The methyl-CpG-binding protein 2 (Mecp2) regulates the hypothalamic mitochondrial function and white adipose tissue...

The neuroepigenetic factor Mecp2 regulates gene expression and is thought to play a crucial role in energy homeostasis. Body weight is regulated at the hypothalamic level, where mitochondrial energy metabolism is necessary for its proper functioning, allowing the hypothalamus to respond to peripheral signals to maintain energy balance and modulate energy expenditure through the sympathetic nervous system. Since the mechanism by which genetic and environmental factors contribute to regulating energy balance is unclear, this study aims to understand the contribution of gene-environment interaction to maintaining energy balance and how its disruption alters hypothalamic cellular energy production, impacting the control of systemic metabolism.

We used a mouse model of epigenetic disruption (Mecp2-null) to evaluate the impact of Mecp2 deletion on systemic and hypothalamic metabolism using physiological and cellular approaches.

Our study shows that the previously reported body weight gain in mice lacking the expression of Mecp2 is preceded by a hypothalamic mitochondrial dysfunction that disrupts hypothalamic function, leading to a dysfunctional communication between the hypothalamus and adipose tissue, thus impairing lipid metabolism. Our study has revealed three crucial aspects of the contribution of this critical epigenetic factor pivotal for a proper gene-environment interaction: i) Mecp2 drives a molecular mechanism to maintain cellular energy homeostasis, which is necessary for the proper functioning of the hypothalamus. ii) Mecp2 is necessary to maintain lipid metabolism in adipose tissue. iii) Mecp2 is a molecular bridge linking hypothalamic cellular energy metabolism and adipose tissue lipid metabolism.

Our results show that Mecp2 regulates the hypothalamic mitochondrial function and white adipose tissue lipid metabolism and probably alters the communication between these two tissues, which is critical for corporal energy homeostasis maintenance.