The role of FGF-21 in promoting diabetic wound healing by modulating high glucose-induced inflammation.

Background: Wound healing is a complex biological process that can be impaired in individuals with diabetes. Diabetic wounds are a serious complication of diabetes that require promoting diagnosis and effective treatment. FGF-21, a member of the endocrine FGF factors family, has caught the spotlight in the treatment of diabetes for its beneficial effects on accelerating human glucose uptake and fat catabolism. However, the therapeutic efficacy of FGF-21 in promoting diabetic wounds remains unknown. This study aims to evaluate the therapeutic potential of FGF-21 in promoting diabetic wound healing. Methods: we investigated the effects of FGF-21 on wound healing related-cells under high-glucose conditions using various assays such as CCK8, scratch assay, flow cytometry analysis, endothelial tube-formation assay, and transmission electron microscopy. Furthermore, we used db/db mice to verify the healing-promoting therapeutic effects of FGF-21 on diabetic wounds. We also conducted qRT-PCR, Western blot, and immunofluorescence staining analyses to elucidate the underlying mechanism. Result: Our results indicate that FGF-21 treatment restored hyperglycemic damage on endothelial cell proliferation, migration, and tube-forming ability. It also reduced endothelial cell death rates under high-glucose conditions. TEM analysis showed that FGF-21 treatment effectively restored mitochondrial damage and morphological changes in endothelial cells caused by glucose. Additionally, qRT-PCR and Western blot analysis indicated that FGF-21 treatment restored inflammatory responses caused by hyperglycemic damage. Animal experiments confirmed these findings, suggesting that FGF-21 may be a promising candidate for the treatment of non-healing diabetic wounds due to its effectiveness in stimulating angiogenesis and anti-inflammatory function. Conclusion: Our study provides evidence that FGF-21 is an essential regulator of wound-related cells under high-glucose conditions and has the potential to be a novel therapeutic target for accelerating diabetic wound healing.

Potential of FGF21 in type 2 diabetes mellitus treatment based on untargeted metabolomics.

Fibroblast growth factor 21 (FGF21) has promise for treating diabetes and its associated comorbidities. It has been found to reduce blood glucose in mice and humans; however, its underlying mechanism is not known. Here, the metabolic function of FGF21 in diabetes was investigated. Diabetic db/db mice received intraperitoneal injections of FGF21 for 28 days, the serum of each mouse was collected, and their metabolites were analyzed by untargeted metabolomics using UHPLC-MS/MS. It was found that FGF21 reduced blood glucose and oral glucose tolerance without causing hypoglycemia. Moreover, administration of FGF21 reduced the levels of TG and LDL levels while increasing those of HDL and adiponectin. Importantly, the levels of 45 metabolites, including amino acids and lipids, were significantly altered, suggesting their potential as biomarkers. We speculated that FGF21 may treat T2DM through the regulation of fatty acid biosynthesis, the TCA cycle, and vitamin digestion and absorption. These findings provide insight into the mechanism of FGF21 in diabetes and suggest its potential for treating diabetes.

FGF21 as a mediator of adaptive changes in food intake and macronutrient preference in response to protein restriction.

Free-feeding animals navigate complex nutritional landscapes in which food availability, cost, and nutritional value can vary markedly. Animals have thus developed neural mechanisms that enable the detection of nutrient restriction, and these mechanisms engage adaptive physiological and behavioral responses that limit or reverse this nutrient restriction. This review focuses specifically on dietary protein as an essential and independently defended nutrient. Adequate protein intake is required for life, and ample evidence exists to support an active defense of protein that involves behavioral changes in food intake, food preference, and food motivation, likely mediated by neural changes that increase the reward value of protein foods. Available evidence also suggests that the circulating hormone fibroblast growth factor 21 (FGF21) acts in the brain to coordinate these adaptive changes in food intake, making it a unique endocrine signal that drives changes in macronutrient preference in the context of protein restriction.

Circulating serum fibroblast growth factor 21 as risk and prognostic biomarker of retinal artery occlusion.

