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Metabolic bone diseases cause bone and joint pain and are manifested as rheumatism. Typical for the rare genetic disease hypophosphatasia is a reduced activity of alkaline phosphatase (AP), where the variable residual activity causes the heterogeneous symptoms (e.g., arthralgia, myalgia and fractures). It is indicated by repeatedly low AP measurements. The diagnosis requires a meticulous medical history and laboratory-based clarification in order to rule out other differential diagnoses. Although supportive measures form the basis of treatment, costly enzyme replacement therapy is a possible treatment option for severe forms. Multidisciplinary care under the direction of a rheumatologist experienced in osteology or an osteologist is crucial in order to provide adequate care to affected patients. Phosphate loss syndromes due to overactivity of fibroblast growth factor 23 (FGF-23) lead to deformities of the lower extremities and short stature (in congenital disorders), bone and muscle pain, muscular weakness and pathological fractures, depending on the time of occurrence during life. In genetic forms of the disease (especially X‑linked hypophosphatemia), supplementation with calcitriol and phosphates and, if necessary, complex corrective surgery in adolescence are traditional treatment methods, which are increasingly being replaced by treatment with antibodies against FGF-23. The acquired variant is a paraneoplastic phenomenon from small mostly benign mesenchymal tumors, which clinically shows a relatively acute course with severe bone pain, pathological fractures and muscle weakness in previously healthy patients and can ideally be cured by resection of the tumor. The disease can be suspected by significantly reduced serum phosphate levels and narrowed down with further laboratory diagnostics. In our opinion, the measurement of calcium, phosphate and alkaline phosphatase should be part of the primary laboratory diagnostics performed by rheumatologists and the follow-up of pathological findings is indicated., Competing Interests: Einhaltung ethischer Richtlinien. Interessenkonflikt: C.-J. Bauer macht folgende Angaben: Vortragshonorare von Lilly, Novartis, Bristol-Myers Squibb, Galapagos, Janssen-Cilag, UCB, AstraZeneca, Abbvie; Beratungshonorar von Abbvie; Forschungsunterstützung von Alexion. V.S. Schäfer macht folgende Angaben: Vortragshonorare von Abbvie, Novartis, BMS, Chugai, Celgene, Medac, Sanofi, Lilly, Hexal, Pfizer, Janssen, Roche, Shire, Onkowissen, Royal College London, Boehringer-Ingelheim, UCB, Fresenius, Alexion; Beratungshonorare von Novartis, Chugai, Abbvie, Celgene, Sanofi, Lilly, Hexal, Pfizer, Amgen, BMS, Roche, Gilead, Medac, Boehringer-Ingelheim, Alexion; Forschungsunterstützung von Novartis, Hexal, Lilly, Roche, Celgene, Universität Bonn, Boehringer-Ingelheim, Butterfly IQ, Medac, Alexion, Deutsche Gesellschaft für Rheumatologie, Bundesministerium für Bildung und Forschung. B. Muche macht folgende Angaben: Vortragshonorare von Alexion, Amgen, Fachverband Rheumatologische Fachassistenz e.V., OSTAK, Osteologie Akademie GmbH, UCB; Beratungshonorare von Alexion, Amgen, Celltrion, Galapagos, Theramex, UCB. Z. Boyadzhieva gibt an, dass kein Intereressenskonflikt besteht. Für diesen Beitrag wurden von den Autor/-innen keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien. Für Bildmaterial oder anderweitige Angaben innerhalb des Manuskripts, über die Patient/-innen zu identifizieren sind, liegt von ihnen und/oder ihren gesetzlichen Vertretern/Vertreterinnen eine schriftliche Einwilligung vor., (© 2025. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Increased dietary inorganic phosphate (P i ) intake stimulates renal P i excretion, in part, by parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23) or dopamine. High dietary P i may also stimulate sympathetic outflow. Rodent studies provided evidence for these regulatory loops, while controlled experiments in healthy humans examined periods of either a few hours or several weeks, and often varied dietary calcium intake. The effects of controlled, isolated changes in dietary P i intake over shorter periods are unknown. We studied the effects of a low or high P i diet on parameters of mineral metabolism in 10 healthy young men. Participants received a standardized diet (1000 mg phosphorus equivalent/day) supplemented with either a phosphate binder (low P i diet) or phosphate capsules (750 mg phosphorus, high P i diet) in a randomized cross-over trial for 5 days with a 7-day washout between diets. High P i intake increased plasma P i levels and 24-h excretion and decreased urinary calcium excretion. High P i intake increased intact FGF23 (iFGF23) and suppressed plasma Klotho without affecting cFGF23, PTH, calcidiol, calcitriol, Fetuin-A, dopamine, epinephrine, norepinephrine, metanephrine, or aldosterone. Higher iFGF23 correlated with lower calcitriol and higher PTH. These data support a role for iFGF23 in increasing renal P i excretion and reducing calcitriol in healthy young men during steady-state high dietary P i intake. High dietary P i intake elevated blood P i levels in healthy young subjects with normal renal function and may therefore be a health risk, as higher serum P i levels are associated with cardiovascular risk in the general population., Competing Interests: Declarations. Competing interests: CAW reports honoraria from Medice and Kyowa Kirin and collaborations with Chugai and Bayer AG outside this study. The rest of the authors declare having no conflict of interest., (© 2024. The Author(s).)

This study examined the involvement of fibroblast growth factor-23 (FGF-23) in primary aldosteronism (PA), a condition characterized by elevated aldosterone levels and hypertension. We recruited patients with unilateral PA (uPA) and observed increased levels of C-terminal FGF-23 (cFGF-23) and C-terminal to intact FGF-23 (iFGF-23) in patients with uPA compared with essential hypertension control participants. Elevated preoperative cFGF-23 levels were associated with adverse outcomes, including mortality and cardiovascular or kidney events. Plasma cFGF-23 levels demonstrated a nonlinear rise with aldosterone, but iFGF-23 levels were not correlated with plasma aldosterone concentration. Higher cFGF-23 levels independently predicted hypertension remission after adrenalectomy for patients with uPA. Patients with uPA, who exhibited elevated cFGF-23 levels, had decreased levels after adrenalectomy. In cell cultures, aldosterone enhanced cleavage of iFGF-23, leading to increased levels of cFGF-23 fragments, an effect mitigated by silencing of family with sequence similarity 20, member C (FAM20C). However, the enhancement of cFGF-23 levels remained unaffected by the furin inhibitor. The study suggests that aldosterone influences FGF-23 phosphorylation by interacting with FAM20C, with docking experiments indicating aldosterone's binding to FAM20C. This work highlights that patients with uPA with elevated cFGF-23 levels are associated with cardiovascular risks, and adrenalectomy reduces cFGF-23. Aldosterone likely promotes cFGF-23 production through FAM20C-mediated phosphorylation of iFGF-23.

The recent discovery of clinically significant data, alongside novel physiological and pathological occurrences surrounding sacubitril/valsartan (Sac/Val) beyond its approved indications, necessitates an urgent reevaluation of its underlying mechanism of action. In the present investigation, we observed a substantial elevation in the serum levels of fibroblast growth factor 21 (FGF21) among patients with acute myocardial infarction (AMI) who were administered Sac/Val, compared to those who were not, utilizing ELISA-based measurements. Furthermore, through the utilization of a mouse model of myocardial infarction induced by ligation of the left anterior descending branch, we confirmed that FGF21 mediates the cardioprotective effect of Sac/Val, employing both loss-of-function and gain-of-function approaches. Molecular docking and SPR experiments validated that Sac/Val can regulate FGF21 via its interaction with PPARs, and verified the role of PPARs in mediating Sac/Val regulation of FGF21 by inhibiting PPARs. In conclusion, we found that Sac/Val can act as an agonist of FGF21, which provides a new idea for the development of FGF21 drugs, and FGF21 as a new target of Sac/Val to ameliorate myocardial infarction, which provides a basis for new indications for Sac/Val., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Background: Skeletal muscle alterations (SMAs) are being increasingly recognized in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and appear to be associated with deleterious outcomes in these patients. However, their actual prevalence and pathophysiology remain to be elucidated., Aim: To determine the prevalence of SMAs and to assess the significance of circulating myokines as biomarkers in patients with MASLD., Methods: Skeletal muscle strength and muscle mass were measured in a cross-sectional study in a cohort of 62 patients fulfilling MASLD criteria, recruited from the outpatient clinics of a tertiary level hospital. The degree of fibrosis and liver steatosis was studied using abdominal ultrasound and transitional elastography. Anthropometric and metabolic characteristics as well as serum levels of different myokines were also determined in the MASLD cohort. Statistical analysis was performed comparing results according to liver fibrosis and steatosis., Results: No significant differences were found in both skeletal muscle strength and skeletal muscle mass in patients with MASLD between different stages of liver fibrosis. Interestingly, serum levels of fibroblast growth factor-21 (FGF21) were significantly higher in patients with MASLD with advanced hepatic fibrosis (F3-F4) than in those with lower fibrosis stages (F0-F2) (197.49 ± 198.27 pg/mL vs 95.62 ± 83.67 pg/mL; P = 0.049). In addition, patients with MASLD with severe hepatosteatosis (S3) exhibited significantly higher serum levels of irisin (1116.87 ± 1161.86 pg/mL) than those with lower grades (S1-S2) (385.21 ± 375.98 pg/mL; P = 0.001)., Conclusion: SMAs were uncommon in the patients with MASLD studied. Higher serum levels of irisin and FGF21 were detected in patients with advanced liver steatosis and fibrosis, respectively, with potential implications as biomarkers., Competing Interests: Conflict-of-interest statement: This research was funded by Persan Farma Laboratoires. Also, this work was supported by contract CP19/00032 from Instituto de Salud Carlos III (ISCIII, Spain) and Fondo Europeo para el Desarrollo Regional (FEDER), and CIBERDEM (ISCIII) to AGR. CEFG was supported by a Sara-Borrell postdoctoral contract (CD20/00199) from ISCIII/FEDER (Spain). AB was supported by a research contract (PEJ-2020-AI/BMD-18301) funded by Comunidad de Madrid (Spain)., (©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.)

