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. 2022 Feb 17;12(1):66.
doi: 10.1038/s41398-022-01824-1.

Metabolic effects of the schizophrenia-associated 3q29 deletion

Rebecca M Pollak  1 , Ryan H Purcell  2   3 , Timothy P Rutkowski  4 , Tamika Malone  4 , Kimberly J Pachura  5 , Gary J Bassell  2   3 , Michael P Epstein  4 , Paul A Dawson  5 , Matthew R Smith  6 , Dean P Jones  6 , Michael E Zwick  7 , Stephen T Warren  4   5   8 , Tamara Caspary  4 , David Weinshenker  4 , Jennifer G Mulle  9   10
Affiliations

Metabolic effects of the schizophrenia-associated 3q29 deletion

Rebecca M Pollak et al. Transl Psychiatry. .

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.

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Conflict of interest statement

The authors report no competing interests.

Figures

Fig. 1
Fig. 1. Experimental approach to interrogating the effect of the B6.Del16+/Bdh1-Tfrc genotype on metabolism and the effect of sex on 3q29 deletion-associated metabolic phenotypes.
All experiments were performed on male and female animals, and the sexes were analyzed separately. Animals were fed either standard diet chow (STD) or high-fat diet chow (HFD) from week 3 to week 20. Animals were weighed weekly from week 1 to week 16; STD weights were previously published by our group [40]. At week 16, a subset of STD- and HFD-treated animals was subjected to indirect calorimetry to assess feeding behavior and metabolic function. At the conclusion of indirect calorimetry, liver tissue was collected for untargeted metabolomics analysis. From weeks 16–20, another subset of STD- and HFD-treated animals was subjected to a behavioral battery.
Fig. 2
Fig. 2. Reduced energy expenditure and respiratory exchange ratio in B6.Del16+/Bdh1-Tfrc mice.
A and B Energy expenditure for A male (n = 12 WT, 7 B6.Del16+/Bdh1-Tfrc) and B female (n = 14 WT, 12 B6.Del16+/Bdh1-Tfrc) mice on the STD over 5 days in CLAMS/Metabolic Cages. C and D RER curves for C male and D female WT and B6.Del16+/Bdh1-Tfrc mice on the STD over 5 days in CLAMS/Metabolic Cages. Data are represented as mean ± SEM. *p < 0.05; **p < 0.01; ***p < 0.001 Statistical analysis was performed using generalized linear models.
Fig. 3
Fig. 3. Untargeted metabolomics reveals metabolite alterations in B6.Del16+/Bdh1-Tfrc mice that are highly sex-dependent.
A Comparison of all nominally significant metabolomic features between the male and female datasets. Up arrows indicate metabolites significantly upregulated in B6.Del16+/Bdh1-Tfrc samples, down arrows indicate metabolites significantly downregulated in B6.Del16+/Bdh1-Tfrc samples. Also refer to Supplement. B and C Hierarchical clustering of B male (n = 12 WT, 7 B6.Del16+/Bdh1-Tfrc) and C) female (n = 14 WT, 12 B6.Del16+/Bdh1-Tfrc) samples using the top 250 ranked metabolomic features. D and E Altered pathways in B6.Del16+/Bdh1-Tfrc mice identified via pathway enrichment analysis of D male and E female datasets. Dashed line denotes statistical significance.
Fig. 4
Fig. 4. A high-fat diet reduces the B6.Del16+/Bdh1-Tfrc weight deficit and affects RER in a sex-specific manner.
A, B 16-week growth curves for HFD-treated (A) male (n = 50 WT, 30 B6.Del16+/Bdh1-Tfrc) and B female (n = 42 WT, 32 B6.Del16+/Bdh1-Tfrc) mice. C and D RER curves for C male (n = 10 WT, 10 B6.Del16+/Bdh1-Tfrc) and D female (n = 10 WT, 10 B6.Del16+/Bdh1-Tfrc) mice on the HFD over 5 days in CLAMS/Metabolic Cages. Data are represented as mean ± SEM. n.s., p > 0.05; *p < 0.05; **p < 0.01; ***p < 0.001 Statistical analysis of growth curves (A, B) was performed using generalized estimating equations. Statistical analysis of RER (C, D) was performed using generalized linear models.
Fig. 5
Fig. 5. Widespread changes in the global metabolic environment of B6.Del16+/Bdh1-Tfrc mice after HFD challenge.
A Comparison of all nominally significant metabolomic features between the HFD-treated male and female datasets. Up arrows indicate metabolites significantly upregulated in B6.Del16+/Bdh1-Tfrc samples, down arrows indicate metabolites significantly downregulated in B6.Del16+/Bdh1-Tfrc samples. Also refer to Supplement. B and C Hierarchical clustering of HFD-treated (B) male (n = 10 WT, 10 B6.Del16+/Bdh1-Tfrc) and C female (n = 10 WT, 10 B6.Del16+/Bdh1-Tfrc) samples using the top 250 ranked metabolomic features. D and E Altered pathways in HFD-treated B6.Del16+/Bdh1-Tfrc mice identified via pathway enrichment analysis of D male and E female datasets. Dashed line denotes statistical significance. Bold text denotes pathways that were identified in both the STD and HFD experiments. F and G Comparison of nominally significant annotated features between STD-treated and HFD-treated (F) male and G female datasets. Up arrows indicate metabolites significantly upregulated in B6.Del16+/Bdh1-Tfrc samples, down arrows indicate metabolites significantly downregulated in B6.Del16+/Bdh1-Tfrc samples. Also refer to Supplement.
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