POMC-specific knockdown of MeCP2 leads to adverse phenotypes in mice chronically exposed to high fat diet

Abstract

Methyl-CpG binding protein 2 (MeCP2) is an epigenetic factor associated with the neurodevelopmental disorders Rett Syndrome and MECP2 duplication syndrome. Previous studies have demonstrated that knocking out MeCP2 globally in the central nervous system leads to an obese phenotype and hyperphagia, however it is not clear if the hyperphagia is the result of an increased preference for food reward or due to an increase in motivation to obtain food reward. We show that mice deficient in MeCP2 specifically in pro-opiomelanocortin (POMC) neurons have an increased preference for high fat diet as measured by conditioned place preference but do not have a greater motivation to obtain food reward using a progressive ratio task, relative to wildtype littermate controls. We also demonstrate that POMC-Cre MeCP2 knockout (KO) mice have increased body weight after long-term high fat diet exposure as well as elevated plasma leptin and corticosterone levels compared to wildtype mice. Taken together, these results are the first to show that POMC-specific loss-of-function Mecp2 mutations leads to dissociable effects on the rewarding/motivational properties of food as well as changes to hormones associated with body weight homeostasis and stress.