PYY is a negative regulator of bone mass and strength

Abstract

Objective Bone loss in anorexia nervosa and following bariatric surgery is associated with an elevated circulating concentration of the gastrointestinal, anorexigenic hormone, peptide YY (PYY). Selective deletion of the PYY receptor Y1R in osteoblasts or Y2R in the hypothalamus results in high bone mass, but deletion of PYY in mice has resulted in conflicting skeletal phenotypes leading to uncertainty regarding its role in the regulation of bone mass. As PYY analogs are under development for treatment of obesity, we aimed to clarify the relationship between PYY and bone mass. Methods The skeletal phenotype of Pyy knockout (KO) mice was investigated during growth (postnatal day P14) and adulthood (P70 and P186) using X-ray microradiography, micro-CT, back-scattered electron scanning electron microscopy (BSE-SEM), histomorphometry and biomechanical testing. Results Bones from juvenile and Pyy KO mice were longer ( P < 0.001), with decreased bone mineral content ( P < 0.001). Whereas, bones from adult Pyy KO mice had increased bone mineral content ( P < 0.05) with increased mineralisation of both cortical ( P < 0.001) and trabecular ( P < 0.001) compartments. Long bones from adult Pyy KO mice were stronger (maximum load P < 0.001), with increased stiffness ( P < 0.01) and toughness ( P < 0.05) compared to wild-type (WT) control mice despite increased cortical vascularity and porosity ( P < 0.001). The increased bone mass and strength in Pyy KO mice resulted from increases in trabecular ( P < 0.01) and cortical bone formation ( P < 0.05). Conclusions These findings demonstrate that PYY acts as a negative regulator of osteoblastic bone formation, implicating increased PYY levels in the pathogenesis of bone loss during anorexia or following bariatric surgery.

Bone Mineral Density Trends During the First Year After Laparoscopic Sleeve Gastrectomy—a Cohort Study on 241 Patients

“…Peptide YY (PYY) is a molecule that has recently gained interest in light of its role in the gut-bone axis. This anorexigenic gut hormone shows significant increase following bariatric surgery and has been proven to be a negative regulator of bone mass and strength in animal studies [40][41][42]. In a recent study on patients undergoing RYGB, postoperative PYY increases negatively correlated with spine BMD and bone formation marker P1NP [43].…”

Associations between Postprandial Gut Hormones and Markers of Bone Remodeling

“…The inverse association between CTX and PYY suggests that PYY may play a role in postprandial bone turnover via catabolic effects on bone. The idea that PYY is a negative regulator of osteoblastic bone formation is supported by studies in PYY receptor knockout mice, which demonstrated accelerated and increased bone growth and mass [ 30 , 31 ]. Studies in humans also previously reported inverse relationships between bone formation and PYY, thereby further linking PYY to bone homeostasis [ 32 , 33 , 34 , 35 ].…”

Bone Phenotyping Approaches in Human, Mice and Zebrafish – Expert Overview of the EU Cost Action GEMSTONE (“GEnomics of MusculoSkeletal traits TranslatiOnal NEtwork”)

“…Ex vivo µCT can be used to measure cortical and trabecular vBMD, cortical thickness, and if used at high enough resolution/voxel size, cortical porosity ( 160 ). It has been used at high-throughput format to identify bones with altered BV/TV, trabecular thickness (Tb.Th) and trabecular number (Tb.N) ( 66 ) and can be used for longitudinal assessment of the same animal over time due to the non-destructive character.…”

“…In dynamic histomorphometry, bone formation and apposition rates are calculated using a timed fluorescent agent which is incorporated into newly formed bone, much like described for human studies. Fluorochromes such as calcein, tetracycline and alizarine red ( 193 ), can even be combined for double labelling that has demonstrated both increased and reduced bone formation and mineral apposition rates in cortical and trabecular bone ( 160 , 192 ).…”