title: The increase in body weight induced by lack of methyl CpG binding protein-2 is associated with altered leptin signalling in the hypothalamus.
abstract: Methyl CpG binding protein-2 (MECP2) is a chromatin-remodelling factor with a dual role in gene expression. Evidence from patients carrying MECP2 mutations and from transgenic mouse models demonstrates that this protein is involved in the control of body weight. However, the mechanism for this has not been fully elucidated. To address this, we used a previously characterized Mecp2-null mouse model and found that the increase in body weight is associated with an increased amount of adipose tissue and high leptin levels. Appropriate body weight control requires the proper expression of pro-opiomelanocortin (Pomc) and agouti-related peptide (Agrp), two neuropeptides essential for satiety and appetite signals, respectively. Our results show that in the absence of Mecp2, Pomc and Agrp mRNA expression are altered, and the mice are leptin resistant. To determine the mechanism underlying the defective leptin sensing, we evaluated the expression of genes and the post-translational modifications associated with leptin signalling, which are fundamental to Pomc and Agrp transcriptional control and proper leptin response. We found a decrease in the phosphorylation level of Akt and its target protein Foxo1, which indicate an alteration in leptin-induced signal transduction. Our results demonstrate that the absence of Mecp2 disrupted body weight balance by altering post-translational modifications in leptin-signalling components that regulate Pomc and Agrp expression.
authors.affiliation: Centro de Estudios Científicos, Valdivia, Chile Universidad de Chile, Santiago, Chile.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Torres-Andrade
authors.affiliation: Centro de Estudios Científicos, Valdivia, Chile Universidad Austral de Chile, Valdivia, Chile.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Moldenhauer
authors.affiliation: Centro de Estudios Científicos, Valdivia, Chile.
authors.forename: Noemí
authors.initials: N
authors.lastname: Gutierrez-Bertín
authors.affiliation: Centro de Estudios Científicos, Valdivia, Chile.
authors.forename: Jessica
authors.initials: J
authors.lastname: Soto-Covasich
authors.affiliation: Centro de Estudios Científicos, Valdivia, Chile Universidad Austral de Chile, Valdivia, Chile.
authors.forename: Cristian
authors.initials: C
authors.lastname: Mancilla-Medina
authors.affiliation: Centro de Estudios Científicos, Valdivia, Chile Universidad Austral de Chile, Valdivia, Chile.
authors.forename: Carolina
authors.initials: C
authors.lastname: Ehrenfeld
authors.affiliation: Centro de Estudios Científicos, Valdivia, Chile bkerr@cecs.cl.
authors.forename: Bredford
authors.initials: B
authors.lastname: Kerr
mesh_terms: D050154:Adiposity; D054369:Agouti-Related Protein / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005786:Gene Expression Regulation; D005838:Genotype; D007031:Hypothalamus / Q000378:metabolism*; D020738:Leptin / Q000378:metabolism*; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000172:deficiency* / Q000235:genetics; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D010766:Phosphorylation; D011333:Pro-Opiomelanocortin / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic; D015430:Weight Gain
chemical_list: D054369:Agouti-Related Protein; C515199:Agrp protein, mouse; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D020738:Leptin; C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D012333:RNA, Messenger; D011333:Pro-Opiomelanocortin; D051057:Proto-Oncogene Proteins c-akt