Deep phenotyping and multi-omics analyses reveal systems-wide metabolic dysregulation in a refined trisomy mouse model of Down syndrome
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eLife Assessment
This valuable study provides a comprehensive metabolic and multi-omics characterization of the Ts66Yah mouse model of Down syndrome, identifying widespread metabolic, inflammatory, and molecular alterations that may help explain metabolic features observed in individuals with Down syndrome. The evidence supporting the authors' conclusions is solid, based on extensive physiological, molecular, and systems-level analyses in both male and female mice, although interpretations of sex-specific metabolic phenotypes and cross-model comparisons would benefit from additional clarification. The work will be of interest to researchers studying Down syndrome biology, metabolism, and the development and application of preclinical disease models.
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Abstract
Trisomy 21 or Down syndrome (DS) affects multi-organ systems across the lifespan. The presence of an extra chromosome, along with genome dosage imbalance due to triplicated genes, contributes to the DS phenotypes. Of the DS mouse models, few are aneuploid with a freely segregating extra chromosome. We previously showed that the aneuploid Ts65Dn mice exhibit metabolic deficits consistent with the metabolic profile of DS. However, the genotype-phenotype relationships in Ts65Dn mice are complicated by the presence of triplicated genes unrelated to human chromosome 21 (Hsa21). To address this issue, we leveraged a refined model, Ts66Yah, where the extra triplicated genes in Ts65Dn have been removed. Deep phenotyping and multi-omics analyses showed that Ts66Yah mice develop pronounced and widespread metabolic disturbances. Despite sexual dimorphism in weight gain, body temperature, lipid and lipoprotein profiles, hepatic injury and adipose fibrosis, both male and female Ts66Yah mice share a common phenotype of pronounced glucose intolerance and insulin resistance, reduced mitochondrial respiratory capacity in visceral fat, altered serum inflammatory cytokine profile, and dysregulated serum and liver metabolomes. Pan-tissue transcriptomes also reveal signatures of immune activation, disrupted metabolic processes and cellular respiration, altered cytokine signaling, enhanced oxidative stress, and extracellular matrix remodeling. These combined changes across tissues disrupt metabolic homeostasis more severely in Ts66Yah than in Ts65Dn mice. Several phenotypes, including glucose intolerance, insulin resistance, tissue fibrosis, and oxidative stress were further exacerbated by an obesogenic diet. This foundational data establishes Ts66Yah as a valuable reference model for the mechanistic and comparative study of metabolic dysfunction in DS.
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eLife Assessment
This valuable study provides a comprehensive metabolic and multi-omics characterization of the Ts66Yah mouse model of Down syndrome, identifying widespread metabolic, inflammatory, and molecular alterations that may help explain metabolic features observed in individuals with Down syndrome. The evidence supporting the authors' conclusions is solid, based on extensive physiological, molecular, and systems-level analyses in both male and female mice, although interpretations of sex-specific metabolic phenotypes and cross-model comparisons would benefit from additional clarification. The work will be of interest to researchers studying Down syndrome biology, metabolism, and the development and application of preclinical disease models.
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Reviewer #1 (Public review):
Summary and Strengths:
In this manuscript, the authors continue their efforts to characterize metabolism-related phenotypes and molecular changes in Down syndrome mouse models, with a focus on Ts66Yah in the present study. Because the phenotypes described are relevant to metabolic abnormalities observed in individuals with Down syndrome, these findings are important. In addition, Ts66Yah is a relatively new model generated by removing the triplicated region of Mmu17 from Ts65Dn, which is not syntenic to Hsa21. Thus, Ts66Yah retains the triplicated region of Mmu16 that is syntenic to a region of Hsa21, carried on an extra chromosome.
Weaknesses:
(1) Figure 3 and Figure 10: The authors should offer a possible explanation for why the GTT and ITT differences between Ts66Yah and wild-type males observed under …
Reviewer #1 (Public review):
Summary and Strengths:
In this manuscript, the authors continue their efforts to characterize metabolism-related phenotypes and molecular changes in Down syndrome mouse models, with a focus on Ts66Yah in the present study. Because the phenotypes described are relevant to metabolic abnormalities observed in individuals with Down syndrome, these findings are important. In addition, Ts66Yah is a relatively new model generated by removing the triplicated region of Mmu17 from Ts65Dn, which is not syntenic to Hsa21. Thus, Ts66Yah retains the triplicated region of Mmu16 that is syntenic to a region of Hsa21, carried on an extra chromosome.
Weaknesses:
(1) Figure 3 and Figure 10: The authors should offer a possible explanation for why the GTT and ITT differences between Ts66Yah and wild-type males observed under chow conditions are no longer evident under HFD conditions. The statement in the Abstract that "both male and female Ts66Yah mice share a common phenotype of pronounced glucose intolerance and insulin resistance" appears stronger than the data support. Under chow conditions, impaired insulin sensitivity by ITT is observed in males but not females. Moreover, although the Abstract states that glucose intolerance and insulin resistance are further exacerbated by HFD, the GTT and ITT abnormalities under HFD appear to be predominantly observed in females, whereas the genotype differences are no longer evident in males. The Abstract should therefore be revised to more accurately reflect these sex- and diet-dependent effects.
