PYY is a negative regulator of bone mass and strength.

Victoria D Leitch,J.H Duncan Bassett,Mary Jane Brassill,Graham R Williams,Alan Boyde,Peter I Croucher,Natalie C Butterfield,Pattara Ma,Holly Evans,John G Logan,Rachel L Batterham,Sofia Rahman

doi:10.1016/j.bone.2019.07.011

Abstract

ObjectiveBone 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.MethodsThe 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.ResultsBones 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).ConclusionsThese 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.

Highlights

Increased fracture risk, are features of the metabolic bone disease caused by caloric restriction or poor nutrition
Growth plate morphology was abnormal at P14 and characterised by decreased proliferative zone (PZ) and increased hypertrophic zone (HZ) widths (Fig. 1B)
The inverse relationship between circulating peptide YY (PYY) and bone mineral density (BMD) raises the possibility of detrimental long-term side-effects affecting bone mass and strength in individuals treated with PYY analogues [21,22]

Summary

Introduction

Increased fracture risk, are features of the metabolic bone disease caused by caloric restriction or poor nutrition. PYY has two active forms, the full length protein PYY(1–36), and the more abundant truncated form, PYY(3–36) that results from rapid N-terminal cleavage by the ubiquitous protease dipeptidyl peptidase-4 (DPP-4). These PYY peptides circulate in plasma and act through Y receptors, Y1, 2 and 5, to regulate food intake and beta-cell mass [8,9,10,11,12,13]. The level of circulating post-prandial PYY is increased following bariatric surgery, procedures that result in the rapid delivery of nutrients to L-cells in the ileum and colon such as Roux-en-Y gastric bypass [16].

Methods

Results

Conclusion