Abstract
The 1.6 Mb 3q29 deletion is associated with developmental and psychiatric phenotypes, including a 40-fold increased risk for schizophrenia. Reduced birth weight and a high prevalence of feeding disorders in patients suggest underlying metabolic dysregulation. We investigated 3q29 deletion-induced metabolic changes using our previously generated heterozygous B6.Del16+/Bdh1-Tfrc mouse model. Animals were provided either standard chow (STD) or high-fat diet (HFD). Growth curves were performed on HFD mice to assess weight change (n = 30–50/group). Indirect calorimetry and untargeted metabolomics were performed on STD and HFD mice to evaluate metabolic phenotypes (n = 8–14/group). A behavioral battery was performed on STD and HFD mice to assess behavior change after the HFD challenge (n = 5–13/group). We found that B6.Del16+/Bdh1-Tfrc animals preferentially use dietary lipids as an energy source. Untargeted metabolomics of liver tissue showed a strong sex-dependent effect of the 3q29 deletion on fat metabolism. A HFD partially rescued the 3q29 deletion-associated weight deficit in females, but not males. Untargeted metabolomics of liver tissue after HFD revealed persistent fat metabolism alterations in females. The HFD did not affect B6.Del16+/Bdh1-Tfrc behavioral phenotypes, suggesting that 3q29 deletion-associated metabolic and behavioral outcomes are uncoupled. Our data suggest that dietary interventions to improve weight phenotypes in 3q29 deletion syndrome patients are unlikely to exacerbate behavioral manifestations. Our study also highlights the importance of assessing sex in metabolic studies and suggests that mechanisms underlying 3q29 deletion-associated metabolic phenotypes are sex-specific.
Highlights
There is growing evidence that metabolic alterations can contribute to neurodevelopmental and neuropsychiatric diseases
Energy expenditure was similar between wild type (WT) and B6.Del16+/Bdh1-Tfrc males (Fig. 2A); in females, energy expenditure was reduced in B6.Del16+/Bdh1-Tfrc animals relative to WT (Fig. 2B)
We evaluated the respiratory exchange ratio (RER) to understand macronutrient metabolism
Summary
There is growing evidence that metabolic alterations can contribute to neurodevelopmental and neuropsychiatric diseases. Mitochondrial function, oxidative stress, and small molecule dysregulation have been implicated in the pathogenesis of idiopathic autism spectrum disorder (ASD), bipolar disorder, major depression, and schizophrenia (SZ) [16,17,18,19,20,21,22,23,24,25], highlighting some etiological similarities between syndromic and idiopathic cases of neuropsychiatric disorders. In light of these data, we sought to investigate the link between metabolism and neurodevelopmental/psychiatric liability, using the 3q29 deletion as a model. Phenotype development in 3q29del and help to further elucidate the relationship between metabolism and neurodevelopmental and neuropsychiatric disease risk
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