Peptide YY Regulates Bone Remodeling in Mice: A Link between Gut and Skeletal Biology

Abstract

Background & AimsGastrointestinal peptides are increasingly being linked to processes controlling the maintenance of bone mass. Peptide YY (PYY), a gut-derived satiety peptide of the neuropeptide Y family, is upregulated in some states that also display low bone mass. Importantly, PYY has high affinity for Y-receptors, particularly Y1R and Y2R, which are known to regulate bone mass. Anorexic conditions and bariatric surgery for obesity influence circulating levels of PYY and have a negative impact on bone mass, but the precise mechanism behind this is unclear. We thus examined whether alterations in PYY expression affect bone mass.MethodsBone microstructure and cellular activity were analyzed in germline PYY knockout and conditional adult-onset PYY over-expressing mice at lumbar and femoral sites using histomorphometry and micro-computed tomography.ResultsPYY displayed a negative relationship with osteoblast activity. Male and female PYY knockout mice showed enhanced osteoblast activity, with greater cancellous bone mass. Conversely, PYY over-expression lowered osteoblast activity in vivo, via a direct Y1 receptor mediated mechanism involving MAPK stimulation evident in vitro. In contrast to PYY knockout mice, PYY over expression also altered bone resorption, as indicated by greater osteoclast surface, despite the lack of Y-receptor expression in osteoclastic cells. While evident in both sexes, cellular changes were generally more pronounced in females.ConclusionsThese data demonstrate that the gut peptide PYY is critical for the control of bone remodeling. This regulatory axis from the intestine to bone has the potential to contribute to the marked bone loss observed in situations of extreme weight loss and higher circulating PYY levels, such as anorexia and bariatric obesity surgery, and may be important in the maintenance of bone mass in the general population.

The hunger games of skeletal metabolism

“…12,13 Treatment of osteoblasts in culture with PYY increased ERK signalling via the Y1 receptor; this response was diminished in the presence of an Y1 antagonist. 9 Thus, taken together, the inhibitory nature of PYY signalling on bone mass is consistent with a number of studies examining the role of the NPY system and its receptors in the regulation of bone mass (reviewed in Khor et al 14 ). Thus, recent murine studies indicate that PYY activity has a negative influence on bone.…”

“…8 However, Wong et al 9 demonstrated that PYY À / À mice have increased bone mass, coincident with an increase in osteoblast activity. 9 The reason for this divergent phenotype is unclear; however, it is emerging that NPY/PYY effects can be context dependent, with stressors, such as cold or restraint, producing opposing effects, linked to stimulation of noradrenaline circuits. 10,11 However, the later study, demonstrating an increase in bone anabolism with PYY deletion, is consistent with a reduction in osteoblast activity and an increase in osteoclastic surface, as evident in adult-onset PYY-overexpressing mice, 9 and with previous studies showing similar responses to loss of NPY/PYY receptors.…”

“…9 The reason for this divergent phenotype is unclear; however, it is emerging that NPY/PYY effects can be context dependent, with stressors, such as cold or restraint, producing opposing effects, linked to stimulation of noradrenaline circuits. 10,11 However, the later study, demonstrating an increase in bone anabolism with PYY deletion, is consistent with a reduction in osteoblast activity and an increase in osteoclastic surface, as evident in adult-onset PYY-overexpressing mice, 9 and with previous studies showing similar responses to loss of NPY/PYY receptors. 12,13 Treatment of osteoblasts in culture with PYY increased ERK signalling via the Y1 receptor; this response was diminished in the presence of an Y1 antagonist.…”

Gastric bypass in obese rats causes bone loss, vitamin D deficiency, metabolic acidosis, and elevated peptide YY

“…Lastly, peptide YY, a gut-derived, satiety hormone produced by the lower GI tract, is increased postprandially after RYGB surgery and associated with bone loss in a variety of studies in adolescents [30,31]. Conflicting findings in knockout mice on the exact role of this hormone in bone metabolism imply that further investigation of peptide YY and bone loss after RYGB is needed [32]. …”

Bariatric Surgery and Bone Loss: Do We Need to Be Concerned?

“…There is also a growing body of literature showing that bariatric surgery alters the secretion of hormones from adipose tissue (notably the adipokines leptin and adiponectin), bone-derived factors such as the osteokine osteocalcin and sclerostin, as well as from the gastrointestinal tract (notably the appetite-regulating gut hormones PYY, GLP-1 and ghrelin), all of which have been shown to have significant effects on bone homeostasis in recent studies. The majority of these data demonstrating involvement of these hormones on bone come from a series of elegant gene knockout studies in rodents [126][127][128]. Current knowledge of the extent of their involvement in any bariatric surgery-induced bone loss and the mechanisms underlying such effects is limited.…”