Introduction: Children with beta-thalassemia major (β-TM) commonly experience metabolic bone diseases. Understanding fibroblast growth factor 23 (FGF-23) levels in these children can shed light on phosphate dysregulation. This study aimed to assess changes in phosphate homeostasis and associated factors, including FGF-23 and explore relationships between iron overload, FGF23 levels, and phosphorus regulation for clinical management of phosphate disorders, in children with β-TM., Methods: 143 β-TM patients (57.3% male, median age 12 years) were recruited from Fatimid Foundation Karachi, a blood transfusion facility from January to October 2022. Clinical and biochemical evaluations were conducted at Aga Khan University Hospital, including serum ferritin, calcium (Ca), phosphate (P), vitamin D levels, and FGF-23. Descriptive and inferential statistics including multivariable analysis were applied., Results: This study enrolled 143 patients, with 57.3% males. The median age was 12 years, with 53% underweight. Blood transfusion rates varied, with 66.4% receiving 2/month. Bone/joint pain was reported by 76.2%, with 60.8% requiring analgesics. Median serum ferritin was 2768.3 ng/mL. Hypophosphatemia and hyperphosphatemia were observed in 5.6% and 3.5% of participants, respectively. Vitamin D deficiency/insufficiency affected 92.3%. Plasma c-FGF23 was elevated in 60.8%, while i-FGF23 was high in 14%. A low TMP-GFR (glomerular filtration rate) was associated with high c-FGF23 and low i-FGF23. Multivariable regression revealed c-FGF23, TMP:GFR, Corrected Ca, iPTH, and an interaction term between corrected Ca and iPTH as predictors of serum P variability (~75%)., Conclusion: The study identified contributors to the variations observed in serum P levels in individuals with β-TM and recommends multidisciplinary care and prospective future studies to form targeted interventions for this population., Competing Interests: No authors have competing interests., (Copyright: © 2025 Jafri et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Purpose: High consumption of ultra-processed food (UPF) is associated with an increased risk of developing chronic diseases. Inflammation may be one of the underlying mechanisms behind this association. However, only a limited number of studies have investigated the association between UPF consumption and a few selected inflammation biomarkers, yielding inconsistent results. This study aimed to assess the cross-sectional association between UPF consumption (as a whole and 10 sub-categories), and 78 circulating proteins related to inflammation., Methods: The present study included 1594 adult participants from the STANISLAS cohort. UPF consumption was estimated using the NOVA classification, and linear regression models were used to assess their association with circulating proteins., Results: UPFs accounted for 28% of the total energy intake and 5.7 servings on average per day. In the unadjusted model, 15 circulating proteins had a significant association with UPF consumption. After adjustment, only (FGF-19) was significantly associated with UPF consumption (β =  - 0.02[- 0.03; - 0.003])., Conclusion: UPF consumption was negatively associated with Fibroblast Growth Factor 19 (FGF-19) serum levels. When considering UPF sub-categories, no circulating proteins were associated with dairy products and dairy desserts. Of note, circulating proteins were differentially associated depending on the sub-category of UPF. Further studies are needed to better understand the link between UPF and inflammation., Competing Interests: Declarations. Conflict of interest: NG has received honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Lilly, Novartis, Novo Nordisk, Roche Diagnostics, NP Medical, and Echosens. The other co-authors declare that they have no conflict of interest., (© 2025. Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: This meta-analysis aims to investigate the impact of abnormalities in mineral metabolic markers, including serum phosphate and calcium, intact parathyroid hormone (iPTH), and fibroblast growth factor 23 (FGF23) on the risk of fractures in patients with chronic kidney disease (CKD)., Methods: A systematic search was conducted across MEDLINE, Web of Science, EMBASE, ClinicalTrials.gov, and the Cochrane Central Register for Controlled Trials. The outcomes were association of mineral metabolic markers with the risk of fractures in patients with chronic kidney disease. Pooled risk estimates and 95% confidence intervals (CIs) were calculated using fixed-effects or random-effects models., Results: Thirty-two studies were included in the meta-analysis. High and low levels of serum phosphate in hemodialysis (HD) patients were both associated with an increased risk of fractures (RR = 1.08, 95% CI 1.02-1.15, P = 0.013; RR = 1.13, 95% CI 1.02-1.25, P = 0.022, respectively). Similarly, abnormal levels of iPTH in CKD patients, both high and low, were associated with increased fracture risk (RR = 1.25, 95% CI 1.20-1.31, P < 0.001; RR = 1.41, 95% CI 1.10-1.82, P = 0.007, respectively). Elevated FGF23 levels were also linked to an increased risk of fractures (RR = 1.32, 95% CI 1.06-1.66, P = 0.015). While a higher level of calcium exhibited a trend towards reduced fracture incidence without statistical significance (RR = 0.90, 95% CI 0.77-1.05, P = 0.181), lower calcium levels tended to increase fracture risk without statistical significance (RR = 1.11, 95% CI 0.99-1.24, P = 0.087). Notably, subjects treated with calcium and phosphorus modulating drugs demonstrated a statistically significant reduction in fractures among CKD patients undergoing dialysis (phosphate binders, RR = 0.79, 95% CI 0.70-0.89; cinacalcet, RR = 0.74, 95% CI 0.59-0.93; vitamin D analogues, RR = 0.82, 95% CI 0.74-0.92, respectively)., Conclusion: This meta-analysis underscores the association between abnormal mineral metabolic markers, including high serum phosphate, iPTH, and FGF23, and an increased risk of fractures in CKD patients. Notably, both elevated and decreased levels of phosphate and iPTH contribute to fracture risk. The efficacy of active vitamin D, phosphorus binders, and cinacalcet in preventing fractures was observed in HD patients but not in the non-dialysis CKD population., Trial Registration: PROSPERO CRD42023493951., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Background: Our mechanistic understanding on metabolic beneficial effects of dietary polyphenols has been hampered for decades due to the lack of functional receptors for those compounds and their extremely low plasma concentrations. Recent studies by our team and others suggest that those dietary polyphenols target gut microbiome, and gut-liver axis and that hepatic fibroblast factor 21 (FGF21) serves as a common target for various dietary interventions., Methods: Utilizing liver-specific FGF21 null mice (lFgf21 -/- ), we are asking a straightforward question: Is hepatic FGF21 required for curcumin or resveratrol, two typical dietary polyphenols, in exerting their metabolic beneficial effect in obesogenic diet-induced obesity mouse models., Results: On low-fat diet feeding, no appreciable defect on glucose disposal was observed in male or female lFgf21 -/- mice, while fat tolerance was moderately impaired in male but not in female lFgf21 -/- mice, associated with elevated random and fasting serum triglyceride (TG) levels, and reduced hepatic expression of Ehhadh and Ppargc1a, which encodes the two downstream effectors of FGF21. On high-fat-high-fructose (HFHF) diet challenge, Fgf21 fl/fl but not lFgf21 -/- mice exhibited response to curcumin intervention on reducing fasting serum TG, and on improving fat tolerance. Resveratrol intervention also affected FGF21 expression or its downstream effectors. Metabolic beneficial effects of resveratrol intervention observed in HFHF diet-challenged Fgf21 fl/fl mice were either absent or attenuated in lFgf21 -/- mice., Conclusion and Significance: We conclude that hepatic FGF21 is required for curcumin or resveratrol in exerting their major metabolic beneficial effect. The recognition that FGF21 as the common target of dietary intervention, demonstrated in current as well as previous investigations, brings us a novel angle in understanding metabolic disease treatment and prevention. It remains to be further explored how various dietary interventions regulate FGF21 expression and function, via certain common or unique gut-liver or gut-brain-liver axis., Competing Interests: Competing interests: The authors declare no competing interests. Ethical approval: All animal experiments were approved by the University Health Network Animal Care Committee (AUP 2949.18) and were performed in accordance with the guidelines of the Canadian Council of Animal Care., (© 2025. The Author(s).)

The multitude of processes in which the liver participates makes it vulnerable to many serious diseases, which can lead to chronic organ failure. Modern medicine bases the treatment of end-stage liver failure on liver transplantation. To ensure the proper functioning of the transplanted liver, a balance of cellular and immunological processes and appropriate concentrations of many different factors are necessary, including, among others, fibroblast growth factors (FGFs). Over the last several years, studies have focused on some FGF growth factors, i.e., FGF19 and FGF21. These two growth factors belong to the FGF19 subfamily, and we concentrate on these two factors in our work. These factors diffuse away from the site of secretion into the blood, acting as hormones. FGF19 is a growth factor with a high therapeutic potential, involved in the homeostasis of bile acids necessary to maintain the proper function of the transplanted liver. FGF21, in turn, plays an important role in regulating lipid and glucose homeostasis. This study aimed to evaluate changes in the concentration of growth factors FGF19 and FGF21 in the plasma of 84 patients before, 24 h, and 2 weeks after liver transplantation (ELISA test was used). Additionally, the correlations of the basic laboratory parameters-alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (GGTP), alkaline phosphatase (ALP), total bilirubin, C-reactive protein (CRP), albumin and hemoglobin (Hb)-with FGF19 and FGF21 were determined. Our studies noted statistically significant changes in FGF19 and FGF21 concentrations before, 24 h, and 2 weeks after liver transplantation. The highest values for FGF19 before liver transplantation and the lowest values 24 h after this surgery were observed for FGF21; the highest concentrations were observed the day after liver transplantation, and the lowest were observed immediately before surgery. Observations of increases and decreases in the concentration of the examined factors at individual time points (before and after transplantation) allow us to suspect that FGF19 has an adaptive and protective function toward the transplanted liver. At the same time, FGF21 may affect the regenerative mechanisms of the damaged organ., Competing Interests: The authors declare no conflicts of interest.

Background: SLE is associated with significant morbidity, especially in the case of renal involvement. Mitochondrial dysfunction plays a significant role in SLE and may be assessed by measuring mitochondrial DNA (mtDNA) and cytokines reflecting mitochondrial stress (mitokines). Circulating mtDNA is a promising biomarker in SLE and appears to be reduced in severe SLE. However, measuring circulating mtDNA is challenging and reported methods are heterogenous. Our study aimed at evaluating whole blood mtDNA to nuclear DNA (nucDNA) ratio using droplet-digital PCR and circulating mitokines, growth differentiation factor 15 (GDF-15) and fibroblast growth factor 21 in SLE with and without renal involvement., Methods: Cross-sectional study involving 195 patients with SLE and age-matched healthy volunteers (HV) as control. Biomarkers were compared in patients with and without renal involvement (defined by estimated glomerular filtration rate <60 mL/min or proteinuria >0.5 g/day) and in those with active and inactive SLE., Results: Compared with HV, patients with SLE displayed lower mtDNA/nucDNA ratios, especially in the case of renal involvement. Accordingly, mitokines were increased in patients with SLE with renal involvement. We found no correlation between mtDNA/nucDNA ratio and global disease activity. Mitokine levels, on the other hand, correlated with disease activity, in particular GDF-15 even after adjusting for renal involvement., Conclusion: Our findings suggest that lower whole blood mtDNA/nucDNA ratio, a surrogate marker for mitochondrial dysfunction, reflects renal damage, while GDF-15 may also reflect disease activity in SLE. Further studies are needed to assess the clinical value of these markers as predictors for active lupus nephritis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Objective: The underlying connections between obesity and non-alcoholic fatty liver disease (NAFLD) are not fully understood. One potential link might be the imbalanced adipokines and hepatokines. We aimed to explore the associations between specific adipokines/hepatokines and NAFLD in Chinese youth and to determine how these biomarkers mediate the obesity-NAFLD relationship., Methods: We analyzed data from the 10-year follow-up visit of the Beijing Children and Adolescents Metabolic Syndrome (BCAMS) study (n = 509; mean age = 20.2 years) for a comprehensive metabolic risk assessment, including liver ultrasound and plasma measurements of adiponectin, leptin, fibroblast growth factor 21 (FGF21), retinol-binding protein 4 (RBP4), and angiopoietin-like protein 8 (ANGPTL8). Longitudinal analysis was performed on a subgroup (n = 307), with complete baseline (mean age = 12.2 years) and follow-up data. Mediation models assessed how obesity at baseline and follow-up influence NAFLD through these biomarkers., Results: Participants with NAFLD exhibited a high prevalence of central obesity (90.9%). Both cross-sectional and prospective analyses identified increased RBP4, FGF21, leptin, and decreased adiponectin levels as significant predictors of NAFLD. More adipokine/hepatokine abnormalities were linked to higher NAFLD risk. Furthermore, ratios reflecting adipokine/hepatokine imbalances, including leptin/adiponectin, FGF21/adiponectin, and RBP4/adiponectin, demonstrated stepwise changes correlating with NAFLD severity (all p < 0.05). Mediation analysis indicated that these four adipokines/hepatokines accounted for approximately 72.4% of the central obesity-NAFLD relationship and 80.1% in the subgroup analysis using baseline childhood data., Conclusions: Dysregulated adipokines/hepatokines may explain the onset or progression of obesity-related NAFLD in youths. Higher RBP4, FGF21 and leptin, alongside lower adiponectin, could serve as early biomarkers for NAFLD., Competing Interests: Declarations. Conflict of interest: Xinghao Yi, Lanwen Han, Lianxia Li, Haoxue Zhu, Ming Li and Shan Gao declare that they have no conflict of interest. Ethical approval: All participants and/or their parents or guardians gave written informed consent through all the study processes. Patient consent: The study protocol was approved by the Ethics Committee at the Beijing Chaoyang Hospital and was in accordance with the declaration of Helsinki on ethical principles for medical research involving human subjects., (© 2024. Asian Pacific Association for the Study of the Liver.)

