Hypothalamic Y2 receptors regulate bone formation

Abstract

Neuropeptide Y (NPY) is a downstream modulator of leptin action, possibly at the level of the arcuate nucleus where NPY neurons are known to express both leptin receptors and Y2 receptors. In addition to the well-described role of NPY and leptin in energy balance and obesity, intracerebroventricular administration of NPY or leptin also causes bone loss. Here we show that Y2 receptor-deficient mice have a twofold increase in trabecular bone volume as well as greater trabecular number and thickness compared with control mice. We also demonstrate that central Y2 receptors are crucial for this process, since selective deletion of hypothalamic Y2 receptors in mature conditional Y2 knockout mice results in an identical increase in trabecular bone volume within 5 weeks. This hypothalamus-specific Y2 receptor deletion stimulates osteoblast activity and increases the rate of bone mineralization and formation, with no effect on osteoblast or osteoclast surface measurements. The lack of any changes in plasma total calcium, leptinemia, or hypothalamo-pituitary-corticotropic, -thyrotropic, -somatotropic, or -gonadotropic output suggests that Y2 receptors do not modulate bone formation by humoral mechanisms, and that alteration of autonomic function through hypothalamic Y2 receptors may play a key role in a major central regulatory circuit of bone formation.

Orexin Regulates Bone Remodeling via a Dominant Positive Central Action and a Subordinate Negative Peripheral Action

“…Interestingly, recent studies suggest that leptin paradoxically increases cortical bone mass at least in part by down-regulating hypothalamic expression of NPY, a neuropeptide that causes bone loss (Baldock et al, 2002; Lee and Herzog, 2009; Wong et al, 2013). Since both trabecular and cortical bone mass was decreased in OX-KO and OX2R-KO mice but increased in OX-Tg mice, we next examined the sympathetic outflow and hypothalamic NPY expression in these mice.…”

Anorexia nervosa and bone metabolism

“…Elevated levels of PYY may also contribute to the low bone mass in AN. Animal models suggest that PYY may be a negative regulator of bone formation -- mice that are deficient in PYY’s receptor, the Y2 receptor, have increased trabecular bone parameters [95]. Similarly, PYY is negatively associated with BMD in girls and women with AN [66, 94] and therefore this hormone may contribute to both the decreased nutrient intake and loss of bone mass in AN.…”

Effects of Neuropeptides and Mechanical Loading on Bone Cell Resorption in Vitro

“…Mice lacking the Y2 receptors for NPY display an increase in appetite and body mass, resulting in higher bone trabecular volumes [17]. Leptin knockout mice results in higher bone mass due to increased bone formation [18].…”