(2) Figure 7B: In the female liver PCA plot, PC1 is labeled as explaining 13.2% of the variance, whereas PC2 explains 21.6%. Since principal components are ordered by decreasing explained variance, PC1 should explain greater variance than PC2. The authors should verify whether the axis labels or percentages are correct.
(3) Figure 14 legend: A cutoff of log2FC > 0 was used, whereas Figure 8 uses a log2FC cutoff of 0.5. The authors should explain the rationale for using different thresholds in the two analyses.
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Reviewer #2 (Public review):
Summary:
The authors of Saqib et al "Deep phenotyping and multi-omics analyses reveal systems-wide metabolic dysregulation in a refined trisomy mouse model of Down syndrome" were testing the hypothesis that metabolic dysregulation in Ts66Yah Down syndrome model, as compared to euploid mice, would replicate metabolic dysregulation in individuals with DS. The authors then compared the results from Ts66Yah mice in the present study mostly with results from Ts65Dn and Dp1Yey mice, where they had reported metabolic differences in previous studies.
Strengths:
Strengths of the methods and results include multiple phenotypes examining potential metabolic differences, analysis of male and female mice separately with appropriate numbers of mice (power), and the ability to compare the results to other DS mouse models, …
Reviewer #2 (Public review):
Summary:
The authors of Saqib et al "Deep phenotyping and multi-omics analyses reveal systems-wide metabolic dysregulation in a refined trisomy mouse model of Down syndrome" were testing the hypothesis that metabolic dysregulation in Ts66Yah Down syndrome model, as compared to euploid mice, would replicate metabolic dysregulation in individuals with DS. The authors then compared the results from Ts66Yah mice in the present study mostly with results from Ts65Dn and Dp1Yey mice, where they had reported metabolic differences in previous studies.
Strengths:
Strengths of the methods and results include multiple phenotypes examining potential metabolic differences, analysis of male and female mice separately with appropriate numbers of mice (power), and the ability to compare the results to other DS mouse models, which is very useful in selecting appropriate DS mouse models to test metabolic and other related phenotypes.
The authors have shown that Ts66Yah mice differ from euploid mice in many of their metabolic parameters. Male and female Ts66Yah mice have differing phenotypes in specific metabolic parameters, but the overall result of glucose intolerance, insulin resistance, altered inflammatory cytokines, and dysregulated serum and liver metabolomes is shared between male and female mice.
Weaknesses:
Weaknesses include how the data are presented. There are some questions about methodology that leave some doubt in the analyses. The comparisons of Ts66Yah to Ts65Dn and Dp1Yey mice are less convincing, mostly due to oversimplifying the genetic constructs of DS mouse models.
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Reviewer #3 (Public review):
The study by Saqib M. et al. aimed to develop a refined murine model for the study of Down syndrome. The authors developed a Ts66Yah murine line by removing triplicated genes using CRISPR technology from the previously developed Ts65Dn. In this study, the authors provide a deep metabolic profiling of the murine model, studying highly metabolic tissues (liver, skeletal muscle and adipose depots) in both sexes.
The major strength of the study is the large variety of metabolic assessments in males and females, identifying key dimorphic features in the model. However, this could also be considered a point of weakness since this is not a hypothesis-driven study, but rather a descriptive/exploratory study.
Due to the thorough description of the model and the metabolic profile, this study will be very useful for …
Reviewer #3 (Public review):
The study by Saqib M. et al. aimed to develop a refined murine model for the study of Down syndrome. The authors developed a Ts66Yah murine line by removing triplicated genes using CRISPR technology from the previously developed Ts65Dn. In this study, the authors provide a deep metabolic profiling of the murine model, studying highly metabolic tissues (liver, skeletal muscle and adipose depots) in both sexes.
The major strength of the study is the large variety of metabolic assessments in males and females, identifying key dimorphic features in the model. However, this could also be considered a point of weakness since this is not a hypothesis-driven study, but rather a descriptive/exploratory study.
Due to the thorough description of the model and the metabolic profile, this study will be very useful for people working on research in Down syndrome. However, there is a lack of information related to cognition, behaviour, and other key features relevant to Down syndrome that would need further study.
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Deep phenotyping and multi-omics analyses reveal systems-wide metabolic dysregulation in a refined trisomy mouse model of Down syndrome https://www.biorxiv.org/content/10.64898/2026.08.26.747201v1
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Deep phenotyping and multi-omics analyses reveal systems-wide metabolic dysregulation in a refined trisomy mouse model of Down syndrome https://www.biorxiv.org/content/10.64898/2026.08.26.747201v1
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