Aims: Fibroblast growth factor 21 (FGF21) decreases hepatic lipogenesis in animal models, and FGF21 analogues decrease serum triglycerides (TG) in adults in phase-2 trials. On the other hand, serum FGF21 is associated with higher TG in observational studies of people with obesity, raising a sort of paradox. We tested the hypothesis that FGF21 is induced by TG in youth with obesity, as a compensatory mechanism., Materials and Methods: We recruited 159 children/adolescents with obesity (80 males, 12.7 ± 2.1 years). Besides serum FGF21 and lipid dosages, we genotyped the Pro446Leu variant at glucokinase regulator (GCKR) as a known marker of genetically increased hepatic de novo lipogenesis, and we used it as an instrumental variable to establish a cause-and-effect relationship between FGF21 and TG, according to a Mendelian randomization analysis., Results: The Pro446Leu variant increased circulating TG (β = +0.35, p < 0.001), which was positively associated with circulating FGF21 (β = +0.42, p < 0.001). The Pro446Leu variant increased FGF-21 (β = +0.14, p = 0.031) with the expected slope (β-coefficient) in case of association entirely mediated by TG: 0.35 (slope between Pro446Ala and TG) × 0.42 (slope between TG and FGF21) = 0.14., Conclusions: Hepatic lipogenesis, marked by GCKR-modulated triglycerides, is significantly associated with increased serum FGF-21 in children/adolescents with obesity., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

X-linked hypophosphatemia (XLH) is a rare genetic disorder caused by excessive fibroblast growth factor 23 (FGF23), leading to low serum phosphate levels resulting in increased risk of fractures and pseudofractures. Burosumab is indicated for the treatment of XLH. In this work, we aimed to understand the quantitative relationship between burosumab-treatment-induced improvements in serum phosphate and reduction in fracture and pseudofracture counts in adults with XLH. Burosumab pharmacokinetic pharmacodynamic data from nine clinical studies were first utilized to update a prior population pharmacokinetic pharmacodynamic (PPKPD) model. The updated PPKPD model predictions for serum phosphate exposures along with other factors (i.e., time and treatment) were utilized to evaluate the relationship on fracture counts using Poisson model. The updated PPKPD model suggested that burosumab concentrations required for 50% of maximal effect decreased with increasing baseline serum phosphate levels. A Poisson model with time from baseline, average serum phosphate, and burosumab treatment described the time-varying fracture and pseudofracture count data appropriately. The model suggested a baseline rate of fracture and pseudofracture of 1.87 counts. The model predicted that fracture counts decrease by 1% each week, and by 23% with each unit increase (1.0 mg/dL) in average serum phosphate from lower limit of normal (2.5 mg/dL). An additional 1% decrease in fracture count each week was attributed to burosumab treatment that could not be explained by improvements in serum phosphate. Overall, the model quantified the relationship between burosumab-treatment-induced serum phosphate improvements and reduction in fracture and pseudofracture counts in patients with XLH over time., (© 2024 The Author(s). The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

The study aims to assess the improvement in bone metabolism in prepubertal girls with Turner Syndrome (TS) after long-term polyethylene glycol recombinant human Growth Hormone (PEG-rhGH) treatment. A 12-month longitudinal prospective study was conducted with 28 prepubertal girls diagnosed with TS. Participants were divided into two groups: 18 received PEG-rhGH therapy (0.1-0.25 mg/kg/week) and 10 did not. Anthropometric measurements, bone turnover markers (BTMs), and serum levels of IGF-1, calcium, and phosphate were collected at baseline and after 12 months. BTMs included bone alkaline phosphatase (BAP), Type I collagen propeptide (CICP), Type I collagen telopeptide (CTX), and fibroblast growth factor 23 (FGF23). After 12 months of PEG-rhGH therapy, the treatment group showed significant increases in growth velocity (GV) and height standard deviation scores (HtSDS). Serum IGF-1 levels increased rapidly within one month and remained elevated. BTMs indicated enhanced bone formation, significantly increasing BAP and CICP, while CTX levels remained low. FGF23 levels initially rose slightly but declined below baseline by 12 months. Elevated blood phosphate levels were observed. PEG-rhGH therapy in children with TS significantly improves linear growth and enhances bone formation markers, benefiting bone metabolism., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Background: Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), is a chronic condition with relapsing-remitting course. Diarrhea and abdominal pain are the most common IBD symptoms. Fibroblast growth factor 19 (FGF19) is an endocrine factor that inhibits hepatic bile acid production and may be used as a diagnostic marker for bile acid malabsorption., Objectives: To assess serum FGF19 levels in active and inactive phases of IBD and find a potential correlation between FGF19 and disease activity., Material and Methods: Fasting serum FGF19 levels were measured in 105 IBD patients (47 UC patients, 41 CD patients without previous ileocecal resection (NR-CD), 17 CD patients after ileocecal resection (IR-CD), and 17 control subjects). The disease activity was assessed using clinical, laboratory and endoscopic criteria., Results: Inverse correlations were found between FGF19 level and intensity of diarrhea (in UC), abdominal pain intensity (in UC and IR-CD) and inflammatory markers (in UC and IR-CD). Moreover, FGF19 concentration was inversely correlated with clinical and endoscopic activity indices in UC and CD., Conclusions: Fluctuations in FGF19 level related to clinical and endoscopic activity of UC and CD revealed a clear pattern of higher values in remission than in active disease phases. Fibroblast growth factor 19 may serve as a potential diagnostic biomarker and constitute a new therapeutic target in IBD.

Objective: To investigate the mediating role of inflammatory biomarkers in the causal effect of body composition on lipids and atherosclerosis., Methods: Retrospective observational study and Mendelian randomization (MR) study were used. Observational analyses were undertaken using data from 4717 children and adolescents aged 6-18 years from Chinese who underwent dual-energy x-ray absorptiometry for body composition. MR analyses were based on summary statistics from UK Biobank, deCODE2021, GLGC, FinnGen and other large consortiums. Inflammatory biomarkers included leptin, insulin, adiponectin, osteocalcin, fibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH)., Results: In retrospective observational study, through osteocalcin, body composition had effects on total cholesterol (TC), triglyceride and low-density lipoprotein cholesterol (LDL). Conversely, fat mass vs. fat-free mass demonstrated opposing effects. Insulin played a role in the association of fat mass with TC and LDL (all P < 0.05). Mediation MR results indicated the causal effect of fat-free mass on coronary atherosclerosis via insulin (indirect effect, OR (odds ratio): 0.95 [95%CI, 0.92-0.98]) and adiponectin (OR: 0.96 [95%CI, 0.93-0.99]). Adiponectin also mediated the causal association of fat mass with coronary heart disease (OR: 1.06 [95%CI, 1.02-1.10]) and coronary atherosclerosis (OR: 1.05 [95%CI, 1.01, 1.09]). Leptin, adiponectin and insulin played roles in mediating the casual effects of body composition on triglyceride and high-density lipoprotein cholesterol., Conclusions: Our findings suggest different body composition exert varying influences on lipids and atherosclerosis through distinct inflammatory biomarkers. The findings may be helpful in tailoring management of body composition based on inflammatory biomarkers with different lipid profiles., Competing Interests: Declaration of interest statement No conflict of interest, financial or otherwise, are declared by the authors., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Breast Implant Illness (BII) is characterized by a cluster of systemic and local symptoms affecting a subset of women with silicone breast implants. While symptom improvement is frequently observed following implant removal, the underlying mechanisms remain poorly understood, and the absence of reliable biomarkers complicates clinical decision-making. Here, we investigate inflammatory protein profiles in 43 women with BII, comparing pre- and post-explantation levels using the Olink Target 96 Inflammation panel and Meso Scale Discovery technology for absolute quantification. Sixteen inflammatory proteins, including MCP-1, CD8A, and CCL11, were elevated post-explantation, with FGF-19 showing the most pronounced increase (64%). FGF-19 levels increased from a median of 136 pg/mL to 195 pg/mL (p = 0.001), comparable to levels in women with silicone breast implants but no BII. We propose that explantation may alleviate FGF-19 signaling disruption, restoring its metabolic benefits. These findings suggest FGF-19 as a potential diagnostic and therapeutic marker for BII, warranting further investigation., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Background: Insulin resistance often occurs in patients with chronic kidney disease (CKD) owing to mineral and bone metabolism disorders. Fibroblast growth factor (FGF)-23 and soluble klotho (s-KL) play crucial roles in linking CKD with mineral and bone metabolism., Objective: This study aimed to examine the relationship between insulin resistance and FGF-23 and s-KL in patients with non-diabetic pre-dialysis patients with CKD., Design and Setting: This research was conducted in the Ankara Bilkent City Hospital Nephrology Clinic. Ankara,Turkey., Methods: This study included 133 male and 150 female patients with pre-dialysis CKD. The patients were compared with 80 healthy individuals. FGF-23 and s-KL levels were determined using enzyme-linked immunosorbent assay kits. The homeostasis model assessment of insulin resistance (HOMA-IR) was used to determine insulin resistance., Results: Creatinine, urine protein/creatinine ratio (UPCR), log10 FGF-23, log 10 s-KL, and HOMA-IR were notably higher, while glomerular filtration rate was notably lower, in patients than in healthy individuals. Stage 5 CKD, log10 FGF-23, creatinine, and UPCR were significantly higher in patients with HOMA-IR > 3.06 compared to those with HOMA-IR ≤ 3.06. No difference was observed in s-KL levels between the two groups. Univariate and multivariate logistic regression analyses revealed an increase in HOMA-IR and log10 FGF-23 values., Conclusions: Insulin resistance, serum FGF-23, and s-KL levels increased in patients compared with healthy individuals. Higher creatinine, proteinuria, and FGF-23 levels were associated with greater insulin resistance. The study highlighted a significant relationship between insulin resistance and FGF-23.

