Sleep in a mouse model of fragile X syndrome is resistant to metabolic manipulations

TL;DR

Mice with fragile X syndrome show sleep issues that are not improved by metformin or high-fat diets, suggesting their sleep problems are not caused by metabolism.

Contribution

The study reveals that sleep deficits in fragile X syndrome mice are not due to metabolic dysfunction, challenging prior assumptions.

Findings

Metformin did not improve sleep in Fmr1 knockout mice but increased their activity.

High-fat diets disrupted sleep in controls but not in Fmr1 knockout mice.

Fmr1 knockout mice showed similar glucose tolerance to wild type despite hyperphagia.

Abstract

Fragile X Syndrome is the most prevalent known genetic cause of intellectual disability (ID), affecting around 1 in 4 000 individuals, and is also highly associated with autism spectrum disorder (ASD). Humans with the disorder and animal models display sleep and metabolic abnormalities. Given growing evidence of links between sleep and metabolism, we sought to determine if metabolic abnormalities underlie sleep deficits in mice lacking the Fragile X messenger ribonucleoprotein 1 (FMR1) gene. We found that metformin, a drug that targets metabolic pathways and has been shown to alleviate other symptoms in FXS, did not rescue sleep in mutant mice. Instead, metformin enhanced activity of Fmr1 knockout (KO) mice. As a way of exaggerating possible metabolic phenotypes, we treated mice with a high fat diet (HFD) and found that although this disrupted the sleep pattern in controls, it did not impact the sleep phenotype in Fmr1 KOs. Increased sleep during the dark phase, caused by HFD in wild type animals, was alleviated by metformin treatment. Metformin also decreased weight gain of wild type animals on a HFD, but the effect was delayed in Fmr1 KO mice. Fmr1 KO mice with or without metformin treatment displayed hyperphagia on a HFD, yet did not show higher weight gain than wild type. And, surprisingly, their glucose tolerance was equivalent to that of wild type mice on metformin. We suggest that Fmr1 KO mice are better able to metabolize fat and so are relatively resistant to its negative effects on sleep and metabolism.

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