Container-aided Integrative QTL and RNA-seq Analysis of Collaborative Cross Mice Supports Distinct Sex-Oriented Molecular Modes of Response in Obesity

Abstract Background: The CC mouse population is a valuable resource to study the genetic basis of complex traits, such as obesity. Although the development of obesity is influenced by environmental factors, the underlying genetic mechanisms play a crucial role in the response to these factors. The interplay between the genetic background and the gene expression pattern can provide further insight into this response, but we lack robust and easily reproducible workflows to integrate genomic and transcriptomic information in the CC mouse population. Results: We established an automated and reproducible integrative workﬂow to analyse complex traits in the CC mouse genetic reference panel at the genomic and transcriptomic levels. We implemented the analytical workﬂow to assess the underlying genetic mechanisms of host susceptibility to diet induced obesity and integrate these results with diet induced changes in the hepatic gene expression of susceptible and resistant mice. Hepatic gene expression diﬀers signiﬁcantly between obese and non-obese mice, with a signiﬁcant sex eﬀect, where male and female mice exhibit diﬀerent responses and coping mechanisms. Conclusion: Integration of the data showed that diﬀerent genes but similar pathways are involved in the genetic susceptibility and disturbed in diet induced obesity. Genetic mechanisms underlying susceptibility to high-fat diet induced obesity diﬀer in female and male mice. The clear distinction we observe in the systemic response to the high-fat diet challenge and to obesity between male and female mice points to the need for further research into distinct sex-related mechanisms in metabolic disease.

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Container-aided integrative QTL and RNA-seq analysis of Collaborative Cross mice supports distinct sex-oriented molecular modes of response in obesity

BMC Genomics ◽

10.1186/s12864-020-07173-x ◽

2020 ◽

Vol 21 (1) ◽

Author(s):

Ilona Binenbaum ◽

Hanifa Abu-Toamih Atamni ◽

Georgios Fotakis ◽

Georgia Kontogianni ◽

Theodoros Koutsandreas ◽

...

Keyword(s):

Gene Expression ◽

High Fat Diet ◽

Complex Traits ◽

Hepatic Gene Expression ◽

High Fat ◽

Mouse Population ◽

Male And Female ◽

Female Mice ◽

Diet Induced Obesity ◽

Genetic Mechanisms

Abstract Background The Collaborative Cross (CC) mouse population is a valuable resource to study the genetic basis of complex traits, such as obesity. Although the development of obesity is influenced by environmental factors, underlying genetic mechanisms play a crucial role in the response to these factors. The interplay between the genetic background and the gene expression pattern can provide further insight into this response, but we lack robust and easily reproducible workflows to integrate genomic and transcriptomic information in the CC mouse population. Results We established an automated and reproducible integrative workflow to analyse complex traits in the CC mouse genetic reference panel at the genomic and transcriptomic levels. We implemented the analytical workflow to assess the underlying genetic mechanisms of host susceptibility to diet induced obesity and integrated these results with diet induced changes in the hepatic gene expression of susceptible and resistant mice. Hepatic gene expression differs significantly between obese and non-obese mice, with a significant sex effect, where male and female mice exhibit different responses and coping mechanisms. Conclusion Integration of the data showed that different genes but similar pathways are involved in the genetic susceptibility and disturbed in diet induced obesity. Genetic mechanisms underlying susceptibility to high-fat diet induced obesity are different in female and male mice. The clear distinction we observed in the systemic response to the high-fat diet challenge and to obesity between male and female mice points to the need for further research into distinct sex-related mechanisms in metabolic disease.

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Container-aided Integrative QTL and RNA-seq Analysis of Collaborative Cross Mice Supports Distinct Sex-Oriented Molecular Modes of Response in Obesity

10.21203/rs.2.13505/v2 ◽

2020 ◽

Author(s):

Ilona Binenbaum ◽

Hanifa Abu-Toamih Atamni ◽

Georgios Fotakis ◽

Georgia Kontogianni ◽

Theodoros Koutsandreas ◽

...

