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 (Npy1r^rfb mice), carrying the inactivation of Npy1r gene in excitatory neurons of the brain limbic system. Compared to their male control (Npy1r^2lox) littermates, male Npy1r^rfb 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 Npy1r^rfb 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.

在实验动物中已经确定了由性激素驱动的基因表达差异，突出了与代谢和行为功能二态性有关的脑神经元种群。神经肽Y-Y1受体（NPY-Y1R）系统是性二态性，对性腺类固醇敏感。在本研究中，我们比较了雄性和雌性条件敲除小鼠（Npy1r ^rfb小鼠）的表型，它们在脑边缘系统的兴奋性神经元中携带Npy1r基因失活。与他们的雄性对照（Npy1r ^2lox）同窝仔^相比，雄性Npy1r ^rfb小鼠表现出下丘脑-垂体-肾上腺（HPA）轴的过度活化，这与焦虑和执行功能障碍，体重减轻，空腹后进食，白色脂肪组织（WAT）质量和血浆瘦素水平有关。相反，与对照雌性小鼠相比，雌性Npy1r ^rfb小鼠表现出焦虑样行为，但HPA轴活性，执行功能和体重无差异。此外，与各自的对照同窝仔猪相比，Npy1r基因的条件失活会引起女性下丘脑弓状（ARC）核中皮下和性腺WAT重量和血浆瘦素水平的增加以及Agouti相关蛋白免疫反应性的代偿性降低。有趣的是，Npy1r在雌性小鼠的ARC和下丘脑旁核中mRNA表达降低，但雄性小鼠未降低。这些结果表明，雌性小鼠对边缘Npy1r基因失活的激素和代谢作用具有恢复力，表明存在确保雌激素稳态所需的雌激素依赖性继电器的存在，该继电器可以由下丘脑Y1R介导。