Up-Regulation of Liver Glucose-6-Phosphatase in X-Linked Hypophosphatemic Mice

Xie, Wensheng; Méchin, Marie-Claire; Dubois, Séverine; Werve, Gérald van de

doi:10.1055/s-2002-33256

Cited by 12 publications

(21 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although phosphate levels are not the sole mediator of mineralization defects in familial hypophosphatemic disorders it is well documented that hypophosphatemia or systemic phosphate status correlates with changes in glucose production, energy metabolism and oxygen consumption [50], [53], [91]–[99]. More recently, the familial hypophosphatemic rickets disorders all show changes in glucose, insulin sensitivity and fat metabolism [50]–[53], [92]–[94], [100]–[102].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

PHEX Mimetic (SPR4-Peptide) Corrects and Improves HYP and Wild Type Mice Energy-Metabolism

2014

View full text Add to dashboard Cite

ContextPHEX or DMP1 mutations cause hypophosphatemic-rickets and altered energy metabolism. PHEX binds to DMP1-ASARM-motif to form a complex with α5β3 integrin that suppresses FGF23 expression. ASARM-peptides increase FGF23 by disrupting the PHEX-DMP1-Integrin complex. We used a 4.2 kDa peptide (SPR4) that binds to ASARM-peptide/motif to study the DMP1-PHEX interaction and to assess SPR4 for the treatment of energy metabolism defects in HYP and potentially other bone-mineral disorders.DesignSubcutaneously transplanted osmotic pumps were used to infuse SPR4-peptide or vehicle (VE) into wild-type mice (WT) and HYP-mice (PHEX mutation) for 4 weeks.ResultsSPR4 partially corrected HYP mice hypophosphatemia and increased serum 1.25(OH)2D3. Serum FGF23 remained high and PTH was unaffected. WT-SPR4 mice developed hypophosphatemia and hypercalcemia with increased PTH, FGF23 and 1.25(OH)2D3. SPR4 increased GAPDH HYP-bone expression 60× and corrected HYP-mice hyperglycemia and hypoinsulinemia. HYP-VE serum uric-acid (UA) levels were reduced and SPR4 infusion suppressed UA levels in WT-mice but not HYP-mice. SPR4 altered leptin, adiponectin, and sympathetic-tone and increased the fat mass/weight ratio for HYP and WT mice. Expression of perlipin-2 a gene involved in obesity was reduced in HYP-VE and WT-SPR4 mice but increased in HYP-SPR4 mice. Also, increased expression of two genes that inhibit insulin-signaling, ENPP1 and ESP, occurred with HYP-VE mice. In contrast, SPR4 reduced expression of both ENPP1 and ESP in WT mice and suppressed ENPP1 in HYP mice. Increased expression of FAM20C and sclerostin occurred with HYP-VE mice. SPR4 suppressed expression of FAM20C and sclerostin in HYP and WT mice.ConclusionsASARM peptides and motifs are physiological substrates for PHEX and modulate osteocyte PHEX-DMP1-α5β3-integrin interactions and thereby FGF23 expression. These interactions also provide a nexus that regulates bone and energy metabolism. SPR4 suppression of sclerostin and/or sequestration of ASARM-peptides improves energy metabolism and may have utility for treating familial rickets, osteoporosis, obesity and diabetes.

show abstract

Section: Discussionmentioning

confidence: 99%

“…These mice are murine homologs for X-linked hypophosphatemic rickets (HYP) and are also hyperglycemic, hypoinsulinemic with altered energy metabolism [49]–[53]. The physiological substrate for PHEX is free ASARM-peptide or the ASARM-motif [54]–[66].…”

Section: Introductionmentioning

confidence: 99%

PHEX Mimetic (SPR4-Peptide) Corrects and Improves HYP and Wild Type Mice Energy-Metabolism

2014

View full text Add to dashboard Cite

show abstract

“…Elevated hepatic G6Pase activity brings about enhanced glyconeogenesis and glycogenolysis, leading to serum glucose elevation [41]. However, another study reported that glucose-6-phosphatase (G6Pase) activity was increased in both XLH mouse model and phosphate-deprived mice [42]. We did not measure G6Pase activity in PUG mice.…”

Section: Discussionmentioning

confidence: 88%

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

Zou

Xiong

Lai

et al. 2015

Sci. China Life Sci.

View full text Add to dashboard Cite

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

show abstract

“…For example mice and humans with inherited hypophosphatemic rickets diseases show accompanying defects in insulin sensitivity, glucose and fat metabolism [13,14,60]. Also, obesity, insulin resistance and cardiovascular disease (CVD) show correlations with FGF23 a major hormone regulating phosphate and mineralization [61,62].…”

Section: Fam20c Kinase: a Nexus To The Fap/mvp Pathways And Energy Mementioning

confidence: 99%

“…Defective thermoregulatory control, defective ATP synthesis with increased metabolic rate and oxygen consumption are key features of X-linked hypophosphatemic rickets mice (HYP) [67,68]. This is accompanied by increased osteoblastic pH, increased gluconeogenesis, increased glucose-6-phosphatase activity and decreased renal and bone GAPDH expression [13,14,60]. Oxygen tension and thus normal ATP synthesis is also required for osteoblast to osteocyte transformation [69].…”

Section: Fam20c Kinase: a Nexus To The Fap/mvp Pathways And Energy Mementioning

confidence: 99%

A unified model for bone–renal mineral and energy metabolism

Rowe

2015

Current Opinion in Pharmacology

View full text Add to dashboard Cite

The beginning of the millennium saw the discovery of a new bone-matrix protein, Matrix Extracellular PhosphogloprotEin (MEPE) and an associated C-terminal motif called ASARM. This motif and other distinguishing features occur in a group of proteins called SIBLINGs. These proteins include dentin matrix protein 1 (DMP1), osteopontin, dentin-sialophosphoprotein (DSPP), statherin, bone sialoprotein (BSP) and MEPE. MEPE, DMP1 and ASARM-motifs regulate expression of a phosphate regulating cytokine FGF23. Further, a trimeric interaction between phosphate regulating endopeptidase homolog X-linked (PHEX), DMP1, and α5β3-integrin that occurs on the plasma-membrane of the osteocyte mediates FGF23 regulation (FAP pathway). ASARM-peptides competitively inhibit the trimeric complex and increase FGF23. A second pathway involves specialized structures, matrix vesicles (MVP pathway). This review will discuss the FAP and MVP pathways and present a unified model for mineral and energy metabolism.

show abstract

Up-Regulation of Liver Glucose-6-Phosphatase in X-Linked Hypophosphatemic Mice

Cited by 12 publications

References 27 publications

PHEX Mimetic (SPR4-Peptide) Corrects and Improves HYP and Wild Type Mice Energy-Metabolism

PHEX Mimetic (SPR4-Peptide) Corrects and Improves HYP and Wild Type Mice Energy-Metabolism

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

A unified model for bone–renal mineral and energy metabolism

Contact Info

Product

Resources

About