As for many human diseases, the incidence of obesity and its associated health risks are sexually dimorphic: worldwide the rate of obesity is higher in women. Sex differences in metabolism, appetite, body composition, and fat deposition are contributing biological factors. Gonadal hormones regulate the development of many sexually dimorphic traits in humans and animals, and, in addition, studies in mice indicate a role for direct genetic effects of sex chromosome dosage on body weight, deposition of fat, and circadian timing of feeding behavior. Specifically, mice of either sex with 2 X chromosomes, typical of normal females, have heavier body weights, gain more weight, and eat more food during the light portion of the day than mice of either sex with a single X chromosome. Here we test the effects of X chromosome dosage on body weight and report that gonadal females with 2 X chromosomes express higher levels of GH gene (Gh) mRNA in the preoptic area (POA) of the hypothalamus than females with 1 X chromosome and males. Furthermore, Gh expression in the POA of the hypothalamus of mice with 2 X chromosomes correlated with body weight; GH is known to have orexigenic properties. Acute infusion of GH into the POA increased immediate food intake in normal (XY) males. We propose that X inactivation-escaping genes modulate Gh expression and food intake, and this is part of the mechanism by which individuals with 2 X chromosomes are heavier than individuals with a single X chromosome.
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