While the role of hypothalamic hormones in regulating eating behaviors has received significant attention over the last decade, the dual function of these hormones in controlling BMD is a new area of investigation. Previous studies in mice have revealed that leptin signaling and Y receptor activation are involved in the central nervous system control of BMD [1
]. Leptin has been proposed to activate the sympathetic nervous system and adrenergic activity, via β2 receptors, which in turn inhibits osteoblast activity [2
]. The downstream mechanism connecting Y receptor activation to decreased BMD has yet to be elucidated.
Y receptors are activated by NPY, PYY, and pancreatic polypeptide (PP) and the specificity of receptor activation is dictated by the affinity of the peptides for each receptor subtype [10
]. NPY and PYY1–36
have similar affinities for Y1, Y2, and Y5 receptors, whereas PYY3–36
has selective affinity for Y2 receptors [18
]. Pancreatic polypeptide has highest affinity for Y4 receptors [10
]. NPY is a neurotransmitter that is synthesized and released from neurons, whereas PYY and PP are gut-derived hormones that circulate with effects at distant central and peripheral sites [10
]. As NPY and PYY have similar receptor affinity profiles, PYY may be a link between the periphery and central nervous system for regulating eating behavior and BMD.
Much of the previous research concerning PYY has focused on its role in regulating energy intake. PYY is released from intestinal cells following caloric intake [16
]. Obese individuals have lower fasting PYY levels and a suppressed rise in PYY following a meal, compared to normal weight individuals [29
]. Studies in humans and rodents have shown that systemic PYY3–36
infusion decreases caloric intake, even in obese subjects [29
]. However, others have been unable to reproduce the anorexic effects of PYY3–36
central or peripheral infusion [31
binds with high affinity to the Y2 receptor and activation of auto-inhibitory Y2 receptors on NPY neurons potentially provides negative feedback for NPY release [13
]. The suppression of NPY release is the proposed mechanism for the anorectic effects of PYY3–36
infusion as Y2 receptor knockout mice do not have appetite suppression with PYY infusion [30
Most previous studies have reported elevated PYY levels in subjects with anorexia nervosa relative to normal weight individuals [22
]. Changes in PYY levels with weight gain are conflicting, with one reporting a decrease [24
] and the other no change [25
] in PYY levels following an increase in weight. Our group has shown that in adolescent girls with anorexia nervosa, BMI and PYY levels were inversely correlated, and a trend toward a decrease in PYY levels followed weight recovery [22
]. Our data show an inverse association between BMI and PYY levels in adult women with anorexia nervosa. By examining a time-course of PYY over 12 hours, our data provide a more integrated assessment of PYY values in this population. In comparing secretion patterns between the extremes of BMI, we found that PYY levels were persistently elevated throughout the sampling period. Whether PYY plays a role in initiation or perpetuation of the food-restriction in anorexia nervosa has yet to be determined.
Both leptin and PYY are peripherally-released molecules which are long-term and short-term signals, respectively, of the energy-replete state [16
]. Their effects in the central nervous system are to decrease subsequent caloric intake. Additionally, leptin has been shown to be catabolic with respect to BMD [1
]. As suggested by our data, the elevated levels of PYY in anorexia nervosa and the associated low BMD characteristic of this disorder suggest that PYY may act similarly to leptin, as a catabolic signal to bone. Assuming that leptin and PYY both relay a catabolic signal to bone, the magnitude of their effect may be highlighted by examining human phenotypes at opposite extremes, obesity and anorexia nervosa. Obese individuals have elevated leptin and low PYY levels, whereas individuals with anorexia nervosa have low leptin and elevated PYY levels. Because obesity is associated with increased BMD [33
] and anorexia nervosa with decreased BMD [21
], this may imply that, if these peptides exert independent effects on bone, PYY may have a dominant effect on bone compared to leptin. To our knowledge, our data are the first to show a significant association between PYY levels and BMD in osteopenic women. The strong correlation between PYY levels and BMD suggest the possibility that PYY plays a critical role in the central nervous system regulation of BMD, and further studies in larger populations are warranted.
Y2 receptor knockout mice have a two-fold increase in trabecular bone volume at the distal femoral metaphysis with increased trabecular number and thickness, and a trend, but no statistically significant increase, in cortical bone. Osteoclast surface was not affected but osteoclast number was reduced. Osteoblast surface, osteoblast number, osteoid surface, and mineralizing surface were all unaffected but rates of mineral apposition and bone formation were increased. As there is no detectable Y receptor expression in bone, this was believed to represent an effect mediated within the central nervous system. These data suggest that signaling through the Y2 receptor suppresses bone formation, particularly trabecular bone [3
]. As PYY3–36
is a preferential Y2 receptor agonist, we hypothesized that states of PYY excess, such as anorexia nervosa, may be detrimental to BMD. Our data are in agreement with this hypothesis, as they demonstrate strong inverse correlations between PYY and BMD in the spine, a region with an increased proportion of trabecular bone. In addition, in a study by Misra et al
., PYY was found to negatively correlate with markers of bone formation and resorption [22
] supporting a role for PYY in the regulation of BMD. However, in contrast with the data regarding the effects of the Y receptor knock-out effects on bone, Wortley et al.
have recently reported a PYY-knock-out mice model with an osteopenic phenotype, including a reduction in trabecular bone mass and decrease in bone strength [20
]. Therefore, an alternative plausible hypothesis is that the high PYY levels in anorexia nervosa may reflect resistance at the level of bone to the positive effects of the PYY. Interestingly, in multivariate stepwise analyses, PYY was more strongly associated with the variability in spine BMD in anorexia nervosa than any other variables entered into the model. However, the use of regression modeling does not prove a causal relationship between PYY levels and BMD, and we cannot rule out that the association observed may simply reflect the strong inverse relationship between PYY and BMI. However, the fact that such strong associations were seen, even within a relatively small group, suggests that further research into a possible role for PYY in reducing BMD is warranted.