Neuropeptide y mediates the short-term hypometabolic effect of estrogen deficiency in mice

Background: Estrogen deficiency increases body weight or total and central adiposity and decreases energy expenditure. Hypothalamic neuropeptide Y (NPY) expression is altered by estrogen deficiency in rodents, but the long-term consequences on energy homeostasis are unknown. Objective: To investigate the role of NPY in the changes in energy expenditure and physical activity, as well as the associated changes in body weight and composition in response to short-term and long-term estrogen deficiency. Design: Sham and ovariectomy (OVX) operations were performed at 8 weeks of age in wild-type (WT) and NPY^-/- mice. Energy expenditure, physical activity, body composition and weight, as well as food intake were measured at 10-18 days (short-term) and 46-54 days (long-term) after OVX. Results: OVX influences energy homeostasis differently at early compared with later time-points. At the early but not the late time point, OVX in WT mice reduced oxygen consumption and energy expenditure and tended to reduce resting metabolic rate. Interestingly, these effects of short-term estrogen deficiency were ablated by NPY deletion, with NPY^-/- mice exhibiting significant increases in energy expenditure and resting metabolic rate. In addition to these hypermetabolic effects, OVX NPY^-/- mice exhibited significantly lower body weight and whole-body fat mass relative to OVX WT controls at the short-term but not the long-term time point. Food intake and physical activity were unaltered by OVX, but NPY^-/- mice exhibited significant reductions in these parameters relative to WT. Conclusion: The effects of estrogen deficiency to reduce energy metabolism are transient, and NPY is critical to this effect as well as the early OVX-induced obesity.