To evaluate the predictive and prognostic value of fibroblast growth factor 21 (FGF21) levels in retinal artery occlusion (RAO) patients. In this case-control study, serum FGF21 levels were detected by using the ELISA method. Multivariable logistic regression analyses were performed to evaluate the significance of FGF21 in assessing the risk of developing RAO and its impact on vision and concurrent ischemic stroke. Compared with control group, serum FGF21 levels were significantly higher (median [IQR] = 230.90[167.40,332.20] pg/ml) in RAO patients. Multivariate logistic regression analysis showed that elevated serum FGF21 levels were associated with a higher risk of RAO occurrence (P = 0.025, OR [95%CI] = 9.672 [2.573, 36.359]) after adjustment for multiple confounding factors. Higher serum FGF21 levels were negatively associated with visual acuity improvement (P = 0.029, OR [95%CI] = 0.466[0.235, 0.925]) and positively correlated with concurrent ischemic stroke (P = 0.04, OR [95% CI] = 1.944[1.029, 3.672]) in RAO patients. Elevated serum FGF21 levels could promote the development of RAO and indicate worse visual prognosis and increase the risk of concurrent ischemic stroke, which might help clinicians early diagnose and treat RAO patients.

Insufficient secretion of pancreatic FGF21 is the toxicological mechanism and therapeutic target of asparaginase-associated pancreatitis.

Asparaginase-associated pancreatitis (AAP) is a severe and potentially life-threatening drug-induced pancreas targeted toxicity in the combined chemotherapy of acute lymphoblastic leukemia among children and adolescents. The toxicological mechanism of AAP is not yet clear, and there are no effective preventive and treatment measures available clinically. Fibroblast growth factor 21 (FGF21) is a secretory hormone that regulates lipid, glucose, and energy metabolism balance. Acinar tissue is the main source of pancreatic FGF21 protein and plays an important role in maintaining pancreatic metabolic balance. In this study, we found that the decrease of FGF21 in pancreas is closely related to AAP. Pegaspargase (1 IU/g) induces widespread edema and inflammatory infiltration in the pancreas of rats/mice. The specific expression of FGF21 in the acinar tissue of AAP rats was significantly downregulated. Asparaginase caused dysregulation of the ATF4/ATF3/FGF21 axis in acinar tissue or cells, and thus mediated the decrease of FGF21. It greatly activated ATF3 in the acinar, which competed with ATF4 for the Fgf21 promoter, thereby inhibiting the expression of FGF21. Pharmacological replacement of FGF21 (1 mg/kg) or PERK inhibitors (GSK2656157, 25 mg/kg) can significantly mitigate the pancreatic tissue damage and reduce markers of inflammation associated with AAP, representing potential strategies for the prevention and treatment of AAP.

Pegbelfermin for reducing transaminase levels in patients with non-alcoholic steatohepatitis: a dose-response meta-analysis of randomized controlled trials.

Background: The efficacy of Pegbelfermin (PGBF) in treating non-alcoholic steatohepatitis (NASH) remains controversial. Therefore, we conducted a dose-response meta-analysis to explore the effect and pattern of PGBF at different dosages and treatment durations on transaminase reduction in NASH patients. Methods: We conducted searches on PubMed, Embase, Cochrane Library, Web of Science, and ClinicalTrials.gov, and supplemented the search with gray literature and manual searches. Randomized controlled trials (RCTs) evaluating the efficacy of PGBF in NASH patients were included. Risk of bias was assessed by Cochrane Risk of Bias Tool 2.0. We used random-effects models, generalized least squares regression, constrained maximum likelihood, and restricted cubic splines to explore the dose-response relationship. Egger's linear regression was employed to assess publication bias. The study is registered with PROSPERO, CRD42023448024. Results: Four RCT studies from the period 2018-2023, involving 546 participants, were included. No participants discontinued PGBF treatment due to adverse events. High-dose PGBF treatment significantly reduced transaminase levels in NASH patients compared to the low-dose group (ALT %: MD = 14.94, 95% CI = 2.11-27.77; AST %: MD = 9.05, 95% CI = 3.17-14.92). Longer treatment duration further decreased transaminase levels (ALT%: MD = 8.81, 95% CI = 4.07-13.56; AST%: MD = 6.72, 95% CI = 2.62-10.81). Egger's test did not reveal significant publication bias (p > 0.05). Further investigation indicated a ceiling effect of PGBF dosage on transaminase reduction at 30 mg/week, and NASH patients experienced a rebound in transaminase levels after 28 weeks of continuous treatment. Conclusion: There is a positive correlation between PGBF dosage and transaminase reduction within a certain range, showing an overall non-linear dose-response relationship. This finding provides guidance for the clinical application of PGBF. Clinicians should be mindful of the dosage ceiling at 30 mg/week and monitor changes in transaminase levels after 28 weeks for timely adjustments in PGBF dosage. Systematic review registration: PROSPERO, CRD42023448024. https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=448024.

