Estrogen Receptor Alpha Is Required to Protect Daily Metabolic Rhythms From Disruption by High-Fat Feeding in Female Mice

Abstract The circadian system is a critical regulator of obesity in male mice, but its role in females is poorly understood. In our previous studies we found that estrogen regulates daily rhythms in female mice to confer resistance to diet-induced obesity, but the mechanism is unknown. Estrogen signals via the classical estrogen receptor alpha (ERα) to regulate metabolism and obesity. Therefore, in this study we tested the hypothesis that estrogen regulates daily metabolic rhythms in females via ERα. To do so, we studied daily rhythms in female global ERα knockout (ERα KO) with the circadian reporter, PERIOD2::LUCIFERASE, mice fed high-fat diet for 6 weeks. ERα KO female mice became obese and hyperglycemic when fed high-fat diet, while wild-type females were resistant to diet-induced obesity. Chronic high-fat diet feeding also reduced the amplitude of the daily rhythm of eating behavior in ERα KO, but not wild-type, female mice. In wild-type females, the amplitude of the locomotor activity rhythm increased during high-fat feeding. In contrast, high-fat feeding decreased the amplitude of the activity rhythm in ERα KO females. The temporal relationship between central and peripheral circadian tissue clocks was disrupted by high-fat feeding in ERα KO females since the phase of the liver PERIOD2::LUCIFERASE rhythm was advanced 4 hours by high-fat feeding in ERα KO mice compared to wild-type females. Taken together these results show that estrogen signals via ERα to protect daily metabolic rhythms from disruption by high-fat feeding in female mice.

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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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Sex and BNIP3 genotype, rather than acute lipid injection, modulate hepatic mitochondrial function and steatosis risk in mice

Journal of Applied Physiology ◽

10.1152/japplphysiol.00035.2020 ◽

2020 ◽

Vol 128 (5) ◽

pp. 1251-1261

Author(s):

Kelly N. Z. Fuller ◽

Colin S. McCoin ◽

Julie Allen ◽

Shelby Bell-Glenn ◽

Devin C. Koestler ◽

...

Keyword(s):

Protein Expression ◽

Mitochondrial Function ◽

Mitochondrial Respiration ◽

High Fat Diet ◽

Wild Type ◽

High Fat ◽

Interacting Protein ◽

Female Mice ◽

Complex Protein ◽

Respiratory Outcomes

This is the first study focusing on hepatic mitochondrial respiratory outcomes in response to lipid overload via a high-fat diet (HFD) combined with intralipid injection. Novel findings include no effect of intralipid injection on mitochondrial outcomes of interest, despite increased circulating lipid concentrations. However, we report pronounced differences in hepatic mitochondrial respiration, complex protein expression, and H2O2 production by sex and BCL-2/adenovirus EIB 19-kDa interacting protein (BNIP3) genotype. Specifically, female mice had lower H2O2 emission globally and on an acute HFD, females had greater hepatic mitochondrial respiration than males, whereas BNIP3 knockout (KO) animals had greater mitochondrial coupling and complex protein expression than wild-type (WT) animals.

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Peroxisome Proliferator-Activated Receptor α Mediates the Effects of High-Fat Diet on Hepatic Gene Expression

Endocrinology ◽

10.1210/en.2005-1132 ◽

2006 ◽

Vol 147 (3) ◽

pp. 1508-1516 ◽

Cited By ~ 194

Author(s):

David Patsouris ◽

Janardan K. Reddy ◽

Michael Müller ◽

Sander Kersten

Keyword(s):

Fatty Acid ◽

Fatty Acid Oxidation ◽

Microarray Analysis ◽

High Fat Diet ◽

Acid Oxidation ◽

Peroxisome Proliferator ◽

Dependent Manner ◽

Wild Type ◽

High Fat ◽

Fat Feeding

Peroxisome proliferator-activated receptors (PPARs) are transcription factors involved in the regulation of numerous metabolic processes. The PPARα isotype is abundant in liver and activated by fasting. However, it is not very clear what other nutritional conditions activate PPARα. To examine whether PPARα mediates the effects of chronic high-fat feeding, wild-type and PPARα null mice were fed a low-fat diet (LFD) or high-fat diet (HFD) for 26 wk. HFD and PPARα deletion independently increased liver triglycerides. Furthermore, in wild-type mice HFD was associated with a significant increase in hepatic PPARα mRNA and plasma free fatty acids, leading to a PPARα-dependent increase in expression of PPARα marker genes CYP4A10 and CYP4A14. Microarray analysis revealed that HFD increased hepatic expression of characteristic PPARα target genes involved in fatty acid oxidation in a PPARα-dependent manner, although to a lesser extent than fasting or Wy14643. Microarray analysis also indicated functional compensation for PPARα in PPARα null mice. Remarkably, in PPARα null mice on HFD, PPARγ mRNA was 20-fold elevated compared with wild-type mice fed a LFD, reaching expression levels of PPARα in normal mice. Adenoviral overexpression of PPARγ in liver indicated that PPARγ can up-regulate genes involved in lipo/adipogenesis but also characteristic PPARα targets involved in fatty acid oxidation. It is concluded that 1) PPARα and PPARα-signaling are activated in liver by chronic high-fat feeding; and 2) PPARγ may compensate for PPARα in PPARα null mice on HFD.

