The Sex Chromosome Trisomy mouse model of XXY and XYY: metabolism and motor performance

BACKGROUND: Klinefelter syndrome (KS), caused by XXY karyotype, is characterized by low testosterone, infertility, cognitive deficits, and increased prevalence of health problems including obesity and diabetes. It has been difficult to separate direct genetic effects from hormonal effects in human studies or in mouse models of KS because low testosterone levels are confounded with sex chromosome complement. METHODS: In this study, we present the Sex Chromosome Trisomy (SCT) mouse model that produces XXY, XYY, XY, and XX mice in the same litters, each genotype with either testes or ovaries. The independence of sex chromosome complement and gonadal type allows for improved recognition of sex chromosome effects that are not dependent on levels of gonadal hormones. All mice were gonadectomized and treated with testosterone for 3 weeks. Body weight, body composition, and motor function were measured. RESULTS: Before hormonal manipulation, XXY mice of both sexes had significantly greater body weight and relative fat mass compared to XY mice. After gonadectomy and testosterone replacement, XXY mice (both sexes) still had significantly greater body weight and relative fat mass, but less relative lean mass compared to XY mice. Liver, gonadal fat pad, and inguinal fat pad weights were also higher in XXY mice, independent of gonadal sex. In several of these measures, XX mice also differed from XY mice, and gonadal males and females differed significantly on almost every metabolic measure. The sex chromosome effects (except for testis size) were also seen in gonadally female mice before and after ovariectomy and testosterone treatment, indicating that they do not reflect group differences in levels of testicular secretions. XYY mice were similar to XY mice on body weight and metabolic variables but performed worse on motor tasks compared to other groups. CONCLUSIONS: We find that the new SCT mouse model for XXY and XYY recapitulates features found in humans with these aneuploidies. We illustrate that this model has significant promise for unveiling the role of genetic effects compared to hormonal effects in these syndromes, because many phenotypes are different in XXY vs. XY gonadal female mice which have never been exposed to testicular secretions

The Number of X Chromosomes Causes Sex Differences in Adiposity in Mice

Sexual dimorphism in body weight, fat distribution, and metabolic disease has been attributed largely to differential effects of male and female gonadal hormones. Here, we report that the number of X chromosomes within cells also contributes to these sex differences. We employed a unique mouse model, known as the “four core genotypes,” to distinguish between effects of gonadal sex (testes or ovaries) and sex chromosomes (XX or XY). With this model, we produced gonadal male and female mice carrying XX or XY sex chromosome complements. Mice were gonadectomized to remove the acute effects of gonadal hormones and to uncover effects of sex chromosome complement on obesity. Mice with XX sex chromosomes (relative to XY), regardless of their type of gonad, had up to 2-fold increased adiposity and greater food intake during daylight hours, when mice are normally inactive. Mice with two X chromosomes also had accelerated weight gain on a high fat diet and developed fatty liver and elevated lipid and insulin levels. Further genetic studies with mice carrying XO and XXY chromosome complements revealed that the differences between XX and XY mice are attributable to dosage of the X chromosome, rather than effects of the Y chromosome. A subset of genes that escape X chromosome inactivation exhibited higher expression levels in adipose tissue and liver of XX compared to XY mice, and may contribute to the sex differences in obesity. Overall, our study is the first to identify sex chromosome complement, a factor distinguishing all male and female cells, as a cause of sex differences in obesity and metabolism

The number of x chromosomes causes sex differences in adiposity in mice.