Keyword(s):

Gene Expression ◽

High Fat Diet ◽

Complex Traits ◽

Hepatic Gene Expression ◽

High Fat ◽

Mouse Population ◽

Male And Female ◽

Female Mice ◽

Diet Induced Obesity ◽

Genetic Mechanisms

Abstract Background: The CC mouse population is a valuable resource to study the genetic basis of complex traits, such as obesity. Although the development of obesity is influenced by environmental factors, the underlying genetic mechanisms play a crucial role in the response to these factors. The interplay between the genetic background and the gene expression pattern can provide further insight into this response, but we lack robust and easily reproducible workflows to integrate genomic and transcriptomic information in the CC mouse population. Results: We established an automated and reproducible integrative workﬂow to analyse complex traits in the CC mouse genetic reference panel at the genomic and transcriptomic levels. We implemented the analytical workﬂow to assess the underlying genetic mechanisms of host susceptibility to diet induced obesity and integrate these results with diet induced changes in the hepatic gene expression of susceptible and resistant mice. Hepatic gene expression diﬀers signiﬁcantly between obese and non-obese mice, with a signiﬁcant sex eﬀect, where male and female mice exhibit diﬀerent responses and coping mechanisms. Conclusion: Integration of the data showed that diﬀerent genes but similar pathways are involved in the genetic susceptibility and disturbed in diet induced obesity. Genetic mechanisms underlying susceptibility to high-fat diet induced obesity diﬀer in female and male mice. The clear distinction we observe in the systemic response to the high-fat diet challenge and to obesity between male and female mice points to the need for further research into distinct sex-related mechanisms in metabolic disease.

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Carbonyl Reductase 1 Overexpression in Adipose Amplifies Local Glucocorticoid Action and Impairs Glucose Tolerance in Lean Mice

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.1639 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A806-A806

Author(s):

Rachel Bell ◽

Elisa Villalobos ◽

Mark Nixon ◽

Allende Miguelez-Crespo ◽

Matthew Sharp ◽

...

Keyword(s):

Adipose Tissue ◽

Glucose Tolerance ◽

Fat Mass ◽

High Fat Diet ◽

Fasting Glucose ◽

High Fat ◽

Male And Female ◽

Over Expression ◽

Female Mice ◽

Diet Induced Obesity

Abstract Glucocorticoids play a critical role in metabolic homeostasis. Chronic or excessive activation of the glucocorticoid receptor (GR) in adipose tissue contributes to metabolic disorders such as glucose intolerance and insulin resistance. Steroid-metabolising enzymes in adipose, such as 11β-HSD1 or 5α-reductase, modulate the activation of GR by converting primary glucocorticoids into more or less potent ligands. Carbonyl reductase 1 (CBR1) is a novel regulator of glucocorticoid metabolism, converting corticosterone/cortisol to 20β-dihydrocorticosterone/cortisol (20β-DHB/F); a metabolite which retains GR activity. CBR1 is abundant in adipose tissue and increased in obese adipose of mice and humans1 and increased Cbr1 expression is associated with increased fasting glucose1. We hypothesised that increased Cbr1/20β-DHB in obese adipose contributes to excessive GR activation and worsens glucose tolerance. We generated a novel murine model of adipose-specific Cbr1 over-expression (R26-Cbr1Adpq) by crossing conditional knock-in mice with Adiponectin-Cre mice. CBR1 protein and activity were doubled in subcutaneous adipose tissue of male and female R26-Cbr1Adpq mice compared with floxed controls; corresponding to a two-fold increase 20β-DHB (1.6 vs. 4.2ng/g adipose; P=0.0003; n=5-7/group). There were no differences in plasma 20β-DHB or corticosterone. Bodyweight, lean or fat mass, did not differ between male or female R26-Cbr1Adpq mice and floxed controls. Lean male R26-Cbr1Adpq mice had higher fasting glucose (9.5±0.3 vs. 8.4±0.3mmol/L; P=0.04) and worsened glucose tolerance (AUC 1819±66 vs. 1392±14; P=0.03). Female R26-Cbr1Adpq mice also had a worsened glucose tolerance but fasting glucose was not altered with genotype. There were no differences in fasting insulin or non-esterified fatty acid between genotypes in either sex. Expression of GR-induced genes Pnpla2, Gilz and Per1, were increased in adipose of R26-Cbr1Adpq mice. Following high-fat diet induced obesity, no differences in bodyweight, lean or fat mass, with genotype were observed in male and female mice, and genotype differences in fasting glucose and glucose tolerance were abolished. In conclusion, adipose-specific over-expression of Cbr1 in lean male and female mice led to increased levels of 20β-DHB in adipose but not plasma, and both sexes having worsened glucose tolerance. The influence of adipose CBR1/20β-DHB on glucose tolerance was not associated with altered fat mass or bodyweight and was attenuated by high-fat diet-induced obesity. These metabolic consequences of Cbr1 manipulation require careful consideration given the wide variation in CBR1 expression in the human population, the presence of inhibitors and enhancers in many foodstuffs and the proposed use of inhibitors as an adjunct for cancer treatment regimens. Reference: Morgan et al., Scientific Reports. 2017; 7.

