene Expression Regulation, Developmental; D020022:Genetic Predisposition to Disease; D007150:Immunohistochemistry; D007249:Inflammation / Q000235:genetics / Q000378:metabolism*; D039382:Maternal Nutritional Physiological Phenomena; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000235:genetics / Q000378:metabolism*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000378:metabolism*