Sexual dimorphism in body weight, fat distribution, and metabolic disease has been attributed largely to differential effects of male and female gonadal hormones. Here, we report that the number of X chromosomes within cells also contributes to these sex differences. We employed a unique mouse model, known as the "four core genotypes," to distinguish between effects of gonadal sex (testes or ovaries) and sex chromosomes (XX or XY). With this model, we produced gonadal male and female mice carrying XX or XY sex chromosome complements. Mice were gonadectomized to remove the acute effects of gonadal hormones and to uncover effects of sex chromosome complement on obesity. Mice with XX sex chromosomes (relative to XY), regardless of their type of gonad, had up to 2-fold increased adiposity and greater food intake during daylight hours, when mice are normally inactive. Mice with two X chromosomes also had accelerated weight gain on a high fat diet and developed fatty liver and elevated lipid and insulin levels. Further genetic studies with mice carrying XO and XXY chromosome complements revealed that the differences between XX and XY mice are attributable to dosage of the X chromosome, rather than effects of the Y chromosome. A subset of genes that escape X chromosome inactivation exhibited higher expression levels in adipose tissue and liver of XX compared to XY mice, and may contribute to the sex differences in obesity. Overall, our study is the first to identify sex chromosome complement, a factor distinguishing all male and female cells, as a cause of sex differences in obesity and metabolism

The Sex Chromosome Trisomy mouse model of XXY and XYY: metabolism and motor performance.

BACKGROUND: Klinefelter syndrome (KS), caused by XXY karyotype, is characterized by low testosterone, infertility, cognitive deficits, and increased prevalence of health problems including obesity and diabetes. It has been difficult to separate direct genetic effects from hormonal effects in human studies or in mouse models of KS because low testosterone levels are confounded with sex chromosome complement. METHODS: In this study, we present the Sex Chromosome Trisomy (SCT) mouse model that produces XXY, XYY, XY, and XX mice in the same litters, each genotype with either testes or ovaries. The independence of sex chromosome complement and gonadal type allows for improved recognition of sex chromosome effects that are not dependent on levels of gonadal hormones. All mice were gonadectomized and treated with testosterone for 3 weeks. Body weight, body composition, and motor function were measured. RESULTS: Before hormonal manipulation, XXY mice of both sexes had significantly greater body weight and relative fat mass compared to XY mice. After gonadectomy and testosterone replacement, XXY mice (both sexes) still had significantly greater body weight and relative fat mass, but less relative lean mass compared to XY mice. Liver, gonadal fat pad, and inguinal fat pad weights were also higher in XXY mice, independent of gonadal sex. In several of these measures, XX mice also differed from XY mice, and gonadal males and females differed significantly on almost every metabolic measure. The sex chromosome effects (except for testis size) were also seen in gonadally female mice before and after ovariectomy and testosterone treatment, indicating that they do not reflect group differences in levels of testicular secretions. XYY mice were similar to XY mice on body weight and metabolic variables but performed worse on motor tasks compared to other groups. CONCLUSIONS: We find that the new SCT mouse model for XXY and XYY recapitulates features found in humans with these aneuploidies. We illustrate that this model has significant promise for unveiling the role of genetic effects compared to hormonal effects in these syndromes, because many phenotypes are different in XXY vs. XY gonadal female mice which have never been exposed to testicular secretions

The Sex Chromosome Trisomy mouse model of XXY and XYY: metabolism and motor performance

