Constitutive loss of DNMT3A causes morbid obesity through misregulation of adipogenesis

Tovy, A.; Reyes, J. M.; Zhang, L.; Huang, Y.-H.; Rosas, C.; Daquinag, A. C.; Guzman, A. G.; Ramabadran, R.; Chen, C.-W.; Gu, T.; Gupta, S.; Ortinau, L.; Park, D.; Cox, A. R.; Rau, R. E.; Hartig, S. M.; Kolonin, M. G.; Goodell, M. A.

doi:10.1101/2021.09.13.460063

bioRxiv · 10.1101/2021.09.13.460063

Constitutive loss of DNMT3A causes morbid obesity through misregulation of adipogenesis

Tovy, A.·Reyes, J. M.·Zhang, L.·Huang, Y.-H.·Rosas, C.·Daquinag, A. C.·Guzman, A. G.·Ramabadran, R.·Chen, C.-W.·Gu, T.·Gupta, S.·Ortinau, L.·Park, D.·Cox, A. R.·Rau, R. E.·Hartig, S. M.·Kolonin, M. G.·Goodell, M. A.

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Abstract

DNA Methyltransferase 3A (DNMT3A) is an important facilitator of differentiation of both embryonic and hematopoietic stem cells. Heterozygous germline mutations in DNMT3A lead to Tatton-Brown-Rahman Syndrome (TBRS), characterized by obesity and excessive height. While DNMT3A is known to impact feeding behavior via the hypothalamus, here we investigated a role in adipocyte progenitors utilizing heterozygous knockout mice that recapitulate cardinal TBRS phenotypes. These mice become morbidly obese due to adipocyte enlargement and tissue expansion. Adipose tissue in these mice exhibited defects in preadipocyte maturation and precocious activation of inflammatory gene networks, including interleukin-6 signaling. Adipocyte progenitor cell lines lacking DNMT3A exhibited aberrant differentiation. Furthermore, mice in which Dnmt3a was specifically ablated in adipocyte progenitors showed enlarged fat depots and increased progenitor numbers, partly recapitulating the TBRS obesity phenotypes. Loss of DNMT3A led to constitutive DNA hypomethylation, such that the DNA methylation landscape of young adipocyte progenitors resemble that of older wild-type mice. Together, our results demonstrate that DNMT3A coordinates both the central and local control of energy storage required to maintain normal weight and prevent inflammatory obesity.

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Tovy, A., Reyes, J. M., Zhang, L., Huang, Y.-H., Rosas, C., Daquinag, A. C., Guzman, A. G., Ramabadran, R., Chen, C.-W., Gu, T., Gupta, S., Ortinau, L., Park, D., Cox, A. R., Rau, R. E., Hartig, S. M., Kolonin, M. G., Goodell, M. A.. 2021-09-15. Constitutive loss of DNMT3A causes morbid obesity through misregulation of adipogenesis. https://doi.org/10.1101/2021.09.13.460063

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