Background: Diabetic neuropathy (DN) is a heterogeneous condition characterized by complex pathophysiological changes affecting both autonomic and somatic components of the nervous system. Inflammation and oxidative stress are recognized contributors to the pathogenesis of DN. This study aims to evaluate the therapeutic potential of dichloroacetic acid (DCA) in alleviating DN symptoms, focusing on its anti-inflammatory and antioxidant properties., Methods: Thirty-two adult male Sprague Dawley rats were divided into four groups: Control, Diabetic, and two DCA-treated groups receiving 5 mg/kg and 10 mg/kg of DCA, respectively. Diabetes was induced with streptozotocin (STZ) injections. Assessments included lipid peroxidation levels, plasma fibroblast growth factor-21 (FGF-21) and transforming growth factor-beta (TGF-β) levels, electrophysiological measurements, histological examination of the sciatic nerve, and motor function tests., Results: Treatment with DCA significantly reduced malondialdehyde (MDA) levels, indicating decreased lipid peroxidation. Plasma TGF-β levels were also lower in the DCA-treated groups, suggesting diminished inflammation. Conversely, plasma FGF-21 levels were elevated. Electrophysiological assessments revealed enhanced compound muscle action potential (CMAP) amplitudes and reduced distal latencies in DCA-treated rats, indicative of improved nerve conduction. Histopathological examinations showed reduced perineural thickness in the sciatic nerves of DCA-treated rats, pointing to decreased fibrosis. Enhanced performance in motor function tests was observed in these rats, implying improved muscle strength and motor capacity., Conclusions: The study demonstrates that DCA therapy significantly reduces oxidative stress and inflammation in a rat model of DN, thereby ameliorating neuropathic symptoms. These results support the potential of DCA as a promising therapeutic agent for DN treatment. Further research is warranted to explore its clinical applications and to provide more detailed insights., Competing Interests: Declarations. Ethics approval and consent to participate: All experimental procedures adhered to the ethical guidelines approved by the Institutional Animal Care and Ethical Committee of the University of Science (Ethical Approval Number: 28210104, Date:13.02.2023). Clinical trial number: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

The effectiveness of established biomarkers for non-alcoholic fatty liver disease (NAFLD) within the updated framework of steatotic liver disease (SLD) remains uncertain. This cohort study examines the association of four metabolic biomarkers-retinol-binding protein 4 (RBP-4), fibroblast growth factor 21 (FGF-21), adiponectin, and osteocalcin-with SLD and its subtypes: metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction with alcohol-related liver disease (MetALD)/alcohol-related liver disease (ALD). Among 3,504 Chinese participants aged 55-70, 938 (26.8%) have developed SLD over 5 years, including 871 with MASLD and 67 with MetALD/ALD. The findings indicate that models incorporating RBP-4, FGF-21, adiponectin, and osteocalcin improve predictive accuracy for SLD beyond conventional models. Notably, adiponectin emerges as the most versatile marker, while elevated baseline levels of FGF-21 or RBP-4 indicate specific needs for metabolic or alcohol-related interventions, respectively, supporting tailored precision medicine strategies., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024. Published by Elsevier Inc.)

Context: Tumor-induced osteomalacia (TIO) is a rare condition with evidence mostly derived from case reports and case series., Objective: We aimed to describe the clinical characteristics of a large cohort of patients diagnosed with TIO, with a focus on patients with nonlocalizing and malignant TIO., Methods: This is a retrospective cohort of patients with TIO in an academic medical center, diagnosed between January 1998 and May 2023. We describe their demographics, biochemistries, tumor features, localization, treatment, and complications., Results: Of 68 patients diagnosed with TIO, 49 (72%) were localizing and 5 (7.4%) were malignant. Of 50 patients who attempted localizing procedures, 29 (58%) achieved cure. Twenty (40%) had persistent disease due to the wrong tumor targeted, or refractory or recurrent tumors, despite up to 6 procedural attempts. There was no difference in demographics, phosphorus, or baseline fibroblast growth factor-23 (FGF23) levels between localizing vs nonlocalizing groups, and malignant vs nonmalignant groups. The lower extremity was the commonest site of localization (37%), with 47% in bone and 53% in soft tissue. Sixty percent of malignant cases were located in the trunk. Tumor size correlated with peak FGF23 (R = 0.566, P < .001) but was not associated with malignancy risk (P = .479). A cut-off FGF23 of >20 times upper limit of normal in the presence of normal renal function (P = .025) and recurrence after initial cure (P = .013) were factors significantly associated with malignancy. The nonlocalizing group had lower survival than the localizing group (P = .0097)., Conclusion: TIO is a condition with significant morbidity. Very high FGF23 levels and disease recurrence are associated with malignant disease. Reasons behind the observation of higher mortality in nonlocalizing TIO should be further explored., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

FGF21 regulates local and systemic metabolic homeostasis. High serum FGF21 was found in obesity, metabolic syndrome, type 2 diabetes mellitus, and coronary heart disease. The pathways linking obesity and breast cancer remain elusive. We aimed to analyze the serum FGF21 in breast cancer patients at diagnosis. Circulating FGF21 levels in 45 breast cancer women (median age 59, range 32-88 years) and 51 age-matched healthy controls were evaluated using a quantitative ELISA assay. Patients' samples were obtained before surgery ahead of any previous therapy. Breast cancer patients showed significantly elevated serum FGF21 (median 267.13, range 28.41-780.45) respect to healthy controls (76.86, 0.00-425.60) (p < 0.0001). A ROC curve determined a cut-off value of 130.64 pg/ml to define positive or high FGF21 levels. Based on this cut-off point, 30/45 (66.7%) breast cancer patients showed positive serum FGF21 levels as compared to 18/51 (35.3%) healthy controls. Circulating FGF21 levels could be useful as a highly sensitive diagnosis biomarker for early breast cancer detection. We did not find any significant association between the serum FGF21 levels, and many clinical-pathological or metabolic parameters determined at the diagnosis of the primary disease. Interestingly, a statistically significant correlation was determined between serum FGF21 and the body mass index (BMI). Furthermore, patients with positive FGF21 serum levels had a worst overall survival (Log Rank Test [Mantle Cox] p = 0.017). We propose serum FGF21 levels determined at the diagnosis of primary breast cancer as a promising diagnostic and prognosis biomarker in this oncological disease., Competing Interests: Declarations. Ethical approval: This research was approved by the Ethics Committee on Research protocols of the Institute of Oncology “Ángel H. Roffo„, School of Medicine of the University of Buenos Aires (UBA). Consent to participate: All patients included in the protocol signed an informed consent. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Context: The pathophysiology of cystinosis-associated metabolic bone disease is complex., Objective: We hypothesized a disturbed interaction between osteoblasts and osteoclasts., Methods: This binational cross-sectional multicenter study included 103 patients with cystinosis (61% children) with chronic kidney disease (CKD) stages 1 to 5D/T at hospital clinics. Ten key bone markers were evaluated., Results: Skeletal complications occurred in two-thirds of the patients, with adults having a 5-fold increased risk compared with children. Patients with CKD stages 1 to 3 showed reduced z-scores for serum phosphate and calcium and suppressed fibroblast growth factor 23 (FGF23) and parathyroid hormone levels, in conjunction with elevated bone-specific alkaline phosphatase levels. Serum phosphate was associated with estimated glomerular filtration rate, combined phosphate and active vitamin D treatment, and native vitamin D supplementation, while serum calcium was associated with age and dosage of active vitamin D. Sclerostin was generally elevated in children, and associated with age, FGF23 levels, and treatment with active vitamin D and growth hormone. The osteoclast marker tartrate-resistant acid phosphatase 5b was increased, and associated with age and treatment with active vitamin D. The ratio of soluble ligand of receptor activator of nuclear factor-κB (sRANKL) and osteoprotegerin (OPG), a surrogate for the regulation of osteoclastogenesis by osteoblasts, was decreased and associated with phosphate and 1,25(OH)2D3 levels. These changes were only partly corrected after transplantation., Conclusion: Bone health in cystinosis deteriorates with age, which is associated with increased osteoclast activity despite counter-regulation of osteoblasts via OPG/RANKL, which in conjunction with elevated sclerostin levels and persistent rickets/osteomalacia, may promote progressive bone loss., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

Background: The connection between fibroblast growth factor 21 (FGF21) and the likelihood of gestational diabetes mellitus (GDM) or preeclampsia (PE) has received more attention recently. Based on published articles, meta-analysis were conducted to explore the differences in FGF21 levels in GDM or PE compared to control groups., Methods: Articles published before April 5, 2024 were searched across four databases: PubMed, Web of Science, Embase, and Cochrane Library, and studies exploring the association of FGF21 levels and GDM or PE were collected. Additionally, ClinicalTrials.gov was also searched for completed and ongoing trials. (Prospero Registration CRD42024504738). The standardized mean differences (SMDs) and 95% confidence intervals (CIs) were utilized to determine FGF21 levels among different groups., Results: This analysis incorporated a total of 16 articles, with 714 GDM and 701 non-GDM in the control group. The GDM-affected pregnant women had greater levels of circulating FGF21 than the control group (SMD = 0.529, 95% CI: 0.168 ~ 0.890, p = 0.004). Moreover, the PE case group covered 120 while the control group contained 134. The findings indicated that pregnant women with PE had significantly greater levels of circulating FGF21 than healthy expectant mothers (SMD = 0.743, 95% CI: 0.527 ~ 0.958, p = 0.000)., Conclusions: Our study found that FGF21 has the potential to serve as a diagnostic marker for GDM or PE. However, due to the limited number of studies and the fact that most data were from the second and third trimesters of pregnancy, more large-scale prospective studies are needed to validate these conclusions, investigate the potential of FGF21 in enabling early diagnosis, and further examine the role of FGF21 in the development and progression of GDM/PE., Trial Registration: Not applicable., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Background: Calcification of the radial artery is one of the main causes of anastomotic stenosis in autogenous arteriovenous fistulas in uremic patients. However, the pathogenesis of calcification is still unknown. This study attempted to screen and validate the risk factors for vascular calcification in patients with uremia., Methods: Serum of blood were collected and tissue samples from radial artery were obtained from 60 uremia patients with or without hemodialysis. General biochemical indicators and calcification-related molecules were collected and detected via ELISA or correlation analysis. In addition, pathological changes and calcification-related molecules in the radial artery were evaluated by HE or immunohistochemical staining., Results: There were differences in total calcium, calcium-phosphorus products, allograft inflammatory factor 1 (AIF-1), intact parathyroid hormone (iPTH), vitamin D (VD), fibroblast growth factor 23 (FGF23) and soluble klotho (sKlotho) in the blood of uremic patients with or without hemodialysis. Furthermore, these factors are related to calcification of the radial artery. The expression of AIF-1, PTHR1, VDR, FGF23 and sKlotho was also increased in the calcified radial artery., Conclusions: The levels of AIF-1, PTH, VDR, FGF23 and sKlotho in serum were associated with calcification of the radial artery in patients with uremia. Furthermore, calcification of the radial artery was further aggravated by abnormalities in calcium and phosphorus in maintenance hemodialysis patients., Competing Interests: Declarations. Ethics approval and consent to participate: This study was carried out in accordance with the Declaration of Helsinki and received ethical approval from the Ethics Committee of the Southern University of Science and Technology Hospital. Informed consent was waived by the Ethics Committee of Southern University of Science and Technology Hospital. Consent for publication: Not applicable. Competing interests: There are no conflicts of interest to declare., (© 2025. The Author(s).)