Investigation of Metabolic and Inflammatory Disorder in the Aging FGF21 Knockout Mouse.

Aging is a physiological condition accomplished with persistent low-grade inflammation and metabolic disorders. FGF21 has been reported to act as a potent longevity determinant, involving inflammatory response and energy metabolism. In this study, we engineered aging FGF21 knockout mice of 36-40 weeks and observed that FGF21 deficiency manifests a spontaneous inflammatory response of lung and abnormal accumulation of lipids in liver. On one hand, inflamed state in lungs and increased circulating inflammatory cytokines were found in FGF21 knockout mice of 36-40 weeks. To evaluate the ability of FGF21 to suppress inflammation, a subsequent study found that FGF21 knockout aggravated LPS-induced pulmonary exudation and inflammatory infiltration in mice, while exogenous administration of FGF21 reversed these malignant phenotypes by enhancing microvascular endothelial junction. On the other hand, FGF21 knockout induces fatty liver in aging mice, characterized by excessive accumulation of triglycerides within hepatocytes. Further quantitative metabolomics and lipidomics analysis revealed perturbed metabolic profile in liver lacking FGF21, including disrupted glucose and lipids metabolism, glycerophospholipid metabolism, and amino acid metabolism. Taken together, this investigation reveals the protective role of FGF21 during aging by weakening the inflammatory response and balancing energy metabolism.

Glucosamine Enhancement of Learning and Memory Functions by Promoting Fibroblast Growth Factor 21 Production.

Fibroblast growth factor 21 (FGF21) plays a crucial role in metabolism and brain function. Glucosamine (GLN) has been recognized for its diverse beneficial effects. This study aimed to elucidate the modulation of FGF21 production by GLN and its impact on learning and memory functions. Using both in vivo and in vitro models, we investigated the effects of GLN on mice fed with a normal diet or high-fat diet and on mouse HT22 hippocampal cells, STHdhQ7/Q7 striatal cells, and rat primary cortical neurons challenged with GLN. Our results indicated that GLN promotes learning and memory functions in mice and upregulates FGF21 expression in the hippocampus, cortex, and striatum, as well as in HT22 cells, STHdhQ7/Q7 cells, and cortical neurons. In animals receiving GLN together with an FGF21 receptor FGFR1 inhibitor (PD173074), the GLN-enhanced learning and memory functions and induction of FGF21 production in the hippocampus were significantly attenuated. While exploring the underlying molecular mechanisms, the potential involvement of NF-κB, Akt, p38, JNK, PKA, and PPARα in HT22 and NF-κB, Akt, p38, and PPARα in STHdhQ7/Q7 were noted; GLN was able to mediate the activation of p65, Akt, p38, and CREB in HT22 and p65, Akt, and p38 in STHdhQ7/Q7 cells. Our accumulated findings suggest that GLN may increase learning and memory functions by inducing FGF21 production in the brain. This induction appears to be mediated, at least in part, through GLN's activation of the NF-κB, Akt, p38, and PKA/CREB pathways.

Impaired Fibroblast Growth Factor 21 (FGF21) Associated with Visceral Adiposity Leads to Insulin Resistance: The Core Defect in Diabetes Mellitus.

The Central nervous system (CNS) is the prime regulator of signaling pathways whose function includes regulation of food intake (consumption), energy expenditure, and other metabolic responses like glycolysis, gluconeogenesis, fatty acid oxidation, and thermogenesis that have been implicated in chronic inflammatory disorders. Type 2 diabetes mellitus (T2DM) and obesity are two metabolic disorders that are linked together and have become an epidemic worldwide, thus raising significant public health concerns. Fibroblast growth factor 21 (FGF21) is an endocrine hormone with pleiotropic metabolic effects that increase insulin sensitivity and energy expenditure by elevating thermogenesis in brown or beige adipocytes, thus reducing body weight and sugar intake. In contrast, during starvation conditions, FGF21 induces its expression in the liver to initiate glucose homeostasis. Insulin resistance is one of the main anomalies caused by impaired FGF21 signaling, which also causes abnormal regulation of other signaling pathways. Tumor necrosis factor alpha (TNF-α), the cytokine released by adipocytes and inflammatory cells in response to chronic inflammation, is regarded major factor that reduces the expression of FGF21 and modulates underlying insulin resistance that causes imbalanced glucose homeostasis. This review aims to shed light on the mechanisms underlying the development of insulin resistance in obese individuals as well as the fundamental flaw in type 2 diabetes, which is malfunctioning obese adipose tissue.

