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J Neurosci. 2014 Nov 12;34(46):15288-96. doi: 10.1523/JNEUROSCI.1316-14.2014.

Dnmt3a in Sim1 neurons is necessary for normal energy homeostasis.

Author information

1
Division of Hypothalamic Research, Departments of Internal Medicine and Pharmacology, and Advanced Scientific Research Leaders Development Unit and Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, 371-8512 Japan, joel.elmquist@UTSouthwestern.edu daisuke.kohno@gunma-u.ac.jp.
2
Division of Hypothalamic Research, Departments of Internal Medicine and Pharmacology, and.
3
Division of Hypothalamic Research, Departments of Internal Medicine and Pharmacology, and Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
4
Division of Hypothalamic Research, Departments of Internal Medicine and Pharmacology, and Departments of Pharmacology and Global Medical Science, Institute of Lifestyle Medicine, and Nuclear Receptor Research Consortium, Yonsei University Wonju College of Medicine, Wonju, 220-701, Republic of Korea.
5
Division of Hypothalamic Research, Departments of Internal Medicine and Pharmacology, and Department of Health and Nutrition, Faculty of Human Life Studies, University of Niigata Prefecture, Higashi-ku, Niigata, 950-8680, Japan, and.
6
Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, 371-8512 Japan.
7
Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California 90095.
8
Division of Hypothalamic Research, Departments of Internal Medicine and Pharmacology, and joel.elmquist@UTSouthwestern.edu daisuke.kohno@gunma-u.ac.jp.

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.

KEYWORDS:

DNA methylation; Dnmt3a; epigenetics; feeding; hypothalamus; obesity

PMID:
25392496
PMCID:
PMC4228132
DOI:
10.1523/JNEUROSCI.1316-14.2014
[Indexed for MEDLINE]
Free PMC Article

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