Background: Liver fibrosis could lead to serious secondary diseases, including osteodystrophy. The interaction between liver and bone has not been fully elucidated, thus existing therapies for osteodystrophy secondary to liver fibrosis are often ineffective. FGF23 was initially found as an endocrine regulator of phosphate homeostasis, but recently, its involvement in fibrosis has been suggested. In this study, we hypothesized that the FGF23 level increases with liver injury, which in turn induces liver fibrosis and osteodystrophy., Methods: Liver fibrosis model mice were generated via carbon tetrachloride administration and bile duct ligation. Fibrosis was assessed using Masson trichrome staining and hydroxyproline assay. The bone structure was evaluated using dual-energy x-ray absorptiometry and microcomputed tomography. Human HSC lines LX-2 and primary rat HSCs were used for in vitro analyses., Results: Carbon tetrachloride-induced and bile duct ligation-induced liver injury increased the serum FGF23 level compared with that in control mice. RNA sequencing analysis of FGF23-treated LX-2 showed that FGF23 promotes the production of matrisome, which helps in forming the extracellular matrix. The FGF receptor antagonist pemigatinib alleviated carbon tetrachloride-induced and bile duct ligation-induced liver fibrosis and the deleterious alterations in bone density and microstructure in mice., Conclusions: The serum FGF23 level increased with liver injury, and FGF23 promoted liver fibrosis. Moreover, pemigatinib alleviated liver fibrosis and hepatic osteodystrophy. These findings suggest that FGF23 mediates the communication between the liver and bone and that FGF23 may be a new therapeutic target for liver fibrosis and subsequent osteodystrophy., (Copyright © 2025 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Our study evaluated the possible interference of Burosumab (human recombinant monoclonal antibody directed against N-terminal domain of FGF23) on the immunoassay of intact FGF23 (iFGF23) with the Liaison XL. The analytical method uses three different antibodies, one of which directed against the N-terminal portion of FGF23. The evaluation of the method accuracy involved the fully automated execution of a dilution test on EDTA plasma from 5 subjects who had not received any monoclonal antibody (mAb), 20 EDTA plasma from patients treated with Burosumab, and 2 EDTA plasma from subjects who had not received any mAb in witch an adequate volume of Burosumab had been added in vitro. One sample with specific diluent (LIAISON® FGF 23) with an adequate volume of Burosumab had been added in vitro. The dilution assay provided highly inaccurate iFGF23 results in samples with therapeutic concentrations of Burosumab and in samples with concentrations below the LoQ (6.5 pg/mL). The addition of Burosumab to the diluent did not produce any analytical interference. Dissociation of iFGF23 from the mAb-target complex in diluted sample could explain the loss of accuracy in the iFGF23 immunoassay using the Liaison XL analyzer. Burosumab could be an interferent in immunoassay procedures of iFGF23.

Overproduction of uric acid caused by increased expression and/or enhanced activity of xanthine oxidase (XO) is one of the major etiologies of hyperuricemia, which had a significant sex differences. As an important enzyme involved in production of reactive oxygen species and uric acid, activity of XO is highly correlated with hyperuricemia and its complications. However, the mechanisms underlying XO dysregulation remain unclear, and sex difference in the prevalence of hyperuricemia has been well known. To explore the potential role of intestinal farnesoid X receptor (FXR) on XO regulation and production, and the mechanisms of sex differences in this pathological process. Two hundred and sixty-one dyslipidemia participants and intestine-specific FXR-knockout mice were used to study the relationship between the intestinal FXR and the serum uric acid level. Western blotting, quantitative real-time PCR, and dual-luciferase reporter assay, were applied to clarify the regulatory role of FXR deficiency on XO. Special inhibitors, agonists, siRNA, sex hormones were used to investigate the mechanism of sex difference in FXR deficiency induced hyperuricemia in cell and animal model. Serum fibroblast growth factor 19 (FGF19) levels were lower in hyperuricemia patients in a sex difference manner. Increased local TNFα level driven by intestinal FXR deficiency/inhibition induced overexpression and hyperactivity of intestinal XO, leading to elevated intestinal uric acid synthesis, and subsequently resulting in hyperuricemia. We found that estrogens inhibited XO expression and activity, whereas androgens enhanced XO activity, leading to the sex difference in FXR deficiency induced hyperuricemia. Infliximab treatment eliminated the sex difference in uric acid levels in intestinal FXR-knockout mice. This study demonstrated the role of intestinal FXR in the pathogenesis of hyperuricemia, and partially elucidated the mechanisms underlying the sex differences of hyperuricemia., Competing Interests: Declaration of competing interest The authors have declared no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: An increase in proximal tubule fluid phosphate concentration is caused by increased serum fibroblast growth factor-23 (FGF23) levels, which resulted in renal tubular damage in a mouse model of chronic kidney disease (CKD). However, few human studies have supported this concept. This study aimed to explore the association among estimated proximal tubule fluid phosphate concentration (ePTFp), serum FGF23 levels, and renal tubular damage biomarkers in middle-aged and older populations with mild decline in renal function., Methods: This cross-sectional study included 218 participants aged ≥45 with CKD stages G2-G4. Anthropometric measurements, blood tests, spot urine biomarkers, renal ultrasonography, cardiovascular assessment, smoking status, and medication usage were obtained in the morning in fasted states. The ePTFp was calculated using serum creatinine, urine phosphate, and creatinine concentrations. Urinary β2-microglobulin (β2-MG) and liver-type fatty acid-binding protein (L-FABP) levels were evaluated to assess renal tubular damage., Results: PTFp, serum FGF23, urinary β2-MG, and urinary L-FABP levels increased with CKD stage progression (stages G2, G3, and G4). However, serum and urine phosphate concentrations were comparable across the CKD stages. Univariate analysis revealed a stronger correlation of ePTFp with serum FGF23, urinary β2-MG, and urinary L-FABP levels than with the corresponding serum and urine phosphate concentrations. Multivariate analyses demonstrated that increased ePTFp was independently associated with elevated serum FGF23 and urinary β2-MG levels, even after adjusting for potential covariates, including the estimated glomerular filtration rate and urinary albumin-to-creatinine ratio., Conclusions: Our results are consistent with the concept in mouse model and suggest that increased ePTFp are associated with increased serum FGF23 levels and renal tubular damage during the early stages of CKD., (Copyright © 2024 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Introduction: Upacicalcet is a novel injectable calcimimetic. This phase 3 multicenter open-label study aimed to assess the long-term efficacy and safety of upacicalcet in hemodialysis (HD) patients with secondary hyperparathyroidism (SHPT)., Methods: Japanese HD patients with serum intact parathyroid hormone (iPTH) levels >240 pg/mL and corrected calcium (cCa) levels ≥8.4 mg/dL were enrolled. Upacicalcet with a dose range of 25-300 µg was administered after each dialysis for 52 weeks. The main efficacy endpoint was the percentage of patients achieving the target iPTH level (60-240 pg/mL)., Results: A total of 157 patients were enrolled, of whom 138 completed the study. Overall, 94.2% of patients achieved the target serum iPTH level at week 52. Neither symptomatic hypocalcemia nor cCa level <7.5 mg/dL occurred despite the negligible increase of concomitant vitamin D receptor activators and calcium carbonate. Upacicalcet improved the control of serum phosphate (P) and calcium levels regardless of baseline PTH levels and decreased intact fibroblast growth factor-23 levels. The largest parathyroid glands shrank, irrespective of their baseline volume or prior calcimimetic usage. Upacicalcet was well tolerated, with no adverse events requiring dose reduction., Conclusion: This is the first study to show that a calcimimetic improves serum P and cCa control without inducing severe hypocalcemia in patients with iPTH levels ≤300 pg/mL. Upacicalcet is efficacious in HD patients with mild-to-severe SHPT, with few safety concerns., Introduction: Upacicalcet is a novel injectable calcimimetic. This phase 3 multicenter open-label study aimed to assess the long-term efficacy and safety of upacicalcet in hemodialysis (HD) patients with secondary hyperparathyroidism (SHPT)., Methods: Japanese HD patients with serum intact parathyroid hormone (iPTH) levels >240 pg/mL and corrected calcium (cCa) levels ≥8.4 mg/dL were enrolled. Upacicalcet with a dose range of 25-300 µg was administered after each dialysis for 52 weeks. The main efficacy endpoint was the percentage of patients achieving the target iPTH level (60-240 pg/mL)., Results: A total of 157 patients were enrolled, of whom 138 completed the study. Overall, 94.2% of patients achieved the target serum iPTH level at week 52. Neither symptomatic hypocalcemia nor cCa level <7.5 mg/dL occurred despite the negligible increase of concomitant vitamin D receptor activators and calcium carbonate. Upacicalcet improved the control of serum phosphate (P) and calcium levels regardless of baseline PTH levels and decreased intact fibroblast growth factor-23 levels. The largest parathyroid glands shrank, irrespective of their baseline volume or prior calcimimetic usage. Upacicalcet was well tolerated, with no adverse events requiring dose reduction., Conclusion: This is the first study to show that a calcimimetic improves serum P and cCa control without inducing severe hypocalcemia in patients with iPTH levels ≤300 pg/mL. Upacicalcet is efficacious in HD patients with mild-to-severe SHPT, with few safety concerns., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Background: A correlation between inflammation and cerebral small vessel disease (CSVD) has been hypothesized by earlier observational research, while this correlation has not been well established. Considering the significant clinical value of this causality determination, Mendelian randomization (MR) was implemented to investigate the causality between inflammatory cytokines and CSVD radiological lesions., Methods: Using the publicly available Genome-Wide Association Study (GWAS) datasets, a bidirectional two-sample MR analysis was employed to infer causality between 91 inflammatory cytokines and CSVD phenotypes [white matter hyperintensity (WHM), fractional anisotropy (FA), mean diffusivity (MD), cerebral microbleeds (CMBs), and lacunar stroke]. A set of methods was used for sensitivity analysis, including Cochran's Q test, MR-Egger intercept method, and MR pleiotropy residual sum and outlier (MR-PRESSO) global test. Furthermore, the strength of causality was assessed using the Bonferroni correction., Results: Our research discovered a mutually predictive bidirectional link between CSVD phenotypes and inflammatory cytokines. Following the application of the Bonferroni correction, fibroblast growth factor 21 (FGF-21) was significantly inversely correlated with an increased risk of CMBs (OR = 0.579, 95 % CI = 0.425-0.789, P = 0.00055). Using sensitivity analysis, heterogeneity, and horizontal pleiotropy were not detected., Conclusion: In this investigation, we established the causality between CSVD and inflammatory cytokines, with FGF-21 in particular significantly reducing the risk of CMBs. With further validation, these findings may provide new targets for the prevention, detection, and intervention of CSVD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Purpose: In patients with Primary Hyperparathyroidism (PHPT) vitamin D deficiency has been associated with more severe presentations. Our aim was to investigate the effects of Vitamin D supplementation on mineral homeostasis and related hormones in individuals with and without PHPT., Methods: Individuals with and without PHPT (CTRL) received 14,000 IU/week of oral vitamin D 3 for 12 weeks. At baseline and endpoint, blood samples were collected to measure 1,25(OH) 2 vitamin D (1,25(OH) 2 D), intact Fibroblast Growth Factor 23 (FGF23), 25OHD, Parathormone, and other biochemical markers. The 1,25(OH) 2 D measurement was performed using liquid chromatography and mass spectrometry (LC-MS/MS)., Results: 70 PHPT patients and 75 CTRL were included, and 55 PHPT and 64 CTRL completed the 12-week protocol. After the intervention, there were significant increases in the FGF23 levels (PHPT: 47.9 ± 27.1 to 76.3 ± 33.3; CTRL: 40.5 ± 13.9 to 59.8 ± 19.8 pg/mL, p < 0.001), and significant decreases in 1,25(OH) 2 D levels (PHPT: 94.8 ± 34.6 to 68.9 ± 25.3; CTRL: 68.7 ± 23.5 to 56.4 ± 20.7 pg/mL, p < 0.001). The reduction of 1,25(OH) 2 D was inversely associated with the increase of FGF23 in both the PHPT (r = -0.302, p = 0.028) and CTRL (r = -0.278, p = 0.027). No changes in plasmatic or uninary calcium concentrations were observed in both groups., Conclusion: The weekly administration of 14,000 IU of Vitamin D3 was safe and efficient to increase in 25OHD levels in both groups. However, a paradoxical decrease in 1,25(OH) 2 D levels measured by LC-MS/MS was associated with a significant increase in FGF23 levels in both groups. This phenomenon might represent a defense against hypercalcemia after vitamin D supplementation and paves the way for new studies in this regard., Competing Interests: Declarations. Conflict of interest: On behalf of all authors, the corresponding author states that there is no conflict of interest. Research involving human participants and/or animals: The study was approved by the Ethics and Research Committee of the Federal University of São Paulo (registration number 89044117.9.0000.5505). Informed consent: All participants signed an Informed Consent Form., (© 2024. The Author(s), under exclusive licence to Italian Society of Endocrinology (SIE).)

