The increase in body weight induced by lack of methyl CpG binding protein‐2 is associated with altered leptin signalling in the hypothalamus

New Findings What is the central question of this study? Previous evidence shows that some patients and mouse models carrying mutations in the methyl CpG binding protein‐2 (MECP2) gene are overweight. However, the underlying mechanism associated with this phenotype has not been fully elucidated. What is the main finding and its importance? UsingMecp2‐null mice, we found that the absence of methyl CpG binding protein‐2 produces a deregulation in leptin signalling and alters the expression of key genes involved in body weight control. These results allow us to gain insight into the cellular mechanisms associated with leptin resistance and obesity. Methyl CpG binding protein‐2 (MECP2) is a chromatin‐remodelling factor with a dual role in gene expression. Evidence from patients carryingMECP2mutations 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 characterizedMecp2‐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,PomcandAgrpmRNA 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 toPomcandAgrptranscriptional 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 regulatePomcandAgrpexpression.