Sex differences in obesity: X chromosome dosage as a risk factor for increased food intake, adiposity and co-morbidities - PubMed (original) (raw)
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Sex differences in obesity: X chromosome dosage as a risk factor for increased food intake, adiposity and co-morbidities
Karen Reue. Physiol Behav. 2017.
Abstract
Obesity is a world-wide problem, and a risk factor for cardiovascular disease, diabetes, cancer and other diseases. It is well established that sex differences influence fat storage. Males and females exhibit differences in anatomical fat distribution, utilization of fat stores, levels of adipose tissue-derived hormones, and obesity co-morbidities. The basis for these sex differences may be parsed into the effects of male vs. female gonadal hormones and the effects of XX vs. XY chromosome complement. Studies employing mouse models that allow the distinction of gonadal from chromosomal effects have revealed that X chromosome dosage influences food intake, which in turn affects adiposity and the occurrence of adverse metabolic conditions such as hyperinsulinemia, hyperlipidemia, and fatty liver. The identification of X chromosome dosage as a player in the behavior and physiology related to obesity suggests novel molecular mechanisms that may underlie sex differences in obesity and metabolism.
Keywords: Body weight; Mouse models; Sex differences.
Copyright © 2017 Elsevier Inc. All rights reserved.
Figures
Fig. 1
Four Core Genotypes mouse model. (A) Breeding scheme to generate offspring with four genotypes: mice with female (F) gonads and either XX or XY chromosome complement, and mice with male (M) gonads and either XX or XY chromosome complement. (B) Schematic view of sex chromosome and Sry gene position in wild-type vs. Four Core Genotype offspring. Y−, Y chromosome lacking Sry gene; Sry gene on chromosome 3 is a transgene.
Fig. 2
Interpretation of results from Four Core Genotypes mouse model. (A) Gonadal effects are detected as differences that are associated with male vs. female gonads. These are evident if XX and XY mice with female gonads differ from XX and XY mice with male gonads. An example of such a trait is shown in bar graph in the lower portion of the panel. (B) Sex chromosome effects are detected as differences that are association with XX vs. XY genotype. These are apparent if XX mice with female or male gonads differ from XY mice with female or male gonads. An example of such a trait is shown in bar graph in the lower portion of the panel. Gonadal and sex chromosome effects are analyzed by two-way ANOVA.
Fig. 3
Weight gain is influenced by X chromosome dosage. (A) Increased body weight in XX vs. XY mice fed a chow diet, regardless of male or female original gonadal type. Mice gonadectomized (GDX) as adults (time 0) were maintained on a chow diet with weekly body weight determinations. Body weights were significantly higher in XX compared to XY mice beginning at week 7 (p < 0.000005). (B) Accelerated diet-induced obesity in XX vs. XY mice. Mice were GDX as adults and started on a high fat/high carbohydrate diet 4 weeks later, when body weights of all genotypes converged (Time 0 on graph). Body weights were significantly higher in XX compared to XY mice beginning at 3 days after the start of the diet (***, p < 0.001). (C) The presence of two X chromosomes dictates higher body weight, regardless of the Y chromosome. Mice from the XY* model were GDX as adults and body weight evaluated on a chow diet. After GDX (Time 0), all body weights converged, followed by increased weight gain in mice with two X chromosomes (XX and XXY) compared to those with a single X chromosome (XO and XY); p < 0.000001). Data from [24].
Fig. 4
Physiological mechanism for enhanced weight gain in XX compared to XY mice. Four Core Genotypes mice were analyzed for energy balance using indirect calorimetry, activity monitoring (horizontal and vertical planes), and food intake monitoring [24,25]. Results revealed that the primary difference in energy balance between XX and XY mice irrespective of original gonadal type was increased food intake in XX mice during the light phase of the circadian cycle. XX mice also had higher respiratory quotient (RQ) during the light phase, likely reflecting their food intake. Data summarized from [24,25].
Fig. 5
XX mice have enhanced development of obesity co-morbidities compared to XY mice. Four Core Genotypes mice that had been fed a high fat/high carbohydrate diet for 16 weeks were assessed for lipid accumulation in the liver, glucose-insulin homeostasis, and circulating lipid levels. Compared to XY mice, XX mice had: greater fatty liver as detected by staining liver sections with hematoxylin & eosin (lipids appear as colorless droplets); higher levels of insulin, leading to higher calculated HOMA value (homeostatic model assessment), and higher total cholesterol levels. Data from [24].
Fig. 6
Elevated expression in XX mouse tissues of genes that escape X chromosome inactivation. Left, X chromosome diagram showing position of some genes that escape X chromosome inactivation. Right, Hepatic gene expression levels for X escapee genes in Four Core Genotypes mice that had been gonadectomized and fed a chow diet. All genes exhibit significantly higher expression levels in tissue from XX compared to XY mice; some genes also exhibit effects based on long-lasting effects from the original male or female gonads. Data were analyzed by two-way ANOVA. **, p < 0.01; †, p <0.0001.
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