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Hepatic gene expression profiles in a long-term high-fat diet-induced obesity mouse model

Gene ◽

10.1016/j.gene.2004.06.015 ◽

2004 ◽

Vol 340 (1) ◽

pp. 99-109 ◽

Cited By ~ 172

Author(s):

Sujong Kim ◽

Insuk Sohn ◽

Joon-Ik Ahn ◽

Ki-Hwan Lee ◽

Yeon Sook Lee ◽

...

Keyword(s):

Gene Expression ◽

Mouse Model ◽

High Fat Diet ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Hepatic Gene Expression ◽

High Fat ◽

Diet Induced Obesity

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Effects of Lingonberry (Vaccinium vitis-idaea L.) Supplementation on Hepatic Gene Expression in High-Fat Diet Fed Mice

Nutrients ◽

10.3390/nu13113693 ◽

2021 ◽

Vol 13 (11) ◽

pp. 3693

Author(s):

Riitta Ryyti ◽

Antti Pemmari ◽

Rainer Peltola ◽

Mari Hämäläinen ◽

Eeva Moilanen

Keyword(s):

Gene Expression ◽

High Fat Diet ◽

Phenotypic Change ◽

Hepatic Gene Expression ◽

High Fat ◽

Nonalcoholic Fatty Liver ◽

Glucose And Lipid Metabolism ◽

Diet Induced Obesity ◽

Intervention Trials ◽

Cycle Regulation

The prevalence of nonalcoholic fatty liver disease (NAFLD) is growing worldwide in association with Western-style diet and increasing obesity. Lingonberry (Vaccinium vitis-idaea L.) is rich in polyphenols and has been shown to attenuate adverse metabolic changes in obese liver. This paper investigated the effects of lingonberry supplementation on hepatic gene expression in high-fat diet induced obesity in a mouse model. C57BL/6N male mice were fed for six weeks with either a high-fat (HF) or low-fat (LF) diet (46% and 10% energy from fat, respectively) or HF diet supplemented with air-dried lingonberry powder (HF + LGB). HF diet induced a major phenotypic change in the liver, predominantly affecting genes involved in inflammation and in glucose and lipid metabolism. Lingonberry supplementation prevented the effect of HF diet on an array of genes (in total on 263 genes) associated particularly with lipid or glucose metabolic process (such as Mogat1, Plin4, Igfbp2), inflammatory/immune response or cell migration (such as Lcn2, Saa1, Saa2, Cxcl14, Gcp1, S100a10) and cell cycle regulation (such as Cdkn1a, Tubb2a, Tubb6). The present results suggest that lingonberry supplementation prevents HF diet-induced adverse changes in the liver that are known to predispose the development of NAFLD and its comorbidities. The findings encourage carrying out human intervention trials to confirm the results, with the aim of recommending the use of lingonberries as a part of healthy diet against obesity and its hepatic and metabolic comorbidities.

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Glutaredoxin1 knockout promotes high-fat diet-induced obesity in male mice but not in female ones

Food & Function ◽

10.1039/d1fo01241j ◽

2021 ◽

Author(s):

Xiao yu Zou ◽

Muhammad Ijaz Ahmad ◽

Di Zhao ◽

Min Zhang ◽

Chunbao Li

Keyword(s):

High Fat Diet ◽

Calorie Intake ◽

Male Mice ◽

High Fat ◽

Male And Female ◽

Female Mice ◽

Diet Induced Obesity

This study aims to explore how high-fat diet and glutaredoxin1 (Glrx1) deficiency affect the development of obesity in male and female mice. High-fat diet induced great differences in calorie intake...

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