Leptin resistance and obesity in mice with deletion of methyl-CpG-binding protein 2 (MeCP2) in hypothalamic pro-opiomelanocortin (POMC) neurons

• Published in: Diabetologia Vol. 57; no. 1; pp. 236 - 245
• Main Authors: Wang, Xiaorui, Lacza, Zsombor, Sun, Yi E., Han, Weiping
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 2014; Springer; Springer Nature B.V
• Subjects: Animals; Biological and medical sciences; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Diabetes. Impaired glucose tolerance; DNA methylation; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Energy; Epigenetics; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Gene expression; Homeostasis; Human Physiology; Hypothalamus; Hypothalamus - metabolism; Internal Medicine; Leptin - metabolism; Male; Medical sciences; Medicine; Medicine & Public Health; Metabolic Diseases; Metabolism; Methyl-CpG-Binding Protein 2 - deficiency; Methyl-CpG-Binding Protein 2 - genetics; Mice; Neurology; Neurons - metabolism; Neuropeptides; Obesity; Obesity - metabolism; Overweight; Pro-Opiomelanocortin - metabolism; Proteins; Los Angeles California; United States > US; Singapore; DNA methylation; Obesity; Energy homeostasis; Epigenetic; Rett syndrome; Leptin resistance; Endocrinopathy; NA methylation; Central nervous system; Homeostasis; Hypothalamus; Prohormone; Encephalon; Binding protein; Proopiocortin; Deletion; Degenerative disease; Nutritional status; Nervous system diseases; Diabetes mellitus; Rodentia; Nutrition disorder; Adipokine; Genetic disease; Cerebral disorder; Target tissue resistance; Vertebrata; Mammalia; Neuron; Mouse; Animal; Leptin; Central nervous system disease; Epigenetics; Methylation
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-013-3072-0

Aims/hypothesis
Pro-opiomelanocortin (POMC) neurons in the arcuate nucleus (ARC) regulate energy homeostasis by secreting α-melanocyte-stimulating hormone (α-MSH), derived from POMC precursor, in response to leptin signalling. Expression of
Pomc
is subject to multiple modes of regulation, including epigenetic regulation. Methyl-CpG-binding protein 2 (MeCP2), a nuclear protein essential for neuronal function, interacts with promoters to influence gene expression. We aim to address whether MeCP2 regulates hypothalamic
Pomc
expression and to investigate the role of epigenetics, particularly DNA methylation, in this process.
Methods
We generated a mouse line with MeCP2 specifically deleted in POMC neurons (
Mecp2
flox
/
y
/
Pomc
-
Cre
[PKO]) and characterised its metabolic phenotypes. We examined the DNA methylation pattern of the
Pomc
promoter and its impact on hypothalamic gene expression. We also studied the requirement of MeCP2 for, and the effects of, DNA methylation on
Pomc
promoter activity using luciferase assays.
Results
PKO mice are overweight, with increased fat mass resulting from increased food intake and respiratory exchange ratio. PKO mice also exhibit elevated plasma leptin. Deletion of MeCP2 in POMC neurons leads to increased DNA methylation of the hypothalamic
Pomc
promoter and reduced
Pomc
expression. Furthermore, in vitro studies show that hypermethylation of the
Pomc
promoter reduces its transcriptional activity and reveal a functional synergy between MeCP2 and cAMP responsive element binding protein 1 (CREB1) in positively regulating the
Pomc
promoter.
Conclusions/interpretation
Our results demonstrate that MeCP2 positively regulates
Pomc
expression in the hypothalamus. Absence of MeCP2 in POMC neurons leads to increased DNA methylation of the
Pomc
promoter, which, in turn, downregulates
Pomc
expression, leading to obesity in mice with an accentuating degree of leptin resistance.