Dnmt3a in Sim1 neurons is necessary for normal energy homeostasis.
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.
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.
Daisuke
D
Kohno
Division of Hypothalamic Research, Departments of Internal Medicine and Pharmacology, and.
Syann
S
Lee
Division of Hypothalamic Research, Departments of Internal Medicine and Pharmacology, and Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
Matthew J
MJ
Harper
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.
Ki Woo
KW
Kim
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.
Hideyuki
http://orcid.org/0000-0002-4574-1772
H
Sone
Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, 371-8512 Japan.
Tsutomu
T
Sasaki
Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, 371-8512 Japan.
Tadahiro
T
Kitamura
Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California 90095.
Guoping
G
Fan
Division of Hypothalamic Research, Departments of Internal Medicine and Pharmacology, and joel.elmquist@UTSouthwestern.edu daisuke.kohno@gunma-u.ac.jp.
Joel K
JK
Elmquist
D000273:Adipose Tissue / Q000502:physiology; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D008078:Cholesterol, LDL / Q000097:blood; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D059305:Diet, High-Fat; D004734:Energy Metabolism / Q000502:physiology*; D005260:Female; D019004:Galanin / Q000096:biosynthesis; D020869:Gene Expression Profiling; D018149:Glucose Intolerance / Q000235:genetics / Q000503:physiopathology; D006706:Homeostasis; D006963:Hyperphagia / Q000150:complications / Q000235:genetics / Q000503:physiopathology; D007328:Insulin / Q000097:blood; D020738:Leptin / Q000097:blood; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism*; D009765:Obesity / Q000097:blood / Q000150:complications / Q000235:genetics / Q000503:physiopathology; D010286:Paraventricular Hypothalamic Nucleus / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D014446:Tyrosine 3-Monooxygenase / Q000096:biosynthesis; D015854:Up-Regulation
D051792:Basic Helix-Loop-Helix Proteins; D008078:Cholesterol, LDL; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D019004:Galanin; D007328:Insulin; D020738:Leptin; D012097:Repressor Proteins; D014446:Tyrosine 3-Monooxygenase; C000717967:DNMT3A protein, human; C000715535:Dnmt3a protein, mouse; C101750:Sim1 protein, mouse
DNA methylation; Dnmt3a; epigenetics; feeding; hypothalamus; obesity