Gene dosage imbalance disrupts systemic metabolism in the Dp16 Down syndrome mouse model
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eLife Assessment
This article describes the comprehensive metabolic phenotype of a mouse model of Down Syndrome, together with supporting transcriptomic, metabolomic, and biochemical data. While the work is largely descriptive, the evidence presented is convincing and highlights similarities and differences in male and female mice. This is a valuable study that provides essential groundwork for the further genetic dissection of dosage-sensitive genes causing metabolic dysregulation in Down Syndrome.
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Abstract
Gene dosage imbalance resulting from an extra copy of human chromosome 21 (Hsa21) contributes to numerous clinical features in Down syndrome (DS). While dysregulated metabolism has long been noted in DS, the underlying cause is poorly understood and vastly understudied. To fill this critical knowledge gap, we conducted a comprehensive metabolic analysis of Dp(16)1Yey/+ mice (abbreviated Dp16), a segmental duplication model carrying a majority of the triplicated Hsa21 gene orthologs. Our multi-tissue transcriptomic analyses reveal shared and sex-specific increases in expression dosage of the triplicated genes in white and brown adipose tissues, liver, skeletal muscle, and hypothalamus. Despite sexual dimorphism in body weight, body temperature, food intake, and physical activity, Dp16 males and females share striking core phenotypes of pronounced insulin resistance, glucose intolerance, impaired lipid clearance, and dyslipidemia. Functional assessments, combined with biochemical, transcriptomic, and metabolomic analyses reveal tissue signatures of immune activation and a pro-inflammatory state, ER and oxidative stress, fibrosis, impaired glucose and fatty acid catabolism, altered lipid and bile acid profiles, and reduced mitochondrial respiration in Dp16 mice. These concerted changes disrupt homeostatic mechanisms that underpin metabolic health, contributing to systemic metabolic dysfunction. An obesogenic diet further exacerbates insulin resistance in Dp16 males and females despite divergent weight gain. The collective phenotypes broadly reflect the metabolic profile of DS. Our extensive molecular, biochemical, and physiological data provide an essential foundation for genetic dissection of dosage-sensitive genes affecting glucose and lipid metabolism, and for testing therapeutic strategies to improve metabolic outcomes in DS.
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eLife Assessment
This article describes the comprehensive metabolic phenotype of a mouse model of Down Syndrome, together with supporting transcriptomic, metabolomic, and biochemical data. While the work is largely descriptive, the evidence presented is convincing and highlights similarities and differences in male and female mice. This is a valuable study that provides essential groundwork for the further genetic dissection of dosage-sensitive genes causing metabolic dysregulation in Down Syndrome.
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Reviewer #1 (Public review):
Summary:
Chen et al. describe metabolic phenotypes in Dp16 Down Syndrome mice, specifically the Dp(16)1Yey/+ mice - segmental duplication model carrying a majority of the triplicated Hsa21 gene orthologs. The group has performed metabolic phenotyping data in chow and high-fat diets, as well as undertaking a transcriptomic and metabolomic approach in tissues such as white and brown adipose tissues, liver, skeletal muscle, and hypothalamus to reveal both shared and sex-specific differences. The group describes sexual dimorphism in body weight, body temperature, food intake, and physical activity. Core shared features are insulin resistance, glucose intolerance, impaired lipid clearance, and dyslipidaemia in the Dp16 mice. They report tissue signatures of immune activation and a pro-inflammatory state, ER and …
Reviewer #1 (Public review):
Summary:
Chen et al. describe metabolic phenotypes in Dp16 Down Syndrome mice, specifically the Dp(16)1Yey/+ mice - segmental duplication model carrying a majority of the triplicated Hsa21 gene orthologs. The group has performed metabolic phenotyping data in chow and high-fat diets, as well as undertaking a transcriptomic and metabolomic approach in tissues such as white and brown adipose tissues, liver, skeletal muscle, and hypothalamus to reveal both shared and sex-specific differences. The group describes sexual dimorphism in body weight, body temperature, food intake, and physical activity. Core shared features are insulin resistance, glucose intolerance, impaired lipid clearance, and dyslipidaemia in the Dp16 mice. They report tissue signatures of immune activation and a pro-inflammatory state, ER and oxidative stress, fibrosis, impaired glucose and fatty acid catabolism, altered lipid and bile acid profiles, and reduced mitochondrial respiration in Dp16 mice.
Strengths:
Overall, this is a good study with detailed, comprehensive data from an excellent group who have previously published on metabolic phenotyping of 2 other Down Syndrome mouse models. Although somewhat descriptive, it does certainly add to the current field and understanding of strengths and weaknesses of Down Syndrome mouse models, as well as identifying new features whilst strengthening previously suggested mechanisms.
Weaknesses:
Many aspects of this study have been described in other Down syndrome mouse models, though there are certainly aspects that are new. It would be useful if the authors could do a direct critique and comparison with previous publications in the area, utilising the same Down Syndrome mouse model. There are also a few limitations in the number of animals used and the interpretation of the data that should be acknowledged.