Introduction: This study investigated the role of fibroblast growth factor 23 (FGF23)/Klotho in the mortality of patients hospitalized with coronavirus disease 2019 (COVID-19), excluding those with chronic kidney disease (CKD)., Methodology: A prospective cross-sectional study was conducted from April 2021 to May 2022. Patients who tested positive for COVID-19 via polymerase chain reaction and were hospitalized, were classified into two groups (survivors and non-survivors) at the end of their hospital follow-up. Demographic data, clinical status, and prognosis were analyzed., Results: A total of 66 patients (age 58.8 ± 17.0 years, 60.6% male) were included. The mean age of non-survivors (67.2 ± 1 years) was significantly higher than the survivors (49.2 ± 1 years; p < 0.0001). FGF23 was significantly elevated in non-survivors (301 ± 20 pg/mL), compared to survivors (160 ± 36 pg/mL; p < 0.0001). Factors with significant differences (p < 0.001) between the two groups were investigated as independent mortality predictors using logistic regression analysis. FGF23 (p = 0.01), age (p = 0.045), and oxygen saturation at admission (p = 0.02) were independent predictors of mortality. High serum FGF23 levels were associated with COVID-19-related mortality; Klotho levels were lower (p = 0.028). Vitamin D was not significantly different between the groups., Conclusion: Elevated serum FGF23 and parathyroid hormone (PTH), and lower Klotho levels, were associated with COVID-19-related mortality in patients without CKD. There was no association with serum vitamin D levels. Further studies are required to establish the relationship between mortality and FGF23/Klotho, PTH, and vitamin D levels., Competing Interests: No Conflict of Interest is declared, (Copyright (c) 2024 Davut Akin, Burcu B Aydogan, Nilufer Emre, Gulsah Gundogdu, Sehmus Ozmen, Ozgen K Erkek, Mehmet Alpua.)

Background: Oxidative stress plays a crucial role in the pathogenesis of HBV. This study aimed to investigate the value of fibroblast growth factor 21 (FGF21) promoter methylation in the occurrence and development of chronic hepatitis B (CHB) oxidative stress., Methods: A total of 241 participants including 221 patients with CHB and 20 healthy controls (HCs) were recruited. Methylation level of FGF21 promoter in peripheral blood mononuclear cells was quantitatively determined. Enzyme-linked immunosorbent assay was used to assess oxidative stress in CHB patients., Results: Our study shows that the FGF21 methylation level was significantly lower in HBeAg-positive CHB patients compared to HBeAg-negative CHB patients and HCs (P < 0.0001). The oxidative stress of HBeAg-positive CHB patients was more severe. Further correlation analysis showed that there was a significant correlation between the methylation level of FGF21 promoter and the occurrence of oxidative stress in CHB patients. In addition, assessment based on FGF21 promoter methylation level proved effective for predicting oxidative stress occurrence and disease progression among CHB patients., Conclusion: FGF21 promoter methylation level is an important marker for predicting oxidative stress and disease progression in patients with CHB., Competing Interests: Declarations. Ethics approval and consent to participate: This study was conducted in accordance with the Declaration of Helsinki and was approved by the Medical Ethical Committee of Qilu Hospital of Shandong University. (#KYLL-202306-021-1). Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Entinostat, a class I HDACs-selective inhibitor, is currently in clinical trials for treating cancers. In some of the trials, Entinostat treatment frequently causes hypophosphatemia and/or hypocalcemia. Moreover, the effect of Entinostat treatment on bone remains incompletely understood. In this study, we found that Entinostat treatment mildly increased the trabecular but not cortical bone volume, without compromising the bone strength, the numbers of Runx2-positive cells and TRAP-positive cells, and the serum levels of P1NP and TRAP-5b. Entinostat treatment significantly reduced the level of Runx2 mRNA but not Runx2 protein, and as a trend attenuated Ctsk expression. Furthermore, Entinostat treatment did not enhance MC3T3-E1 cell proliferation in vitro. These findings suggest that Entinostat increases trabecular bone volume not by regulating osteoblastogenesis or osteoclastogenesis, but possibly by attenuating the resorption capacity. Unexpectedly, Entinostat treatment increased the expression of Fgf23, whose protein is a hormone that regulates the serum level of phosphate (Pi). Meanwhile, Entinostat treatment increased the serum level of the active form (intact) Fgf23 and reduced that of Pi and calcium (Ca) as well. This study raised a concern about the anabolic effects of Entinostat in bone, and demonstrated that Entinostat treatment causes hypophosphatemia and hypocalcemia by upregulating Fgf23 mRNA and increasing intact Fgf23 protein in serum., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background and Objectives : Uric acid (UA) and the markers of mineral bone metabolism and inflammation are commonly altered in patients with chronic kidney disease (CKD) and are associated with the risk of cardiovascular complications and death. Studies point to a link between high serum UA and mineral bone homeostasis and inflammation, but controversy remains. The aim of this study was to evaluate the relationship between UA levels and mineral bone metabolism and inflammation biomarkers in a sample of Mexican patients with CKD 3a-5. Materials and Methods : This cross-sectional study included 146 Mexican patients with CKD 3a-5. In addition, 25 healthy subjects were included in the study with the aim of generating reference data for comparisons. Metabolic parameters including UA serum concentrations, mineral bone metabolism (parathormone (PTH), fibroblast growth factor 23 (FGF23), calcium, and phosphate), and inflammation (interleukin (IL)-1β, IL-6, and tumor necrosis factor-alpha (TNF-α)) biomarkers were measured in all of the samples and compared as a function of the estimated glomerular function rate (eGFR) or UA levels. Results : Intact PTH, FGF23, and cytokines were higher in advanced CKD stages. Patients with hyperuricemia had significantly higher values of FGF23 and TNF-α compared with those without hyperuricemia. The eGFR was found to be significantly and negatively correlated with all markers. Uric acid was significantly correlated with phosphate, iPTH, FGF23, and TNF-α, whereas iPTH was significantly correlated with FGF23, TNF-α, and FGF23. Finally, a multivariate analysis confirmed the relationship of eGFR with all the tested biomarkers, as well as other relationships of iPTH with UA and TNF-α and of FGF23 with UA and TNF-α. Conclusions : This study supports the relationship between uric acid and levels of mineral bone metabolism and inflammation biomarkers in patients with CKD at middle to advanced stages. In the follow-up of patients with CKD, monitoring and controlling UA levels through nutritional or pharmacological interventions could help in the prevention of alterations related to mineral bone metabolism.

Background and Aims: Previous study reported that plasma fibroblast growth factor 21 (FGF-21) was associated with poor prognosis in patients with ischemic stroke. The purpose of present study was to prospectively investigate the relationship between plasma FGF-21 and post-stroke cognitive impairment (PSCI)., Methods: A total of 600 patients from 7 hospitals were included in this study and plasma FGF-21 levels were examined for all the participants. Cognitive impairment was evaluated using Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) at 3 months after ischemic stroke onset., Results: 323(53.8 %) or 419(69.8 %) participants had PSCI according to MMSE or MoCA at 3 months, respectively. After adjustment for age, National Institutes of Health stroke score, education, and other covariates, the odds ratio of PSCI defined by MMSE and MoCA for the highest vs lowest quartile of plasma FGF-21 was 1.77(1.05-2.98) and 2.40(1.35-4.29), respectively. Multiple-adjusted spline regression model showed a linear association between FGF-21 levels and PSCI (all P < 0.005 for linearity). Subgroup analyses further confirmed these results., Conclusion: Elevated plasma FGF-21 level was associated with PSCI at 3 months after stroke independently of established conventional risk factors, suggesting that plasma FGF-21 may have potential prognostic value in risk stratification of PSCI., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 International Brain Research Organization (IBRO). Published by Elsevier Inc. All rights reserved.)

