Conditional Deletion of Hypothalamic Y2 Receptors Reverts Gonadectomy-induced Bone Loss in Adult Mice

Abstract

Reduction in levels of sex hormones at menopause in women is associated with two common, major outcomes, the accumulation of white adipose tissue, and the progressive loss of bone because of excess osteoclastic bone resorption exceeding osteoblastic bone formation. Current antiresorptive therapies can reduce osteoclastic activity but have only limited capacity to stimulate osteoblastic bone formation and restore lost skeletal mass. Likewise, the availability of effective pharmacological weight loss treatments is currently limited. Here we demonstrate that conditional deletion of hypothalamic neuropeptide Y2 receptors can prevent ongoing bone loss in sex hormonedeficient adult male and female mice. This benefit is attributable solely to activation of an anabolic osteoblastic bone formation response that counterbalances persistent elevation of bone resorption, suggesting the Y2-mediated anabolic pathway to be independent of sex hormones. Furthermore, the increase in fat mass that typically occurs after ovariectomy is prevented by germ line deletion of Y2 receptors, whereas in male mice body weight and fat mass were consistently lower than wild-type regardless of sex hormone status. Therefore, this study indicates a role for Y2 receptors in the accumulation of adipose tissue in the hypogonadal state and demonstrates that hypothalamic Y2 receptors constitutively restrain osteoblastic activity even in the absence of sex hormones. The increase in bone formation after release of this tonic inhibition suggests a promising new avenue for osteoporosis treatment.With age, changes in endocrine function can significantly affect physiological processes often with detrimental effects on health. One of the most substantial changes occurs with menopause in women, with cessation of estrogen production by the ovaries. This abrupt and dramatic decrease in estrogen production results in a number of acute and long term physiological effects, among the most notable of these being the loss of bone leading to the development of osteoporosis and increased deposition of white adipose tissue, contributing to an increased risk of heart disease and associated complications.In the adult skeleton, bone mass and strength are determined by the multicellular process of bone remodeling, in which osteoclastic bone resorption is followed by osteoblastic bone formation. This turnover process is normally tightly coupled, such that the amount of bone resorbed equals the amount of bone formed, maintaining a constant bone mass. Multiple endocrine factors regulate turnover, in particular the sex hormones estrogen and testosterone, which protect bone by exerting anti-apoptotic effects on osteoblasts and pro-apoptotic effects on osteoclasts, in addition to suppressing osteoclast activity through both direct and indirect mechanisms (1, 2). Loss of sex hormones following menopause in women or in hypogonadal males results in increased osteoclast activity and loss of bone mass. Most current osteoporosis treatments inhibit bone resorption; however, although thes...

Neuropeptide Y and sex hormone interactions in humoral and neuronal regulation of bone and fat

“…Importantly, the elevated osteoblast activity that characterizes the skeletal phenotype of Y2 −/− mice was maintained following gonadectomy in both female and male mice [13]. Moreover, protection against gonadectomy-induced bone loss was also evident following hypothalamus-specific deletion of Y2 receptors in both male and female mice [13]. This effect is attributable to improved bone formation, and is evident despite coincident increases in bone resorption [13].…”

“…Interestingly, the increase in fat mass that typically occurs after ovariectomy is prevented by germline deletion of Y2 receptors, and in male mice body weight and fat mass were consistently lower than wild type regardless of sex hormone status. This indicates a role for Y2 receptors in the accumulation of adipose tissue in the hypogonadal state, and demonstrates that hypothalamic Y2 receptors constitutively restrain osteoblast activity even in the absence of sex hormones [13]. Thus, inhibition of hypothalamic NPY signaling via Y2 deletion provides relative protection against ovariectomy-induced bone loss and deterioration of bone microarchitecture in long bones, and inhibition of hypothalamic Y2 activity as a therapy for estrogen-deficient bone loss could thus be particularly effective.…”

“…As shown above, lack of Y2 receptor signaling by members of the NPY family such as NPY results in elevated bone formation and bone mass [9]. Interestingly, while gonadectomy induces a significant reduction in cancellous bone volume in both wild-type and Y2 −/− mice [13], cancellous bone volume in gonadectomized Y2 −/− mice remains significantly greater than that in wild-type mice [13]. Importantly, the elevated osteoblast activity that characterizes the skeletal phenotype of Y2 −/− mice was maintained following gonadectomy in both female and male mice [13].…”

“…Interestingly, while gonadectomy induces a significant reduction in cancellous bone volume in both wild-type and Y2 −/− mice [13], cancellous bone volume in gonadectomized Y2 −/− mice remains significantly greater than that in wild-type mice [13]. Importantly, the elevated osteoblast activity that characterizes the skeletal phenotype of Y2 −/− mice was maintained following gonadectomy in both female and male mice [13]. Moreover, protection against gonadectomy-induced bone loss was also evident following hypothalamus-specific deletion of Y2 receptors in both male and female mice [13].…”

The endogenous opioid dynorphin is required for normal bone homeostasis in mice

“…In this manner, upregulation of dynorphin and kappa receptor expression, known to occur in response to chronic opiate exposure , may increase central NPY expression and -given the known role of hypothalamic NPY expression to inhibit bone (Baldock et al, 2009(Baldock et al, , 2002Allison et al, 2006) -thereby suppress bone formation and reduce bone mass and strength. Importantly, inhibition of this pathway may enable attenuation of the skeletal side-effects of chronic opiate exposure, without modulation of the analgesic effects, which occur predominantly through the mu-opioid receptor.…”