Abstract Background Klinefelter syndrome (KS), caused by XXY karyotype, is characterized by low testosterone, infertility, cognitive deficits, and increased prevalence of health problems including obesity and diabetes. It has been difficult to separate direct genetic effects from hormonal effects in human studies or in mouse models of KS because low testosterone levels are confounded with sex chromosome complement. Methods In this study, we present the Sex Chromosome Trisomy (SCT) mouse model that produces XXY, XYY, XY, and XX mice in the same litters, each genotype with either testes or ovaries. The independence of sex chromosome complement and gonadal type allows for improved recognition of sex chromosome effects that are not dependent on levels of gonadal hormones. All mice were gonadectomized and treated with testosterone for 3 weeks. Body weight, body composition, and motor function were measured. Results Before hormonal manipulation, XXY mice of both sexes had significantly greater body weight and relative fat mass compared to XY mice. After gonadectomy and testosterone replacement, XXY mice (both sexes) still had significantly greater body weight and relative fat mass, but less relative lean mass compared to XY mice. Liver, gonadal fat pad, and inguinal fat pad weights were also higher in XXY mice, independent of gonadal sex. In several of these measures, XX mice also differed from XY mice, and gonadal males and females differed significantly on almost every metabolic measure. The sex chromosome effects (except for testis size) were also seen in gonadally female mice before and after ovariectomy and testosterone treatment, indicating that they do not reflect group differences in levels of testicular secretions. XYY mice were similar to XY mice on body weight and metabolic variables but performed worse on motor tasks compared to other groups. Conclusions We find that the new SCT mouse model for XXY and XYY recapitulates features found in humans with these aneuploidies. We illustrate that this model has significant promise for unveiling the role of genetic effects compared to hormonal effects in these syndromes, because many phenotypes are different in XXY vs. XY gonadal female mice which have never been exposed to testicular secretions

Kinematics of the southern Red Sea-Afar Triple Junction and implications for plate dynamics

International audienceGPS measurements adjacent to the southern Red Sea and Afar Triple Junction, indicate that the Red Sea Rift bifurcates south of 17 degrees N latitude with one branch following a continuation of the main Red Sea Rift (similar to 150 degrees Az.) and the other oriented more N-S, traversing the Danakil Depression. These two rift branches account for the full Arabia-Nubia relative motion. The partitioning of extension between rift branches varies approximately linearly along strike; north of similar to 16 degrees N latitude, extension (similar to 15 mm/yr) is all on the main Red Sea Rift while at similar to 13 degrees N, extension (similar to 20 mm/yr) has transferred completely to the Danakil Depression. The Danakil Block separates the two rifts and rotates in a counterclockwise sense with respect to Nubia at a present-day rate of 1.9 +/- 0.1 degrees/Myr around a pole located at 17.0 +/- 0.2 degrees N, 39.7 +/- 0.2 degrees E, accommodating extension along the rifts and developing the roughly triangular geometry of the Danakil Depression. Rotating the Danakil Block back in time to close the Danakil Depression, and assuming that the rotation rate with respect to Nubia has been roughly constant, the present width of the Danakil Depression is consistent with initiation of block rotation at 9.3 +/- 4 Ma, approximately coincident with the initiation of ocean spreading in the Gulf of Aden, and a concomitant similar to 70% increase in the rate of Nubia-Arabia relative motion

Differential gene expression in liver and fat tissues of X chromosome genes that escape inactivation.

<p>Genes previously shown to escape X chromosome inactivation (see text) were assessed for expression levels by quantitative PCR in liver and adipose tissue (subcutaneous inguinal and gonadal depots) of gonadectomized, chow fed FCG mice shown in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002709#pgen-1002709-g001" target="_blank">Figure 1B</a> (10 months post-GDX). (A) Statistical differences in gene expression levels among the FCG genotypes for genes escaping X chromosome inactivation. For each gene, the p value for differences between XX and XY, and female (F) vs. male (M), are shown. Several escapees exhibit increased expression in liver and/or adipose tissues of XX compared to XY mice; a few genes also exhibit differences between levels in gonadal females and gonadal males. <i>Mid1</i> shows a unique pattern, with lower expression levels in XX compared to XY tissues. The full name for <i>Rik</i> is 2610029G23Rik. NS, not significantly different. (B–D) mRNA levels are shown for liver and gonadal fat tissue of FCG mice for <i>Eif2s3x</i>, <i>Kdm6a</i>, and <i>Ddx3x</i>. Values shown for all bars represent mean ± SEM for the number of each genotype indicated. **, p<0.01; ‡, p<0.000001.</p

Relative contributions of sex hormones, sex chromosomes, and gonads to sex differences in tissue gene regulation.