Growth hormone resistance induced by amino acid deprivation in fao cells is independent of FGF21.

Adequate dietary intake of amino acids is imperative for normal animal growth. Our previous work using rat hepatocarcinoma Fao cells demonstrated that growth hormone (GH) resistance, coupled with a concurrent reduction in insulin-like growth factor 1 (Igf1) mRNA levels, may underlie the growth retardation associated with a low-protein diet (LPD). In this study, we investigated whether FGF21 contributes to liver GH resistance in Fao rat hepatoma cells under amino acid deprivation conditions. Mice subjected to an LPD exhibited growth retardation, compromised GH signaling in the liver, and decreased blood IGF-1 levels compared with those on a control diet. To assess the potential involvement of fibroblast growth factor (FGF) 21, produced in response to amino acid deficiency, in the development of GH resistance, we examined GH signaling and Igf1 mRNA levels in Fao cells cultured in amino acid-deprived medium. Despite the inhibition of Fgf21 expression by the integrated stress response inhibitor, an inhibitor of the eukaryotic initiation factor 2-activating transcription factor 4 pathway, GH resistance persisted in response to amino acid deprivation. Additionally, the introduction of FGF21 into the control medium did not impair either GH signaling or GH-induced Igf1 transcription. These data suggest that, in Fao cells, amino acid deprivation induces GH resistance independently of FGF21 activity. By shedding light on the mechanisms behind growth retardation-associated GH resistance linked to amino acid deficiencies, our findings provide valuable insights for clinicians in formulating effective treatment strategies for individuals facing these challenges.

Ultrasound­targeted microbubble destruction technology delivering ß­klotho to the heart enhances FGF21 sensitivity and attenuates heart remodeling post­myocardial infarction.

Fibroblast growth factor (FGF)21 is a peptide hormone that improves mitochondrial function and energy metabolism, and the deficiency of its co­receptor ß­klotho (KLB) causes decreased FGF21 sensitivity. The present study examined whether the cardiac delivery of plasmids containing the KLB gene via ultrasound­targeted microbubble destruction (UTMD) enhances the efficacy of FGF21 against heart failure post­acute myocardial infarction (AMI). For this purpose, the levels of FGF21 in patients and rats with heart dysfunction post­infarction were determined using ELISA. Sprague­Dawley rats received the 3X UTMD­mediated delivery of KLB@cationic microbubbles (KLB@CMBs) 1 week following the induction of AMI. Echocardiography, histopathology and biochemical analysis were performed at 4 weeks following the induction of AMI. The results revealed that patients with heart failure post­infarction had higher serum FGF21 levels than the healthy controls. However, the downstream signal, KLB, but not α­klotho, was reduced in the heart tissues of rats with AMI. As was expected, treatment with FGF21 did not substantially attenuate heart remodeling post­infarction. It was found that decreased receptors KLB in the heart may result in the insensitivity to FGF21 treatment. In vivo, the UTMD technology­mediated delivery of KLB@CMBs to the heart significantly enhanced the effects of FGF21 administration on cardiac remodeling and mitochondrial dysfunction in the rats following infarction. The delivery of KLB to the heart by UTMD and the administration of FGF21 attenuated mitochondrial impairment and oxidative stress by activating nuclear factor erythroid 2­related factor 2 signals. On the whole, the present study demonstrates that the cardiac delivery of KLB significantly optimizes the cardioprotective effects of FGF21 therapy on adverse heart remodeling. UTMD appears a promising interdisciplinary approach with which to improve heart failure post­myocardial infarction.

A strategy for oral delivery of FGF21 for mitigating inflammation and multi-organ damage in sepsis.

