Rett Syndrome May Predispose Patients to High-fat Diets and Obesity, Study in Mice Finds

A high-fat diet can lead to extreme obesity in Rett syndrome patients due to excessive calorie intake, and to brain networks unable to fully control feeding behavior, a mouse study suggests.

The easy availability of high-fat foods in modern diets may further compound the problem — whose root cause is genetic — because this gene error also led diseased mice to show a clear preference for fatty foods.

The study, “High-fat diet accelerates extreme obesity with hyperphagia in female heterozygous Mecp2-null mice,” was published in the journal Plos One.

Rett syndrome is a neurodevelopmental disease due to a mutation in the MECP2 gene, which provides instructions for making a protein called MeCP2. This protein helps regulate gene activity and is important for the function of several types of cells, including nerve cells.

Patients with Rett syndrome characteristically have developmental regression, autistic behavior, stereotypical hand movements, and epileptic seizures. Additionally, several reports indicate they are at a higher risk of obesity.

But the underlying cause that might link Rett syndrome to obesity is unclear.

An association between Rett syndrome and obesity has been demonstrated through animal experiments, with researchers finding that mice which do not express the MECP2 gene (Mecp2-null) and are fed a normal diet still become overweight. But no weight gain occurs when these animals are then genetically engineered to express the MECP2 gene, suggesting the important role of MECP2 in regulating weight. (Gene expression is the process by which information in a gene is synthesized to create a working product, like a protein.)

Researchers at the Kyoto Prefectural University of Medicine in Japan examined the expression of genes that are related to the central network of feeding behavior control in the brain. This includes analyzing gene expression of the hypothalamus (a part of the brain that plays a role in metabolizing fat) and dopamine reward circuitry (which regulates feeding behavior by “rewarding” an individual for certain essential activities, such as eating).

The study looked at gene expression in female Rett syndrome mice (Mecp2-null mice), which were fed either a normal or high-fat diet. Animals on a normal diet had typical body weight and food consumption patterns. However, Rett syndrome mice on a high-fat diet became very obese, with evidence of hyperphagia (excessive hunger, and an abnormally large food intake).

These animals were also “extremely” overweight in comparison to healthy mice on a high-fat diet, the study reported, suggesting this increase is not due simply to diet, but to a deficiency in the MeCP2 protein.

The main cause of obesity in Rett syndrome mice fed this diet was a significant rise in calorie intake, indicating that there might be a dysregulation in brain networks that control feeding behavior. In fact, researchers found that Rett syndrome mice had higher levels of the agouti-related peptide — a protein that works to increase appetite, and decrease metabolism and energy expenditure.

Levels of proopiomelanocortin, a small protein that plays a role in suppressing food intake, were also found to be lower-than-usual in Rett syndrome mice on this diet. And the mice had high levels of the hormone leptin, which plays a major role in appetite and satiety in the hypothalamus.

“Based on these results, we propose that an increase in calorie intake under the [high fat diet] condition was the inducible cause of the extreme obesity in Mecp2^+/- [Rett syndrome] mice since there was no difference in body weight and calorie intake between Mecp2^+/-– ND [normal diet] and WT-ND [healthy or wild-type, normal diet] mice,” the scientists said.

Rett syndrome mice also significantly preferred the high-fat diet over a normal diet. The researchers found that gene expression changes in the dopamine reward circuitry were responsible for this preference, leading to addiction-like eating behavior.

“Based on our results, we consider the hypothesis that the easy access to palatable high-fat foods in the modern lifestyle could induce early-onset obesity in humans with [Rett syndrome],” the researchers concluded.