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DNA hypomethylation of inflammation-associated genes in adipose tissue of female mice after multigenerational high fat diet feeding

International Journal of Obesity volume 38, pages 198–204 (2014)Cite this article

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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.

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Acknowledgements

We thank Bo Yang (College of Life Sciences, Wuhan University, Wuhan, People’s Republic of China) for technical assistance with the heat map and Professor Xin Chen (UCSF, USA) for critical reading the manuscript. This work was supported by the National Basic Research Program of China (2009BC918304 and 2012CB524901), the Natural Science Foundation of China (Nos. 30970607, 81172971, 81222043 and 31271370) and the Program for New Century Excellent Talents in University (NECT10-0623 and NECT11-0170).

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Author notes

  1. Y Ding and J Li: These authors contributed equally to this work.

Authors and Affiliations

  1. College of Life Sciences, Wuhan University, Wuhan, People’s Republic of China

    Y Ding, J Li, S Liu, L Zhang, H Xiao, J Li & L Zheng

  2. Diabetes Center, Wuhan University, Wuhan, People’s Republic of China

    Y Ding, J Li & L Zheng

  3. Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan, People’s Republic of China

    H Chen & K Huang

  4. Departments of Pathology, Neuroscience and Neurology, Case Western Reserve University, Cleveland, OH, USA

    R B Petersen

  5. Centre for Biomedicine Research, Wuhan Institute of Biotechnology, Wuhan, People’s Republic of China

    K Huang

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Ding, Y., Li, J., Liu, S. et al. DNA hypomethylation of inflammation-associated genes in adipose tissue of female mice after multigenerational high fat diet feeding. Int J Obes 38, 198–204 (2014). https://doi.org/10.1038/ijo.2013.98

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