Metabolic impact of sex chromosomes

Molecular Biology Institute, University of California, Los Angeles
Adipocyte 04/2013; 2(2):74-79. DOI: 10.4161/adip.23320
Source: PubMed


Obesity and associated metabolic diseases are sexually dimorphic. To provide better diagnosis and treatment for both sexes, it is of interest to identify the factors that underlie male/female differences in obesity. Traditionally, sexual dimorphism has been attributed to effects of gonadal hormones, which influence numerous metabolic processes. However, the XX/XY sex chromosome complement is an additional factor that may play a role. Recent data using the four core genotypes mouse model have revealed that sex chromosome complement-independently from gonadal sex-plays a role in adiposity, feeding behavior, fatty liver and glucose homeostasis. Potential mechanisms for the effects of sex chromosome complement include differential gene dosage from X chromosome genes that escape inactivation, and distinct genomic imprints on X chromosomes inherited from maternal or paternal parents. Here we review recent data in mice and humans concerning the potential impact of sex chromosome complement on obesity and metabolic disease.

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    • "Our previous findings demonstrated that Id2À/À mice exhibit altered feeding and locomotor rhythms, sex-and age-dependent enhanced glucose tolerance and insulin sensitivity, and sex-dependent elevated glucose uptake in skeletal muscle and brown adipose tissue [9]. It is well known that risk, development and manifestation of obesity, metabolic syndrome and insulin-resistance are sexually dimorphic [10] [11]. Here we extend our studies on the characterization of the Id2À/À mouse metabolic phenotype under energy-rich diet challenge in a sex-specific context. "
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    ABSTRACT: Inhibitor of DNA binding 2 (ID2) is a helix-loop-helix transcriptional repressor rhythmically expressed in many adult tissues. Our previous studies have demonstrated that Id2 null mice have altered expression of circadian genes involved in lipid metabolism, altered circadian feeding behavior, and sex-specific enhancement of insulin sensitivity and elevated glucose uptake in skeletal muscle and brown adipose tissue. Here we further characterized the Id2−/− mouse metabolic phenotype in a sex-specific context and under low and high fat diets, and examined metabolic and endocrine parameters associated with lipid and glucose metabolism. Under the low-fat diet Id2−/− mice showed decreased weight gain, reduced gonadal fat mass, and a lower survival rate. Under the high-fat diet, body weight and gonadal fat gain of Id2−/− male mice was comparable to control mice and survival rate improved markedly. Furthermore, the high-fat diet treated Id2−/− male mice lost the enhanced glucose tolerance feature observed in the other Id2−/− groups, and there was a sex-specific difference in white adipose tissue storage of Id2−/− mice. Additionally, a distinct pattern of hepatic lipid accumulation was observed in Id2−/− males: low lipids on the low-fat diet and steatosis on the high-fat diet. In summary, these data provides valuable insights into the impact of Id2 deficiency on metabolic homeostasis of mice in a sex-specific manner.
    Full-text · Article · Aug 2014 · Biochemical and Biophysical Research Communications
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    • "Due to these findings, the entwined nature of lipid and glucose metabolism and the interlocked relationship of the molecular circadian clock with metabolic processes [5], we hypothesized that ID2 contributes to the regulation of glucose homeostasis, energy utilization and the temporal regulation of feeding. It is well known that risk, development and manifestation of obesity, metabolic syndrome and insulin-resistance are sexually dimorphic, and animal models suggest contributing roles of both gonadal hormones and sex chromosomes [13]–[16]. Moreover, the effect of aging on the circadian clock and on glucose homeostasis has been reported in humans and animal models [17]–[20]. "
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    ABSTRACT: Inhibitor of DNA binding 2 (ID2) is a helix-loop-helix transcriptional repressor rhythmically expressed in many adult tissues. Our earlier studies have demonstrated a role for ID2 in the input pathway, core clock function and output pathways of the mouse circadian system. We have also reported that Id2 null (Id2-/-) mice are lean with low gonadal white adipose tissue deposits and lower lipid content in the liver. These results coincided with altered or disrupted circadian expression profiles of liver genes including those involved in lipid metabolism. In the present phenotypic study we intended to decipher, on a sex-specific basis, the role of ID2 in glucose metabolism and in the circadian regulation of activity, important components of energy balance. We find that Id2-/- mice exhibited altered daily and circadian rhythms of feeding and locomotor activity; activity profiles extended further into the late night/dark phase of the 24-hr cycle, despite mice showing reduced total locomotor activity. Also, male Id2-/- mice consumed a greater amount of food relative to body mass, and displayed less weight gain. Id2-/- females had smaller adipocytes, suggesting sexual-dimorphic programing of adipogenesis. We observed increased glucose tolerance and insulin sensitivity in male Id2-/- mice, which was exacerbated in older animals. FDG-PET analysis revealed increased glucose uptake by skeletal muscle and brown adipose tissue of male Id2-/- mice, suggesting increased glucose metabolism and thermogenesis in these tissues. Reductions in intramuscular triacylglycerol and diacylglycerol were detected in male Id2-/- mice, highlighting its possible mechanistic role in enhanced insulin sensitivity in these mice. Our findings indicate a role for ID2 as a regulator of glucose and lipid metabolism, and in the circadian control of feeding/locomotor behavior; and contribute to the understanding of the development of obesity and diabetes, particularly in shift work personnel among whom incidence of such metabolic disorders is elevated.
    Full-text · Article · Sep 2013 · PLoS ONE
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    ABSTRACT: Energy metabolism in humans is tuned to distinct sex-specific functions that potentially reflect the unique requirements in females for gestation and lactation, whereas male metabolism may represent a default state. These differences are the consequence of the action of sex chromosomes and sex-specific hormones, including estrogens and progesterone in females and androgens in males. In humans, sex-specific specialization is associated with distinct body-fat distribution and energy substrate-utilization patterns; i.e., females store more lipids and have higher whole-body insulin sensitivity than males, while males tend to oxidize more lipids than females. These patterns are influenced by the menstrual phase in females, and by nutritional status and exercise intensity in both sexes. This minireview focuses on sex-specific mechanisms in lipid and glucose metabolism and their regulation by sex hormones, with a primary emphasis on studies in humans and the most relevant pre-clinical model of human physiology, non-human primates.
    Full-text · Article · Nov 2014 · Frontiers in Endocrinology
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