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Deficiency of Growth Differentiation Factor 3 Protects against Diet-Induced Obesity by Selectively Acting on White Adipose

Molecular Endocrinology ◽

10.1210/me.2007-0322 ◽

2009 ◽

Vol 23 (1) ◽

pp. 113-123 ◽

Cited By ~ 36

Author(s):

Joseph J. Shen ◽

Lihua Huang ◽

Liunan Li ◽

Carolina Jorgez ◽

Martin M. Matzuk ◽

...

Keyword(s):

Adipose Tissue ◽

High Fat Diet ◽

Molecular Mechanisms ◽

Normal Weight ◽

Metabolic Rates ◽

Wild Type ◽

High Fat ◽

Diet Induced Obesity ◽

Differentiation Factor ◽

Tgfβ Superfamily

Growth differentiation factor 3 (GDF3) is a member of the TGFβ superfamily. White adipose is one of the tissues in which Gdf3 is expressed, and it is the only tissue in which expression increases in response to high-fat diet. We generated Gdf3−/− mice, which were indistinguishable from wild-type mice and had normal weight curves on regular diet. However, on high-fat diet Gdf3−/− mice were resistant to the obesity that normally develops in wild-type mice. Herein we investigate the physiological and molecular mechanisms that underlie this protection from diet-induced obesity and demonstrate that GDF3 deficiency selectively affects white adipose through its influence on basal metabolic rates. Our results are consistent with a role for GDF3 in adipose tissue, with consequential effects on energy expenditure that ultimately impact adiposity.

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Tpcn2 knockout mice have improved insulin sensitivity and are protected against high-fat diet-induced weight gain

Physiological Genomics ◽

10.1152/physiolgenomics.00135.2017 ◽

2018 ◽

Vol 50 (8) ◽

pp. 605-614

Author(s):

Hong He ◽

Katie Holl ◽

Sarah DeBehnke ◽

Chay Teng Yeo ◽

Polly Hansen ◽

...

Keyword(s):

Body Weight ◽

Weight Gain ◽

Insulin Sensitivity ◽

Glucose Tolerance ◽

Knockout Mice ◽

High Fat Diet ◽

Wild Type ◽

High Fat ◽

Male And Female ◽

Female Mice

Type 2 diabetes is a complex disorder affected by multiple genes and the environment. Our laboratory has shown that in response to a glucose challenge, two-pore channel 2 ( Tpcn2) knockout mice exhibit a decreased insulin response but normal glucose clearance, suggesting they have improved insulin sensitivity compared with wild-type mice. We tested the hypothesis that improved insulin sensitivity in Tpcn2 knockout mice would protect against the negative effects of a high fat diet. Male and female Tpcn2 knockout (KO), heterozygous (Het), and wild-type (WT) mice were fed a low-fat (LF) or high-fat (HF) diet for 24 wk. HF diet significantly increases body weight in WT mice relative to those on the LF diet; this HF diet-induced increase in body weight is blunted in the Het and KO mice. Despite the protection against diet-induced weight gain, however, Tpcn2 KO mice are not protected against HF-diet-induced changes in glucose or insulin area under the curve during glucose tolerance tests in female mice, while HF diet has no significant effect on glucose tolerance in the male mice, regardless of genotype. Glucose disappearance during an insulin tolerance test is augmented in male KO mice, consistent with our previous findings suggesting enhanced insulin sensitivity in these mice. Male KO mice exhibit increased fasting plasma total cholesterol and triglyceride concentrations relative to WT mice on the LF diet, but this difference disappears in HF diet-fed mice where there is increased cholesterol and triglycerides across all genotypes. These data demonstrate that knockout of Tpcn2 may increase insulin action in male, but not female, mice. In addition, both male and female KO mice are protected against diet-induced weight gain, but this protection is likely independent from glucose tolerance, insulin sensitivity, and plasma lipid levels.

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Role of human pregnane X receptor in high fat diet-induced obesity in pre-menopausal female mice

Biochemical Pharmacology ◽

10.1016/j.bcp.2014.03.019 ◽

2014 ◽

Vol 89 (3) ◽

pp. 399-412 ◽

Cited By ~ 25

Author(s):

Krisstonia Spruiell ◽

Dominique Z. Jones ◽

John M. Cullen ◽

Emmanuel M. Awumey ◽

Frank J. Gonzalez ◽

...

Keyword(s):

High Fat Diet ◽

Pregnane X Receptor ◽

High Fat ◽

Female Mice ◽

Diet Induced Obesity

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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/v1 ◽

2019 ◽

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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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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