Background: Diabetic retinopathy (DR), a leading cause of vision loss worldwide, is a common complication of type 2 diabetes mellitus (T2DM) driven by chronic hyperglycemia and microvascular damage. Fibroblast growth factor 21 (FGF21) is crucial in blood sugar regulation and has been linked to DR incidence and severity. While some studies suggest that FGF21 levels may contribute to the DR incidence, others propose a protective role. This discrepancy necessitates further analysis, prompting this study to evaluate the association between FGF21 levels and DR incidence and severity in T2DM patients., Methods: A systematic search was conducted through MEDLINE, Web of Science, Scopus, and Embase up to May 2024 for studies evaluating the association between FGF21 and DR incidence and severity. A random-effect model meta-analysis was performed to calculate the pooled standardized mean difference (SMD) and 95% confidence intervals (CI). A univariate meta-regression was performed to analyze factors influencing pooled size estimates. All statistical analyses were performed using STATA 17 software., Result: This systematic review and meta-analysis of 5,852 participants revealed that FGF21 was positively correlated with DR (SMD 3.11; 95% CI [0.92-5.30], p = 0.005) and sight-threatening DR (STDR) incidence (SMD 3.61; 95% CI [0.82-6.41], p = 0.01). There was no significant difference in FGF21 levels in DR vs STDR ( p = 0.79). Subgroup analysis revealed a significant difference in DR incidence between LDL groups, with higher DR incidence in the group with low-density lipoprotein (LDL) levels >100 ( P < 0.00001). Meta-regression revealed no variables significantly influenced the pooled size estimates., Conclusion: A higher level of FGF21 was associated with higher DR and STDR incidence among T2DM patients, highlighting its potential utilization as a biomarker for DR detection and enabling the exploration of FGF21-based treatment strategies. However, variables independently predicting DR among patients with elevated FGF21 levels shall be explored further., Prospero Id: CRD42024559142., Competing Interests: The authors declare that they have no competing interests., (© 2024 Basir et al.)

A number of studies have reported an association between phosphorus, red blood cell (RBC) production, and iron metabolism. However, it is difficult to distinguish whether the effect of phosphorus is direct or through the actions of FGF23, and it is not clear whether phosphorus is positively or negatively associated with RBC production. In the present study, we investigated the effects of a) increased phosphorus load and b) phosphorus deficiency on erythropoiesis and iron metabolism in association with FGF23. Mice were fed either a 1.2% or 1.65% phosphorus diet and compared to mice fed a control diet containing 0.6% of phosphorus. Moreover, we used two mouse models of hypophosphatemia-induced either by dietary intervention in the form of a low phosphorus (LP) diet (0.02% of Pi) or genetically in a mouse model of X-linked hypophosphatemia (XLH)-that had opposite FGF23 levels. Phosphorus supplementation appropriately increased FGF23 levels leading to excretion of excess phosphorus and normalization of serum phosphorus levels. We also found that a phosphorus-rich diet results in inflammation-induced hypoferremia associated with reduced iron export leading to tissue iron overload. Moreover, high phosphorus intake results in ineffective erythropoiesis caused by decreased production (decreased RBCs, hemoglobin, hematocrit, and erythroid progenitors in the bone marrow) and increased destruction of RBCs, leading to anemia despite increased EPO secretion. These complications occur through the actions of elevated FGF23 in the presence of normophosphatemia. Our data also show that LP diet induces a decrease in the serum concentrations of phosphorus and FGF23, resulting in increased RBC counts, hemoglobin concentration, and hematocrit compared to mice fed normal diet. Moreover, serum iron and transferrin saturation were increased and positively correlated with serum ferritin, liver ferritin protein and mRNA expression in mice fed LP diet. However, hyp mice, the murine model of XLH, exhibit hypophosphatemia and high serum FGF23 levels, along with low number of circulating RBCs, hemoglobin, and hematocrit compared to wild-type mice. In the bone marrow, hyp mice showed reduced number of erythroid progenitors and formed significantly less BFU-E colonies compared to control mice. Serum iron levels and transferrin saturation were also decreased in hyp mice in comparison to control mice. Taken together, our data show that FGF23 acts independent of phosphorus levels to regulate erythropoiesis and iron homeostasis., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Park et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Aims: To evaluate the relation between maternal concentrations of progranulin (PGRN), adipocyte fatty acid-binding protein (AFABP), brain-derived neurotrophic factor (BDNF), and fibroblast growth factor 21 (FGF21) throughout pregnancy with neonatal weight and length at birth and at one month of age, as well as with the percentage of fat mass at one month of age. Besides, we evaluated the association between maternal organokine concentrations with pregestational nutritional status and gestational weight gain (GWG)., Methods: Longitudinal study of 100 healthy pregnant women and their neonates. Conventional biochemical tests were performed and maternal organokine concentrations were measured by ELISA. Neonatal percent fat mass was determined using the PEA POD system, and weight and length were measured using a soft tape measure and a baby scale. Multiple linear regression models were made to predict neonatal anthropometric measurements and adiposity., Results: In all women, PGRN concentrations significantly increased as pregnancy progressed, while AFABP concentrations increased until the third trimester and the highest BDNF concentrations were observed in the second trimester of pregnancy. In contrast, FGF21 concentrations did not change during pregnancy. Only maternal obesity was associated with some differences in AFABP and FGF21 concentrations. Gestational age at birth, maternal age and third-trimester PGRN concentrations predicted weight (gestational age at birth: β=0.11; maternal age: β=-0.033; PGRN: β=0.003, p <0.001) and, together with first-trimester BDNF concentrations, length (gestational age at birth: β=0.76; maternal age: β=-0.21; PGRN: β=0.24; BDNF: β=0.06, p <0.001) at birth. Maternal age and third-trimester BDNF concentrations predicted one-month-old neonate length (maternal age: β=-1.03; BDNF: β=0.45, p <0.001). Pregestational body mass index (pBMI), GWG, second-trimester FGF21 concentrations, and third-trimester AFABP concentrations predicted neonatal fat mass percentage (pBMI: β=-0.58; GWG: β=-0.32; FGF21: β=-0.004; AFABP: β=-1.27, p <0.001) at one month of age., Conclusion: Maternal PGRN, AFABP, and BDNF concentrations, but not FGF21, vary throughout pregnancy. These organokines and maternal characteristics can be useful in the prediction of neonatal weight, length, and percentage fat mass., Competing Interests: OP-P is a speaker of Nestle Nutrition Institute and Exeltis Pharma Mexico. No relationship of any kind exists regarding this manuscript. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Valencia-Ortega, Galicia-Hernández, Castillo-Santos, Molerés-Orduña, Arceo-Cerna, Perichart-Perera, Rodríguez-Cano, Rodríguez-Hernández, Estrada-Gutierrez, Camacho-Arroyo and Solis-Paredes.)

Background: We aimed to examine the relationship between serum FGF20 (fibroblast growth factor 20) levels and stroke prognosis in a multicenter cohort study., Methods and Results: Patients with ischemic stroke/transient ischemic attack were prospectively recruited from 5 participating centers and followed up at 3 months and 1 year. FGF20 levels were measured using the ELISA method. The primary outcome was poor stroke functional outcome (modified Rankin Scale score of 3-6), and secondary outcomes included death and composite vascular events. Multivariable logistic regression analysis or Cox proportional hazards regression analysis was employed to estimate the relationship between FGF20 and study outcomes. Mediation analysis was conducted to examine the mediating effects of traditional risk factors on the association between FGF20 and stroke outcomes. A total of 1011 patients with ischemic stroke were included in the study. After adjusting for potential confounding factors, an elevated serum FGF20 level was associated with a reduced risk of the poor outcome and death. Multivariable adjusted spline regression analysis demonstrated a linear correlation between serum FGF20 levels and the stroke outcomes. The incorporation of FGF20 alongside conventional risk factors marginally enhanced the reclassification of adverse outcomes. Renal function and white blood cell count partially mediated the relationship between FGF20 and the prognosis of ischemic stroke., Conclusions: Elevated FGF20 level is associated with decreased risks of adverse outcomes after ischemic stroke, which was partially mediated by renal function and white blood cells with a modest amount, indicating that serum FGF20 might serve as a promising biomarker for predicting stroke prognosis., Registration: URL: https://www.chictr.org.cn; Unique identifier: ChiCTR2100051104.

In contrast to the extensive evidence from animal studies, only few human data are available on the relation of vascular growth factors and collateral function as well as on the conditions which may modify their release or function. In 31 patients with total coronary occlusion (TCOs) blood was collected from distal to the occlusion site (collateral circulation) and from the aortic root (systemic circulation). Serum was used to assess its mitogenic potential in [ 3 H]-thymidine incorporation assay on human umbilical vein endothelial cells. Serum from patients with the duration of occlusion between 1 and 3 months was significantly more mitogenic as compared to either shorter or longer duration of occlusion. None of the demographic or clinical factors correlated with the mitogenic activity of serum. Serum from patients with TCOs shows a particular time-dependent mitogenic profile with a maximal activity between 1 and 3 months following the occlusion. This profile corresponds to the experimentally described time-line of strongest collateral development and indicates the time-window for possible modification., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background and Aims: Type 2 Diabetes mellitus (T2DM) has reached an epidemic status worldwide. Targeting bile acid signaling has therapeutic potential for treating T2DM. However, the effect of bile acid on T2DM and related mechanisms remains unclear. Here, we explored the role of bile acid in T2DM and elucidated the mechanisms involved., Methods: We established an STZ-induced rat model of T2DM and divided it into an bile acid-treated group and saline control group according to the random number table method. We incubated the bile acid-treated group with human bile acid via middle small intestine intubation and the saline control group was incubated with the same amount of normal saline. We compared the fasting body mass, fasting blood glucose (FBG), 2-hour postprandial blood glucose (2h-PG), fasting plasma insulin (FINS), fasting plasma triglyceride (TG), cholesterol, and total bile acid levels between the two groups one week before surgery and one to four weeks after surgery. Mechanically, Western blot, IHC, and ELISA assays were employed to detect the effect of bile acid on the TGR5/GLP-1 and FXR/FGF15 pathways., Results: Bile acid injection could increase the FINS level and decrease the 2h-PBG level of T2DM rats. In addition, bile acid injection did not affect FBG, fasting body mass, TG, CH, and total bile acid. At the same time, bile acid injection could activate the TGR5/GLP-1 pathway but could not influence the FXR/FGF15 pathway., Conclusion: Bile acids treatment promotes glucose homeostasis in the STZ-induced T2MD rat model via the following mechanism by activating the TGR5/GLP-1 signaling pathway rather than FXR/FGF15 pathway to improve glucose tolerance and thus achieve glucose homeostasis. The bile acid/TGR5/GLP-1 signaling pathway may be a crucial mechanism of controlling the blood glucose of T2DM rats, and TGR5/GLP-1 pathway may constitute novel targets for treating T2DM.

