Sex-dependent regulation of hypothalamic neuropeptide Y-Y1 receptor gene expression in leptin treated obese (ob/ob) or lean mice.

Pharmacological and genetic studies have shown that the Y1 receptor (Y1R) for Neuropeptide Y (NPY) plays a crucial role in the control of feeding behavior under metabolic conditions of low leptin levels or leptin deficiency. In this study, we investigated the effect of leptin deficiency and leptin replacement on Y1R gene expression in the hypothalamus of lean and obese Y1R/LacZ transgenic mice (TgY1R/LacZ) carrying the murine Y1R promoter linked to the LacZ gene that induces the expression of ß-galactosidase. Two daily intraperitoneal injections with leptin (1µg/g of body weight for one week) of male and female lean (TgY1R/LacZ+/+) and obese (TgY1R/LacZob/ob) mice induced a significant decrease of body weight in both sexes and genotypes. In males, leptin administration decreased ß-galactosidase activity in the PVN and DMH of lean mice, and increased transgene expression in the same hypothalamic nuclei of obese mice. Sex-related differences were also observed in both genotypes, since leptin treatment failed to affect transgene expression in hypothalamus of lean and obese female mice. These results provide further evidence for a sexual dimorphism of the hypothalamic NPY-Y1R-mediated pathway in response to changes in leptin circulating levels.

Sex-dependent regulation of hypothalamic neuropeptide Y-Y1 receptor gene expression in moderate/high fat, high-energy diet-fed mice.

In this study we investigated whether long-term consumption of a moderate/high fat (MHF), high-energy diet can affect the gene expression of the Y(1) receptor (Y(1)R) for neuropeptide Y (NPY) in the dorsomedial (DMH), ventromedial (VMH), arcuate (ARC) and paraventricular (PVN) hypothalamic nuclei of male and female Y(1)R/LacZ transgenic mice, carrying the murine Y(1)R promoter linked to the LacZ gene. MHF diet-fed male mice showed an increased consumption of metabolizable energy that was associated with a significant increase in body weight as compared with chow-fed controls. In parallel, consumption of a MHF diet for 8 weeks significantly decreased Y(1)R/LacZ transgene expression in the DMH and VMH of male mice whereas no changes were found in the ARC and PVN. Leptin treatment reduced body weight of both MHF diet- and chow-fed male mice but failed to prevent the decrease in Y(1)R/LacZ transgene expression apparent in the DMH and VMH of male mice after 8 weeks of MHF diet intake. Conversely, no significant changes of metabolizable energy intake, body weight or hypothalamic beta-galactosidase expression were found in MHF diet-fed female Y(1)R/LacZ transgenic mice. A gender-related difference of Y(1)R/LacZ transgenic mice was also observed in response to leptin treatment that failed to decrease body weight of both MHF diet- and chow-fed female mice. Results herein demonstrate that Y(1)R/LacZ FVB mice show a sexual dimorphism both on energy intake and on nucleus-specific regulation of the NPY Y(1)R system in the hypothalamus. Overall, these results provide new insights into the mechanism by which diet composition affects the hypothalamic circuit that controls energy homeostasis.

Evidence of altered neuropeptide Y content and neuropeptide Y1 receptor gene expression in the hypothalamus of pregnant transgenic mice.

Alterations in the density of neuropeptide Y (NPY)-immunoreactive fibers and of NPY1 receptor gene expression in the hypothalamus of Y1R/LacZ transgenic pregnant mice were investigated. In the paraventricular nucleus of mice on the 18th d of pregnancy NPY immunoreactivity was significantly decreased, and NPY1 receptor gene expression, as measured by histochemical staining of beta-galactosidase and in situ hybridization of NPY1 receptor mRNA, was significantly increased compared with those in estrous mice. Conversely, pregnant transgenic mice displayed a significant induction of NPY immunoreactivity and a reduction of NPY1 receptor gene expression in the ventromedial nucleus. A significant increase in Y1R/LacZ transgene expression and NPY1 receptor mRNA, but no changes in NPY immunoreactivity were observed in the arcuate nucleus of mice on the 18th d of pregnancy. These results suggest that the elevated expression of NPY in the ventromedial nucleus may contribute to the state of leptin resistance that occurs during pregnancy.