| Summary: | Background: Sex differences in obesity and related diseases are well established. Gonadal hormones are a major determinant of these sex differences. However, sex differences in body size and composition are evident prior to exposure to gonadal hormones, providing evidence for gonadal-independent contributions attributable to the XX or XY sex chromosome complement. Large-scale genetic studies have revealed male/female differences in the genetic architecture of adipose tissue amount and anatomical distribution. However, these studies have typically neglected the X and Y chromosomes. Scope of the review: Here we discuss how the sex chromosome complement may influence obesity, lipid levels, and inflammation. Human sex chromosome anomalies such as Klinefelter syndrome (XXY), as well as mouse models with engineered alterations in sex chromosome complement, support an important role for sex chromosomes in obesity and metabolism. In particular, the Four Core Genotypes mouse model—consisting of XX mice with either ovaries or testes, and XY mice with either ovaries or testes—has revealed an effect of X chromosome dosage on adiposity, hyperlipidemia, and inflammation irrespective of male or female gonads. Mechanisms may include enhanced expression of genes that escape X chromosome inactivation. Major conclusions: Although less well studied than effects of gonadal hormones, sex chromosomes exert independent and interactive effects on adiposity, lipid metabolism, and inflammation. In particular, the presence of two X chromosomes has been associated with increased adiposity and dyslipidemia in mouse models and in XXY men. The enhanced expression of genes that escape X chromosome inactivation may contribute, but more work is required. Keywords: Genetics, Gonadal hormones, Adipose tissue, Sex chromosome anomalies, X chromosome inactivation, Mouse models
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