Sex differences in physiology and disease in mammals result from the effects of three classes of factors that are inherently unequal in males and females: reversible (activational) effects of gonadal hormones, permanent (organizational) effects of gonadal hormones, and cell-autonomous effects of sex chromosomes, as well as genes driven by these classes of factors. Often, these factors act together to cause sex differences in specific phenotypes, but the relative contribution of each and the interactions among them remain unclear. Here, we used the four core genotypes (FCG) mouse model with or without hormone replacement to distinguish the effects of each class of sex-biasing factors on transcriptome regulation in liver and adipose tissues. We found that the activational hormone levels have the strongest influence on gene expression, followed by the organizational gonadal sex effect, and last, sex chromosomal effect, along with interactions among the three factors. Tissue specificity was prominent, with a major impact of estradiol on adipose tissue gene regulation and of testosterone on the liver transcriptome. The networks affected by the three sex-biasing factors include development, immunity and metabolism, and tissue-specific regulators were identified for these networks. Furthermore, the genes affected by individual sex-biasing factors and interactions among factors are associated with human disease traits such as coronary artery disease, diabetes, and inflammatory bowel disease. Our study offers a tissue-specific account of the individual and interactive contributions of major sex-biasing factors to gene regulation that have broad impact on systemic metabolic, endocrine, and immune functions

Increased body weight and fat mass in XX versus XY mice on a chow diet.

<p>(A) Body weight of four core genotype (FCG) mice at day 21 and day 45, prior to gonadectomy (GDX), and at 10 months after GDX. F, gonadal female; M, gonadal male. Values represent the mean ± SEM for the number of animals indicated in each bar. Significant comparisons for sex chromosome complement and for gonadal sex are denoted by brackets. A significant interaction of sex chromosome complement and gonadal sex is denoted by “Int.”. The p values are as described at the end of the legend. (B) Body weight curve for FCG mice from the point of gonadectomy through 10 months following gonadectomy. Values represent mean ± SEM. Values are significantly different between mice with XX vs. XY genotypes beginning at week 7 following GDX and beyond that. (C) Body composition of mice in panel (B) determined by NMR in FCG mice at 10 months after GDX. (D) Fat pad mass in mice from panel (B) at 10 months following GDX expressed as absolute mass (grams) or relative to kidney weight, which is invariant among the genotypes. (E) Plasma leptin levels and leptin mRNA levels in inguinal adipose tissue. *, p<0.05; **, p<0.01; ***, p<0.001; †, p<0.0001; ‡, p<0.000001.</p

Diet-induced fatty liver and impaired glucose homeostasis are more pronounced in XX than XY mice.

<p>FCG mice were fed a high fat-high carbohydrate diet for 16 weeks. All values represent mean ± SEM. (A) XX mice had increased liver mass and hepatic triglyceride levels compared to XY mice. (B) Hematoxylin and eosin staining of liver sections shows hepatic lipid droplet accumulation in XX mice. In the lower panel, thin layer chromatography demonstrates increased triglyceride levels in liver of XX mice relative to XY mice. (C) Fasting glucose and insulin levels, and homeostatic model assessment (HOMA) were determined. XX mice had significantly higher insulin levels than XY mice. (D) Fasting plasma triglyceride (TG) and free fatty acid (FFA) levels were higher in gonadal males than in gonadal females. (E) Increased triglyceride accumulation in XX liver is associated with increased peroxisome proliferator-activated receptor γ (<i>Pparg</i>) and diacylglycerol acyltransferase 1 (<i>Dgat1</i>) mRNA levels. (F) Increased expression levels for fatty acid oxidation genes acyl CoA oxidase 1 (<i>Aox</i>1) and carnitine palmitoyltransferase 1α (<i>Cpt1a</i>) in liver of XX mice. (G) Increased expression of Aox1 in skeletal muscle of gonadal male mice. *, p<0.05; **, p<0.01; ***, p<0.001; †, p<0.0001.</p