Dnmt3a in sim1 neurons is necessary for normal energy homeostasis

Daisuke Kohno, Syann Lee, Matthew J. Harper, Ki Woo Kim, Xhideyuki Sone, Tsutomu Sasaki, Tadahiro Kitamura, Guoping Fan, Joel K. Elmquist

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Obesity rates continue to rise throughout the world. Recent evidence has suggested that environmental factors contribute to altered energy balance regulation. However, the role of epigenetic modifications to the central control of energy homeostasis remains unknown. To investigate the role of DNA methylation in the regulation of energy balance, we investigated the role of the de novo DNA methyltransferase, Dnmt3a, in Single-minded 1 (Sim1) cells, including neurons in the paraventricular nucleus of the hypothalamus (PVH). Dnmt3a expression levels were decreased in the PVH of high-fat-fed mice. Mice lacking Dnmt3a specifically in the Sim1 neurons, which are expressed in the forebrain, including PVH, became obese with increased amounts of abdominal and subcutaneous fat. The mice were also found to have hyperphagia, decreased energy expenditure, and glucose intolerance with increased serum insulin and leptin. Furthermore, these mice developed hyper-LDL cholesterolemia when fed a high-fat diet. Gene expression profiling and DNA methylation analysis revealed that the expression of tyrosine hydroxylase and galanin were highly upregulated in the PVH of Sim1-specific Dnmt3a deletion mice.DNAmethylation levels of the tyrosine hydroxylase promoter were decreased in thePVHof the deletion mice. These results suggest that Dnmt3a in thePVHis necessary for the normal control of body weight and energy homeostasis and that tyrosine hydroxylase is a putative target of Dnmt3a in the PVH. These results provide evidence for a role for Dnmt3a in the PVH to link environmental conditions to altered energy homeostasis.

Original languageEnglish (US)
Pages (from-to)15288-15296
Number of pages9
JournalJournal of Neuroscience
Volume34
Issue number46
DOIs
StatePublished - Nov 12 2014

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Paraventricular Hypothalamic Nucleus
Hypothalamus
Homeostasis
Neurons
Tyrosine 3-Monooxygenase
DNA Methylation
Abdominal Subcutaneous Fat
Galanin
Ideal Body Weight
Hyperphagia
Glucose Intolerance
Methyltransferases
High Fat Diet
Gene Expression Profiling
Prosencephalon
Leptin
Epigenomics
Energy Metabolism
Obesity
Fats

Keywords

  • DNA methylation
  • Dnmt3a
  • Epigenetics
  • Feeding
  • Hypothalamus
  • Obesity

ASJC Scopus subject areas

  • Neuroscience(all)
  • Medicine(all)

Cite this

Dnmt3a in sim1 neurons is necessary for normal energy homeostasis. / Kohno, Daisuke; Lee, Syann; Harper, Matthew J.; Kim, Ki Woo; Sone, Xhideyuki; Sasaki, Tsutomu; Kitamura, Tadahiro; Fan, Guoping; Elmquist, Joel K.

In: Journal of Neuroscience, Vol. 34, No. 46, 12.11.2014, p. 15288-15296.

Research output: Contribution to journalArticle

Kohno, D, Lee, S, Harper, MJ, Kim, KW, Sone, X, Sasaki, T, Kitamura, T, Fan, G & Elmquist, JK 2014, 'Dnmt3a in sim1 neurons is necessary for normal energy homeostasis', Journal of Neuroscience, vol. 34, no. 46, pp. 15288-15296. https://doi.org/10.1523/JNEUROSCI.1316-14.2014
Kohno, Daisuke ; Lee, Syann ; Harper, Matthew J. ; Kim, Ki Woo ; Sone, Xhideyuki ; Sasaki, Tsutomu ; Kitamura, Tadahiro ; Fan, Guoping ; Elmquist, Joel K. / Dnmt3a in sim1 neurons is necessary for normal energy homeostasis. In: Journal of Neuroscience. 2014 ; Vol. 34, No. 46. pp. 15288-15296.
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