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

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.

Perinatal exposure to high fat diet alters expression of MeCP2 in the hypothalamus.

Obesity is a complex disease that is the result of a number of different factors including genetic, environmental, and endocrine abnormalities. Given that monogenic forms of obesity are rare, it is important to identify other mechanisms that contribute to its etiology. Methyl-Cp-G binding protein 2 (MeCP2) is a neuroepigenetic factor that binds to methylated regions of DNA to influence transcription. Past studies demonstrate that disruption in MeCP2 function produces obesity in mice. Using a diet-induced obesity mouse model, we show that perinatal exposure to high fat diet significantly decreases MeCP2 protein expression in the hypothalamus of female mice, effects not seen when high fat diet is given to mice during adulthood. Moreover, these effects are seen specifically in a subregion of the hypothalamus known as the arcuate nucleus with females having decreased MeCP2 expression in rostral areas and males having decreased MeCP2 expression in intermediate regions of the arcuate nucleus. Interestingly, mice gain more weight when exposed to high fat diet during adulthood relative to mice exposed to high fat diet perinatally, suggesting that perhaps high fat diet exposure during adulthood may be affecting mechanisms independent of MeCP2 function. Collectively, our data demonstrate that there are developmentally sensitive periods in which MeCP2 expression is influenced by high fat diet exposure and this occurs in a sexually dimorphic manner.