Insulin suppresses the production of fibroblast growth factor 23 (FGF23)

Bär, Ludmilla; Feger, Martina; Fajol, Abul; Klotz, Lars‐Oliver; Zeng, Shufei; Läng, Florian; Hocher, Berthold; Föller, Michael

doi:10.1073/pnas.1800160115

Cited by 103 publications

(104 citation statements)

References 64 publications

(64 reference statements)

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“…Insulin is a direct negative regulator of FGF23 synthesis: By activating PI3K/PKB/Akt/FOXO1 signalling, insulin suppresses the production of FGF23 . Similarly, insulin‐like growth factor 1 (IGF1) inhibits FGF23 gene expression through this pathway .…”

Section: Homeostatic Regulation Of Fgf23mentioning

confidence: 99%

Regulation of fibroblast growth factor 23 (FGF23) in health and disease

et al. 2019

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Fibroblast growth factor 23 (FGF23) is mainly produced in the bone and, upon secretion, forms a complex with a FGF receptor and coreceptor αKlotho. FGF23 can exert several endocrine functions, such as inhibiting renal phosphate reabsorption and 1,25‐dihydroxyvitamin D3 production. Moreover, it has paracrine activities on several cell types, including neutrophils and hepatocytes. Klotho and Fgf23 deficiencies result in pathologies otherwise encountered in age‐associated diseases, mainly as a result of hyperphosphataemia‐dependent calcification. FGF23 levels are also perturbed in the plasma of patients with several disorders, including kidney or cardiovascular diseases. Here, we review mechanisms controlling FGF23 production and discuss how FGF23 regulation is perturbed in disease.

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Section: Homeostatic Regulation Of Fgf23mentioning

confidence: 99%

Regulation of fibroblast growth factor 23 (FGF23) in health and disease

et al. 2019

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“…Proinflammatory cytokines, such as interleukin‐6 and tumour necrosis factor‐alpha, may stimulate FGF23 expression directly or indirectly via 1,25‐hydroxyvitamin D . Insulin has recently been shown to suppress FGF23 transcription in osteoblast‐like cells; in healthy volunteers, FGF23 levels decreased as insulin levels increased following an oral glucose tolerance test . SG is associated with decreases in circulating inflammatory markers and improvements in insulin sensitivity, both of which may result in decreased FGF23 production.…”

Section: Discussionmentioning

confidence: 99%

Fibroblast growth factor 23 levels decline following sleeve gastrectomy

Billington

Murphy

Gamble

et al. 2019

Clinical Endocrinology

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The bone-derived protein fibroblast growth factor 23 (FGF23) is a key regulator of phosphate and vitamin D homeostasis. A number of pieces of evidence link both circulating phosphate and FGF23 concentrations with measures of adiposity, cardiovascular risk and mortality. 1-7 Our group 8 and others 1-3 have demonstrated positive associations between circulating FGF23 and body mass index (BMI), fat mass and abdominal circumference in cross-sectional human studies. Furthermore, positive associations between FGF23 concentrations Abstract Objective: Levels of fibroblast growth factor 23 (FGF23) have been positively associated with measures of adiposity, cardiovascular disease and mortality. It is unclear whether the relationship of FGF23 with cardiovascular disease and mortality is confounded by obesity. We aimed to determine whether FGF23 concentrations decline following a reduction in adiposity after sleeve gastrectomy (SG). Design:The effect of SG on FGF23 was evaluated in 22 obese adults (59% male) with type 2 diabetes. Fat mass, weight, BMI, plasma intact FGF23, parathyroid hormone (PTH) and leptin were determined at baseline and at 12 months following SG.Results: At baseline, median (IQR) age was 51 (43-54) years, fat mass 47.8 (41.0-59.4) kg, BMI 40.9 (36.9-46.9) kg/m 2 and FGF23 66.2 (55.3-82.9) pg/mL.Significant changes in median BMI (−10.8 kg/m 2 , 95% CI: −12.9 to −7.2, P < 0.0001), fat mass (−20.0 kg, 95% CI: −26.7 to −12.4, P < 0.0001) and weight (−34.7 kg, 95% CI −40.0 to −23.1, P < 0.0001) were observed after SG. FGF23 (−12.4 pg/mL, 95% CI: −19.5 to 2.0, P = 0.005), PTH (−1.1 pmol/L, 95% CI: −1.7 to 0.2, P = 0.009) and leptin (−1687 pg/mL, 95% CI −4524 to −563, P = 0.01) declined following SG. Change in FGF23 was not significantly associated with change in measures of adiposity, PTH or leptin.Conclusions: FGF23 concentrations decline in the setting of significant weight loss following SG, implying that increased FGF23 concentrations are a downstream consequence of obesity, which may confound its association with cardiometabolic dysfunction. Mediators of the relationship between adiposity and FGF23 require further elucidation. K E Y W O R D Sadiposity, bariatric surgery, bone mineral density, fibroblast growth factor 23, leptin, obesity, parathyroid hormone

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“…Cell culture and experiments with UMR106 rat osteoblast-like cells were conducted as described before [39]. Briefly, cells were cultured in DMEM highglucose medium containing 10% FBS and penicillin-streptomycin at 37°C and 5%…”

Section: Cell Culturementioning

confidence: 99%

“…The identification of molecular regulators of FGF23 production is of high interest and relevance. Known regulators include PTH [28], 1,25(OH) 2 D 3 [29], phosphate [30,31], inflammatory cytokines and factors such as TNFα [32], IL-1/6 [4,[33][34][35], or NFκB [33,36], TGFβ [37], AMP-dependent protein kinase (AMPK) [38] or insulin-dependent PI3 kinase signaling [39].…”

Section: Introductionmentioning

confidence: 99%

PKC regulates the production of fibroblast growth factor 23 (FGF23)

Bär

Hase

Föller

2019

Preprint

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Serine/threonine protein kinase C (PKC) is activated by diacylglycerol that is released from membrane lipids by phospholipase C in response to activation of G protein-coupled receptors or receptor tyrosine kinases. PKC isoforms are particularly relevant for proliferation and differentiation of cells including osteoblasts. Osteoblasts/osteocytes produce fibroblast growth factor 23 (FGF23), a hormone regulating renal phosphate and vitamin D handling. PKC activates NFκB, a transcription factor complex controlling FGF23 expression. Here, we analyzed the impact of PKC on FGF23 synthesis. Fgf23 expression was analyzed by qRT-PCR in UMR106 osteoblastlike cells and in IDG-SW3 osteocytes. Phorbol ester 12-O-tetradecanoylphorbol-13-acetate (PMA), a PKC activator, up-regulated Fgf23 expression. In contrast, PKC inhibitors calphostin C, Gö6976, sotrastaurin and ruboxistaurin supressed Fgf23 gene expression. NFκB inhibitor withaferin A abolished the stimulatory effect of PMA on Fgf23. PKC is a powerful regulator of FGF23 synthesis, an effect which is at least partly mediated by NFκB.

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Insulin suppresses the production of fibroblast growth factor 23 (FGF23)

Cited by 103 publications

References 64 publications

Regulation of fibroblast growth factor 23 (FGF23) in health and disease

Regulation of fibroblast growth factor 23 (FGF23) in health and disease

Fibroblast growth factor 23 levels decline following sleeve gastrectomy

PKC regulates the production of fibroblast growth factor 23 (FGF23)

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