Metabolic impact of sex chromosomes

Abstract

Obesity and the metabolic syndrome are complex diseases regu-lated by many genetic and environmental factors. It is well known that risk, development and manifestations of obesity-related conditions such as diabetes and atherosclerosis are sexually dimorphic. Sex differences in obesity are strongly influenced by gonadal hormone effects. 1,2 However, an additional fundamental difference that may contribute to metabolic differences between females and males lies within the nucleus of each cell—the XX and XY sex chromosome complement. The sex chromosome complement of female and male cells imposes several known genetic differences 3 (Fig. 1). For example, female cells with an XX chromosome complement never express any of the 78 protein-coding genes, nor an unknown number of noncoding RNAs, that are present on the Y chromosome. In addition, only XX cells undergo the process of transcriptional inactivation of one of the two X chromosomes during early devel-opment as a mechanism to balance gene dosage between males and females. 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.