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Reviewer #2 (Public review):
Summary:
Human DS is associated with metabolic dysfunction in humans, but the precise details of this have not been studied in detail. Here, the authors use a mouse model of DS to study systemic metabolic and transcriptional responses in key metabolic tissues to provide a deep understanding of the metabolic changes associated with DS. As part of his work, the authors also aimed to help inform the selection of a mouse model that best reflects the metabolic profile of DS, through comparison with other DS model metabolic data.
The data presented in this model will be of interest to those in the field of metabolism. The immediate impact is unclear, but the breadth of data presented makes this a very useful resource.
Strengths:
(1) This work builds on other comprehensive analyses that the authors have performed …
Reviewer #2 (Public review):
Summary:
Human DS is associated with metabolic dysfunction in humans, but the precise details of this have not been studied in detail. Here, the authors use a mouse model of DS to study systemic metabolic and transcriptional responses in key metabolic tissues to provide a deep understanding of the metabolic changes associated with DS. As part of his work, the authors also aimed to help inform the selection of a mouse model that best reflects the metabolic profile of DS, through comparison with other DS model metabolic data.
The data presented in this model will be of interest to those in the field of metabolism. The immediate impact is unclear, but the breadth of data presented makes this a very useful resource.
Strengths:
(1) This work builds on other comprehensive analyses that the authors have performed in other DS mouse models.
(2) The authors note common metabolic disturbances between male and female mice (e.g., insulin resistance) alongside clearly sexually dimorphic phenotypes (e.g., body weight). Studying both sexes in this context is important.
(3) The authors have written the paper in a way that integrates a large number of observations well. There is complex data, and a high degree of sexual dimorphism. The study has generated a valuable and wide-ranging dataset comprising molecular, biochemical, and physiological data that will be useful for further, more mechanistic studies of metabolism in DS.
(4) For specific observations, like the findings of altered body temperature in male and female mice, the authors undertake follow-up hypothesis-driven analyses of BAT mitochondria and specific hormones. Although these analyses do not explain the change in temperature, they ensure the study is not purely descriptive in nature.
Weaknesses:
(1) Assessing metabolism using dynamic testing is a strength. ITT, GTT and LTTs are included.
(2) The dosing for GTTs, ITTs and LTTs was performed per body weight. But the mice under chow and HFD had different body weights. This may compromise the interpretation of the data. Further, ITTs are presented as percentage change, and this can be heavily influenced by baseline glucose measures. The changes appear quite dramatic, so can the authors plot the raw data instead?
(3) In addition, throughout the manuscript, it is not clear which tissues are the most dominant in disrupting metabolism. The ITT and GTT are composite measures across tissues. Tissue-specific analyses using a clamp technique or isolated tissues may provide more clarity here.
(4) One of the aims of the study was "to help inform the selection of mouse model that best reflects the metabolic profile of DS". The discussion does not contain a comparison between the previous work on different strains and relative to known human data.
(5) Data availability. Raw metabolomic data should be made available.
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Reviewer #3 (Public review):
Summary:
The article by Chen et al. describes the comprehensive metabolic profiling of DP16 mice, a Down syndrome model that carries a duplicated segment of the mouse chromosome syntenic to human chromosome 21. The authors note that this model is superior to previously used models, based on genetics, as ~65% of the chromosome 21 orthologues. The metabolic phenotypes also appear to be more consistent with those observed in humans with Down Syndrome. The study lays the groundwork for a more detailed genetic dissection of dosage-sensitive genes that contribute to the metabolic deficits observed in Down Syndrome.
Strengths:
There is an enormous amount of data in this manuscript, and the methods are described with adequate attention to detail. A strength of the manuscript is that both male and female mice were …
Reviewer #3 (Public review):
Summary:
The article by Chen et al. describes the comprehensive metabolic profiling of DP16 mice, a Down syndrome model that carries a duplicated segment of the mouse chromosome syntenic to human chromosome 21. The authors note that this model is superior to previously used models, based on genetics, as ~65% of the chromosome 21 orthologues. The metabolic phenotypes also appear to be more consistent with those observed in humans with Down Syndrome. The study lays the groundwork for a more detailed genetic dissection of dosage-sensitive genes that contribute to the metabolic deficits observed in Down Syndrome.
Strengths:
There is an enormous amount of data in this manuscript, and the methods are described with adequate attention to detail. A strength of the manuscript is that both male and female mice were analyzed, so that concordant and discordant phenotypes were identified. Both males and females had evidence of insulin resistance. Transcriptomic and metabolomic data revealed impaired pathways for lipid metabolism, a pro-inflammatory state, reduced mitochondrial health and oxidative stress. Although the effects of a high-fat diet on weight gain were divergent, this diet caused worsened insulin resistance in both males and females.
The discussion is excellent. Limitations of the study are well described. This reviewer does not identify any critical missing data.
Weaknesses:
It might have been helpful to have included blood pressure measurements, given the differences in 19-Nor-deoxycorticosterone. The discussion references several articles that describe sex-dependent differences in metabolic phenotypes in humans with Down syndrome, and it might have been helpful to state more explicitly whether these differences correlate with those observed here in mice.
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