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Dnmt3a in Sim1 neurons is necessary for normal energy homeostasis.

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. DNA methylation levels of the tyrosine hydroxylase promoter were decreased in the PVH of the deletion mice. These results suggest that Dnmt3a in the PVH is 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.
AuthorsDaisuke Kohno, Syann Lee, Matthew J Harper, Ki Woo Kim, Hideyuki Sone, Tsutomu Sasaki, Tadahiro Kitamura, Guoping Fan, Joel K Elmquist
JournalThe Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 34 Issue 46 Pg. 15288-96 (Nov 12 2014) ISSN: 1529-2401 [Electronic] United States
PMID25392496 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2014 the authors 0270-6474/14/3415288-09$15.00/0.
Chemical References
  • Basic Helix-Loop-Helix Transcription Factors
  • Cholesterol, LDL
  • Insulin
  • Leptin
  • Repressor Proteins
  • Sim1 protein, mouse
  • Galanin
  • Tyrosine 3-Monooxygenase
  • DNA (Cytosine-5-)-Methyltransferase
  • DNA methyltransferase 3A
Topics
  • Adipose Tissue (physiology)
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors (metabolism)
  • Cholesterol, LDL (blood)
  • DNA (Cytosine-5-)-Methyltransferase (genetics, metabolism, physiology)
  • DNA Methylation
  • Diet, High-Fat
  • Energy Metabolism (physiology)
  • Female
  • Galanin (biosynthesis)
  • Gene Expression Profiling
  • Glucose Intolerance (genetics, physiopathology)
  • Homeostasis
  • Hyperphagia (complications, genetics, physiopathology)
  • Insulin (blood)
  • Leptin (blood)
  • Male
  • Mice
  • Mice, Knockout
  • Neurons (metabolism)
  • Obesity (blood, complications, genetics, physiopathology)
  • Paraventricular Hypothalamic Nucleus (metabolism)
  • Repressor Proteins (metabolism)
  • Tyrosine 3-Monooxygenase (biosynthesis)
  • Up-Regulation

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