Objectives: Experimental and genetic studies suggest that fibroblast growth factor 21 (FGF21) modulates macronutrient and alcohol preferences, but evidence of such regulation in humans remains scarce. To address this gap in translation, we aimed to map the relationships between plasma FGF21 levels, FGF21 genetic variation and habitual macronutrient intake in a large human population., Methods: We fine-mapped and performed colocalization of the FGF21 genetic region in GWAS summary statistics of plasma FGF21 levels and macronutrient intake. UK Biobank data were used to investigate the associations between FGF21 genetic variants, plasma FGF21 protein levels, and macronutrient intake (including alcohol) assessed with repeated 24-hour recalls. One- and two-sample mendelian randomization were performed to estimate the effects of plasma FGF21 on macronutrient intake., Results: We show that the main macronutrient-associated variant rs838133 and the FGF21 cis-pQTL rs838131, both in the FGF21 gene, are distinct genetic signals. Effect directions also suggest that the influence of FGF21 variation on macronutrient intake appear more complex than by direct mediation through plasma FGF21. Only when considering this complexity at FGF21, is plasma FGF21 estimated to reduce alcohol and increase protein and fat intake using mendelian randomization. Importantly, plasma FGF21 levels also appear markedly elevated by primarily high alcohol and low protein intake., Conclusions: These findings support the feedback diet-regulatory mechanism of FGF21 in humans, but highlights the need for mechanistic characterization of the complex FGF21 genetic region., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Niels Grarup reports a relationship with Novo Nordisk that includes: employment. Matthew P Gillum reports a relationship with Novo Nordisk that includes: employment. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Objectives: To determine the influence of a patent foramen ovale and fibroblast growth factor-21 on core temperature (Tc) responses in SCUBA divers. Additionally, we aimed to quantify the individual and combined influences of wetsuit thickness and anthropometric data on Tc changes during the dives., Design: An experimental study comparing the Tc responses between divers with (n = 17) and without a patent foramen ovale (n = 14)., Methods: A total of 31 divers participated in the study. Tc was measured pre- and post-dive in 17-18 °C sea water using a telemetric pill. Additionally, blood was drawn pre-dive and ~1-2 h post-dive for measurement of fibroblast growth factor-21., Results: There was no influence of a patent foramen ovale on the Tc responses during SCUBA diving in either dive profile (p > 0.05). Additionally, there was no influence of SCUBA diving on fibroblast growth factor-21 concentrations (p > 0.05). The strongest positive and significant associations with the ∆Tc/min were found when multiplying wetsuit thickness in millimeters by body mass (r 2  = 0.3147, p = 0.0010), BMI (r 2  = 0.3123, p = 0.0011), and body surface area (r 2  = 0.2877, p = 0.0019). There was a significant, negative linear relationship between the body surface area to mass ratio and ∆Tc/min (r 2  = 0.2812, p = 0.0032)., Conclusions: These data suggest that Tc regulation during recreational SCUBA diving can be facilitated in part by the appropriate choice of wetsuit thickness for a given set of anthropometric characteristics., Competing Interests: Declaration of interest statement None., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: This research investigates the determinants of circulating FGF21 levels in a cohort reflecting metabolic disease progression, examining the associations of circulating FGF21 with morphology and function of adipose tissue (AT), and with metabolic adjustments following metabolic surgery., Methods: We measured serum FGF21 in 678 individuals cross-sectionally and in 189 undergoing metabolic surgery longitudinally. Relationships between FGF21 levels, AT histology, transcriptomes and proteomes, cardiometabolic risk factors, and post-surgery metabolic adjustments were assessed using univariate and multivariate analyses, causal mediation analysis, and network integration of AT transcriptomes and proteomes., Findings: FGF21 levels were linked to central adiposity, subclinical inflammation, insulin resistance, and cardiometabolic risk, and were driven by circulating leptin and liver enzymes. Higher FGF21 were linked with AT dysfunction reflected in fibro-inflammatory and lipid dysmetabolism pathways. Specifically, visceral AT inflammation was tied to both FGF21 elevation and liver dysfunction. Post-surgery, FGF21 peaked transitorily at three months. Mediation analysis highlighted an underlying increased AT catabolic state with elevated free fatty acids (FFA), contributing to higher liver stress and FGF21 levels (total effect of free fatty acids on FGF21 levels: 0.38, p < 0.01; proportion mediation via liver 32%, p < 0.01). In line with this, histological AT fibrosis linked with less pronounced FGF21 responses and reduced fat loss post-surgery (FFA and visceral AT fibrosis: rho = -0.31, p = 0.030; FFA and fat-mass loss: rho = 0.17, p = 0.020)., Interpretation: FGF21 reflects the liver's disproportionate metabolic stress response in both central adiposity and after metabolic surgery, with its dynamics reflecting an AT-liver crosstalk., Funding: This work was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) through CRC 1052, project number 209933838, CRC1382 and a Walther-Benjamin Fellowship and by a junior research grant by the Medical Faculty, University of Leipzig, and by the Federal Ministry of Education and Research (BMBF), Germany, FKZ: 01EO1501. Part of this work was supported by the European Union's Seventh Framework Program for research, technological development and demonstration under grant agreement HEALTH-F4-2012-305312 and by the CRC1382 and the Novo Nordisk Foundation and by the Deutsche Forschungsgemeinschaft (DFG, German Research foundation) project number 530364326., Competing Interests: Declaration of interests MB received honoraria as a consultant and speaker from Amgen, AstraZeneca, Bayer, Boehringer-Ingelheim, Lilly, Novo Nordisk, Novartis and Sanofi. RC received support for attending meetings and/or travel from the National Doctoral Programme in Infection and Antibiotics (NDPIA) by The Swedish Research Council (VR, Vetenskapsrådet) and DFG (German Research Association). All other authors declare no conflict of interest. TK received two unrestricted research grants from Echosens and Canon Medical Systems., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose: One of the key functions of brown adipose tissue is its positive impact on metabolism. This study aimed to examine the potential involvement of brown fat-related hormones in the development of metabolically healthy obesity. Specifically, we sought to compare the levels of NRG4, FGF21, and irisin between metabolically healthy and unhealthy individuals with obesity., Methods: Patients with BMI ≥ 30 kg/m 2 and aged between 20 and 50 years were included in the study. Among these patients, those who did not have any metabolic syndrome criteria except for increased waist circumference were defined as metabolically healthy obese. Age, gender, BMI, body fat, and muscle mass, matched metabolically healthy and unhealthy obese groups were compared in terms of FGF21, irisin, and NRG4 levels., Results: Metabolically healthy and unhealthy obese groups were similar in terms of age and gender. There was no difference between the two groups in terms of BMI, weight, total body fat, muscle, fat-free mass, distribution of body fat and muscle mass. No statistically significant difference was found between irisin, NRG4, and FGF21 levels between metabolically healthy and unhealthy individuals with obesity. It was found that irisin had a significant inverse correlation with BMI and body fat percentage., Conclusion: The present study showed no difference between metabolically healthy and unhealthy obese individuals in terms of irisin, FGF21, and NRG4 levels. The weak association between irisin and BMI and body fat percentage may suggest a potential link between irisin with metabolic health., Competing Interests: Compliance with ethical standards Conflict of interest The authors declare no competing interests. Ethical approval The study was approved by the Ethical Committee of the Clinical Research of Göztepe Training and Research Hospital with number 2020/0577 on 30.09.2020. (Clinical Trial Gov Number NCT05232695). Research involving human and animal participants All procedures performed in this study, which involves human participants, were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent Informed consent was obtained from all individual participants included in the study., (© 2024. The Author(s).)

Background: Chronic, mildly insufficient sleep is associated with increased cardiometabolic risk, but whether the regulation of thyroid hormones and related growth factors are mechanisms of this association is unclear. We investigated whether 6 wk of mild sleep restriction (SR) alters levels of free thyroxine (FT4), thyroid stimulating hormone (TSH), and fibroblast growth factor-21 (FGF-21), a modulator of FT4, in adults with adequate habitual sleep (AS; 7-9 h/night)., Methods: Healthy adults participated in one of two randomized, crossover studies with identical 6-wk intervention phases: AS and SR (1.5 h/night < AS). Fasted blood samples were collected at baseline and endpoint of each phase. Outcomes were concentrations of FT4, TSH, and FGF-21 (women only). Linear mixed models tested the effects of SR vs AS on the outcomes, adjusting for baseline levels, week, sex, and sex-by-condition interaction., Results: Thirty participants (20 women; 73% racial/ethnic minority; age 21-64 y [M±SD = 36.2 ± 12.8 y]) were included. In the full sample, no effects of SR on FT4 (β±SE = 0.02 ± 0.04, p = 0.654) or TSH (β±SE = -0.02 ± 0.04, p = 0.650) were observed; however, there were sex-by-condition interactions for both FT4 (p-interaction = 0.056) and TSH (p-interaction = 0.049). In sex-stratified analyses, TSH was reduced in SR vs. AS in women (β±SE = -0.11 ± 0.04, p = 0.011, Cohen's f 2  = 0.55) but not men (β±SE = 0.09 ± 0.08, p = 0.261). Among women (n = 17), FGF-21 was not significantly different between conditions (β±SE = 8.51 ± 17.70, p = 0.638)., Conclusion: Prolonged mild SR reduces TSH in women, whereas FT4 and FGF-21 remain unaffected compared with AS. If sustained, disruptions to the thyrotropic axis in women may contribute to their more pronounced cardiometabolic risk in response to SR compared with men., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Burosumab is approved for the treatment of hypophosphatemia in persistent tumor-induced osteomalacia. This work exemplifies a model-informed drug development approach that evaluated burosumab pharmacokinetics and pharmacokinetic/pharmacodynamics in the ultrarare tumor-induced osteomalacia population to support adult and pediatric dosing. Data from tumor-induced osteomalacia participants were combined with data from X-linked hypophosphatemia to understand pharmacokinetic and pharmacokinetic/pharmacodynamic characteristics and covariates specific to tumor-induced osteomalacia. Pharmacokinetic and pharmacokinetic/pharmacodynamic simulations were performed using final models to support dosing recommendations for adults and extrapolation to pediatric patients. Burosumab pharmacokinetics were described using a one-compartment model with first-order absorption and body weight as a significant covariate. Pharmacokinetic/pharmacodynamic relationships were described using a sigmoidal Emax model with significant covariates of baseline fibroblast growth factor 23 on baseline fasting serum phosphate and potency of burosumab response and tumor-induced osteomalacia disease state resulting in a steep slope of response; however, the covariates are not clinically meaningful. Simulations demonstrated that, in pediatric patients, starting doses of burosumab 0.3 and 0.4 mg/kg every 2 weeks at steady state would achieve normal serum phosphate levels in ≥ 30% of patients with relatively low risk of hyperphosphatemia (< 3%). In adults, burosumab 0.3 and 0.5 mg/kg every 4 weeks achieves similar percentages of responders and a relative low risk of hyperphosphatemia (< 7%). Serum phosphate titration-based burosumab dosing increased the probability of achieving normal serum phosphate levels. The models supported a model-informed drug development approach for global approvals of titration-based burosumab dosing, guided by monitoring fasting serum phosphate levels., (© 2024 Kyowa Kirin, Inc. Clinical Pharmacology & Therapeutics © 2024 American Society for Clinical Pharmacology and Therapeutics.)