Sex steroid modulation of neuronal control on bone and energy homeostasis

Abstract

Neuropeptide Y (NPY) has been shown to regulate bone metabolism centrally, through the neurons located within the arcuate nucleus of the hypothalamus and directly via Y1 receptors on osteoblastic cells. NPY signalling has been shown to regulate adiposity and energy homeostasis via the Y receptors. Importantly, sex hormones are key regulators of bone metabolism, with estrogen and androgen deficiency resulting in significant amounts of bone loss. Loss of sex hormones results in altered energy homeostasis which contributes to obesity. Importantly, there is an interaction between these two systems, with sex hormones regulating central NPY expression. Thus, this project investigates the interaction of NPY and sex hormones in the regulation of bone metabolism and energy homeostasis.

The anabolic response of germline NPY knockout mice to androgen deficiency is similar to that of Y2 receptor deletion. Y1 receptor signalling appears to have a unique response to androgen deficiency, with the anabolic response being abolished in the absence of androgens. In order to investigate the location of this unique interaction, mice with selective osteoblastic deletion of the Y1 receptor under control of the osteoblast-specific α1(I)-collagen promoter were generated. This study revealed that the anabolic effects of Y1 receptors are dependent upon androgens and are locally mediated within the osteoblast.

Estrogen deficiency decreases energy expenditure and consequently causes changes in body composition. In order to determine the role of hypothalamic NPY expression 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 were investigated in mice with NPY deletion. This study demonstrates that the effect of estrogen deficiency to reduce energy expenditure is transient. NPY is an important mediator of this early decrease in energy expenditure in response to estrogen deficiency. These observations suggest that the perimenopausal period may be a key time point at which to intervene in order to prevent or attenuate menopause-induced obesity in women.

Taken together, these data demonstrate the interactions of NPY and sex hormones in the regulation of bone and energy homeostasis. Understanding the signalling of these interactions will target management of menopause and treatment of diseases such as osteoporosis.