Genetic, metabolic, and molecular insights into the diverse outcomes of diet-induced obesity in mice
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Evaluation Summary:
In the present study, Bachmann and Morel et al., report a comprehensive survey of metabolic phenotypes and liver outcomes (gene expression, complex activities) in a unique subset of genetically diverse mouse strains. The authors focus on sex- and diet-dependent effects where notable differences are observed. These data will be a useful reference source for those interested in diet effects on metabolic phenotypes across various inbred mouse strains.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)
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Abstract
Overweight and obesity are increasingly common public health issues worldwide, leading to a wide range of diseases from metabolic syndrome to steatohepatitis and cardiovascular diseases. While the increase in the prevalence of obesity is partly attributable to changes in lifestyle (i.e. increased sedentarity and changes in eating behaviour), the metabolic and clinical impacts of these obesogenic conditions varies between sexes and genetic backgrounds. The conception of personalised treatments of obesity and its complications require a thorough understanding of the diversity of responses to conditions such as high-fat diet intake. By analysing nine genetically diverse mouse strains, we show that much like humans, mice respond to high-fat diet in a genetic- and sex-dependent manner. Physiological and molecular responses to high-fat diet are associated with expression of genes involved in immunity and mitochondrial function. Finally, we find that mitochondrial function may explain part of the diversity of physiological responses. By exploring the complex interactions between genetics and metabolic phenotypes via gene expression and molecular traits, we shed light on the importance of genetic background and sex in determining metabolic outcomes. In addition to providing the community with an extensive resource for optimizing future experiments, our work serves as an exemplary design for more generalizable translational studies.
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Evaluation Summary:
In the present study, Bachmann and Morel et al., report a comprehensive survey of metabolic phenotypes and liver outcomes (gene expression, complex activities) in a unique subset of genetically diverse mouse strains. The authors focus on sex- and diet-dependent effects where notable differences are observed. These data will be a useful reference source for those interested in diet effects on metabolic phenotypes across various inbred mouse strains.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)
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Reviewer #1 (Public Review):
In the present study, Bachmann and Morel et al., report a comprehensive survey of metabolic phenotypes and liver outcomes (gene expression, complex activities) in a unique subset of genetically diverse mouse strains. The authors focus on sex- and diet-dependent effects where notable differences are observed. The study is particularly appealing in that many gene x sex or gene x diet impacts are described; however, is also highly descriptive in nature.
Broadly, this reviewer's opinion is that the study was carefully designed and that potentially metabolically-relevant information is available, but is not apparent in the present manuscript. The authors successfully highlighted areas of diet- and sex-specific impacts and pointed out several important process while much remains to be described.
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Reviewer #2 (Public Review):
The authors compared the 8 mouse strains of the collaborative cross plus DBA, which they have studied extensively as part of their work with the BXD recombinant inbred strain panel. This is a high-altitude view comprising whole-animal phenotypes (glucose tolerance, body weight, RER, exercise tolerance), liver mitochondrial function as assessed by citrate synthase activity and electron transfer complex activities, and liver transcriptomics. They observed strong sex effects, and somewhat weaker strain effects on the phenotypes. Interestingly, there were stronger sex effects on the liver transcriptome than on the physiological phenotypes.
Correlation analysis showed that some of the phenotypes were correlated with sex while others were correlated with strain. Complex I and V activities were negatively …
Reviewer #2 (Public Review):
The authors compared the 8 mouse strains of the collaborative cross plus DBA, which they have studied extensively as part of their work with the BXD recombinant inbred strain panel. This is a high-altitude view comprising whole-animal phenotypes (glucose tolerance, body weight, RER, exercise tolerance), liver mitochondrial function as assessed by citrate synthase activity and electron transfer complex activities, and liver transcriptomics. They observed strong sex effects, and somewhat weaker strain effects on the phenotypes. Interestingly, there were stronger sex effects on the liver transcriptome than on the physiological phenotypes.
Correlation analysis showed that some of the phenotypes were correlated with sex while others were correlated with strain. Complex I and V activities were negatively correlated with body fat and positively correlated with VO2 max and running distance.
This study, while providing valuable reference information for 9 mouse strains and their response to diet, did not make major mechanistic discoveries, but likely will be followed up with such studies. Many of the correlations have been observed in other mouse studies, including ones from the authors' laboratory.
The provision of the high-volume data in the form of a user-friendly web site is a very useful contribution to the community and may motivate laboratories studying metabolism in mice to make better informed choices of mouse strains for the study of particular phenotypes and genes.
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Reviewer #3 (Public Review):
In an effort to disentangle the complexity of obesity in mammals this group has studied a range of metabolic phenotypes in 9 different inbred mouse strains. Importantly, 8 of the 9 strains are the founder strains that were used to construct the Collaborative Cross, an invaluable mouse panel that was constructed a number of years ago to study the genetics of complex phenotypes. This study involves males and females from each strain exposed to either a chow mouse diet or a western diet (WD) for about 13 weeks. The study shows that much like humans, mice respond to high-fat diet in a genetic- and gender dependent manner. For example, some animals put on a lot of weight in response to the WD while others do not. Some develop insulin resistance while others are seemingly protected. In an effort to get to the …
Reviewer #3 (Public Review):
In an effort to disentangle the complexity of obesity in mammals this group has studied a range of metabolic phenotypes in 9 different inbred mouse strains. Importantly, 8 of the 9 strains are the founder strains that were used to construct the Collaborative Cross, an invaluable mouse panel that was constructed a number of years ago to study the genetics of complex phenotypes. This study involves males and females from each strain exposed to either a chow mouse diet or a western diet (WD) for about 13 weeks. The study shows that much like humans, mice respond to high-fat diet in a genetic- and gender dependent manner. For example, some animals put on a lot of weight in response to the WD while others do not. Some develop insulin resistance while others are seemingly protected. In an effort to get to the bottom of these discrepancies an extensive analysis of liver gene expression is undertaken. This shows that western diet feeding is associated with expression of genes involved in immunity and protein translation. Mitochondrial function was also assessed and this was also found to vary between strains. These studies shed light on the importance of genetic background and sex in determining metabolic outcomes.
The Shiny App described in the paper is likely to provide an invaluable resource for the community although it is a pity that all phenotypes were not housed within this resource. These studies add to the growing literature that shows that the metabolic response to diet in mammals is highly complex and they foreshadow how difficult it will be to study this in humans where it is so difficult to control environmental factors by comparison to mouse. While the studies are of high quality and the manuscript is well written, the manuscript lacks a clear and simple message or conclusion. Another major limitation is that the molecular analysis involved studies in liver, a major player in whole body metabolic homeostasis, yet there were no specific liver metabolic phenotypes that enabled a solid correlative analysis of these data.
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