Glucose metabolic abnormality is associated with defective mineral homeostasis in skeletal disorder mouse model

Abstract

Bone was reported as a crucial organ for regulating glucose homeostasis. In this study, we found that Phex mutant mice (PUG), a model of human X-linked hypophosphatemic rickets (XLH), displayed metabolic abnormality in addition to abnormal phosphate homeostasis, skeletal deformity and growth retardation. Glucose tolerance was elevated with enhanced insulin sensitivity in PUG, though circulating insulin level decreased. Interestingly, bone mineral density defects and glucose metabolic abnormality were both rescued by adding phosphorus-and calcium-enriched supplements in daily diet. Serum insulin level, glucose tolerance and insulin sensitivity showed no differences between PUG and wild-type mice with rescued osteocalcin (OCN) following treatment. Our study suggested that OCN is a potential mediator between mineral homeostasis and glucose metabolism. This investigation brings a new perspective on glucose metabolism regulation through skeleton triggered mineral homeostasis and provides new clues in clinical therapeutics of potential metabolic disorders in XLH patients. glucose metabolism, mineral homeostasis, bone, Phex, X-linked hypophosphatemic rickets Citation:Zou JH, Xiong XW, Lai BB, Sun M, Tu X, Gao X. Glucose metabolic abnormality is associated with defective mineral homeostasis in skeletal disorder mouse model. [5,6]. In the past decades, bone was studied as an endocrinal organ [7,8]. Interactions between bone and energy metabolism aroused extensive interests and concerns [911]. Phex is mainly expressed in osteoblasts and odontoblasts [1214] and its mutations lead to reduced 1,25-(OH) 2 D 3 and elevated circulating FGF23 (fibroblast growth factor 23) [1517]. 1,25-(OH) 2 D 3 and its receptor could influence expression of uncoupling protein (UCP) in adipocytes [18,19]. In vitro studies demonstrate that the role of 1,25-(OH) 2 D 3 in lipid metabolism is regulator of peroxisome proliferator-activated receptor alpha (Ppara) [20]. Circulating FGF23 is also associated with fat mass and serum lipids [21]. In mouse models of XLH, like Hyp mice, decreased renal glucose reabsorption activity [22], increased glucose production in renal proximal tubules [23] and osteoblasts [24] were observed. The only known physiological substrate of PHEX protein, acidic serine aspartate-rich MEPE associated motif (ASARM peptide), could regulate glucose metabolism and insulin signaling [14]. The above findings indicate PHEXmediated association between skeletal function and energy