Conditional inactivation of Npy1r gene in mice induces sex-related differences of metabolic and behavioral functions.

Sex hormone-driven differences in gene expression have been identified in experimental animals, highlighting brain neuronal populations implicated in dimorphism of metabolic and behavioral functions. Neuropeptide Y-Y1 receptor (NPY-Y1R) system is sexually dimorphic and sensitive to gonadal steroids. In the present study we compared the phenotype of male and female conditional knockout mice (Npy1rrfb mice), carrying the inactivation of Npy1r gene in excitatory neurons of the brain limbic system. Compared to their male control (Npy1r2lox) littermates, male Npy1rrfb mice exhibited hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis that is associated with anxiety and executive dysfunction, reduced body weight growth, after-fasting refeeding, white adipose tissue (WAT) mass and plasma leptin levels. Conversely, female Npy1rrfb mice displayed an anxious-like behavior but no differences in HPA axis activity, executive function and body weight, compared to control females. Moreover, conditional inactivation of Npy1r gene induced an increase of subcutaneous and gonadal WAT weight and plasma leptin levels and a compensatory decrease of Agouti-related protein immunoreactivity in the hypothalamic arcuate (ARC) nucleus in females, compared to their respective control littermates. Interestingly, Npy1r mRNA expression was reduced in the ARC and in the paraventricular hypothalamic nuclei of female, but not male mice. These results demonstrated that female mice are resilient to hormonal and metabolic effects of limbic Npy1r gene inactivation, suggesting the existence of an estrogen-dependent relay necessary to ensure the maintenance of the homeostasis, that can be mediated by hypothalamic Y1R.