Fibroblast growth factor 21 (FGF21) shows great therapeutic potential in metabolic, neurodegenerative and inflammatory diseases. However, current FGF21 administration predominantly relies on injection rather than oral ingestion due to its limited stability and activity post-gastrointestinal transit, thereby hindering its clinical utility. Milk-derived exosomes (mEx) have emerged as a promising vehicle for oral drug delivery due to their ability to maintain structural integrity in the gastrointestinal milieu. To address the challenge associated with oral delivery of FGF21, we encapsulated FGF21 within mEx (mEx@FGF21) to protect its activity post-oral administration. Additionally, we modified the surface of mEx@FGF21 by introducing transferrin (TF) to enhance intestinal absorption and transport, designated TF-mEx@FGF21. In vitro results demonstrated that the surface modification of TF promoted FGF21 internalization by intestinal epithelial cells. Orally administered TF-mEx@FGF21 showed promising therapeutic effects in septic mice. This study represents a practicable strategy for advancing the clinical application of oral FGF21 delivery.

Urinary Excretion of Biomolecules Related to Cell Cycle, Proliferation, and Autophagy in Subjects with Type 2 Diabetes and Chronic Kidney Disease.

Dysregulation of cell cycle, proliferation, and autophagy plays a pivotal role in diabetic kidney disease. In this study, we assessed urinary excretion of molecular regulators of these processes that mediate their effects via the PI3K/AKT/mTOR pathway in subjects with long-term type 2 diabetes (T2D) and different patterns of chronic kidney disease (CKD). We included 140 patients with T2D and 20 non-diabetic individuals in a cross-sectional study. Urinary PTEN, Beclin-1, sirtuin 1 (SIRT1), Klotho, fibroblast growth factor 21 (FGF21), and connective tissue growth factor (CTGF) were assessed using ELISA. Patients with T2D, when compared to control, demonstrated increased excretion of PTEN, Beclin-1, SIRT1, FGF21, CTGF, and decreased urinary Klotho (all p < 0.05). In the diabetic group, PTEN, FGF21, and CTGF were significantly higher in patients with declined renal function, while Klotho was lower in those with elevated albuminuria. FGF21 and PTEN correlated inversely with the estimated glomerular filtration rate. There was a negative correlation between Klotho and urinary albumin-to-creatinine ratio. In multivariate models, Klotho and PTEN were associated with albuminuric CKD independently. The results provide further support for the role of PTEN, BECN1, FGF21, Klotho, and CTGF in development albuminuric and non-albuminuric CKD in diabetes.

FGF21 protects against ischaemia reperfusion injury in normal and fatty livers.

BACKGROUND: Liver ischaemia/reperfusion (I/R) injury, which is an inevitable clinical problem of liver resection, liver transplantation and haemorrhagic shock. Fibroblast growth factor 21 (FGF21) was intimately coupled with multiple metabolic processes and proved to protect against apoptosis and inflammatory response in hepatocytes during hepatic I/R injury. However, the regulatory mechanisms of FGF21 in hepatic I/R injury remains unknown. Therefore, we hypothesize that FGF21 protects hepatic tissues from I/R injury. METHODS: Blood samples were available from haemangiomas patients undergoing hepatectomy and murine liver I/R model and used to further evaluate the serum levels of FGF21 both in humans and mice. We further explored the regulatory mechanisms of FGF21 in murine liver I/R model by using FGF21-knockout mice (FGF21-KO mice) and FGF21-overexpression transgenic mice (FGF21-OE mice) fed a high-fat or ketogenic diet. RESULTS: Our results show that the circulating levels of FGF21 were robustly decreased after liver I/R in both humans and mice. Silencing FGF21 expression with FGF21-KO mice aggravates liver injury at 6 h after 75 min of partial liver ischaemia, while FGF21-OE mice display alleviated hepatic I/R injury and inflammatory response. Compared with chow diet mice, exogenous FGF21 decreases the levels of aminotransferase, histological changes, apoptosis and inflammatory response in hepatic I/R injury treatment mice with a high-fat diet. Meanwhile, ketogenic diet mice are not sensitive to hepatic I/R injury. CONCLUSIONS: The circulating contents of FGF21 are decreased during liver warm I/R injury and exogenous FGF21 exerts hepatoprotective effects on hepatic I/R injury. Thus, FGF21 regulates hepatic I/R injury and may be a key therapeutic target.

Regeneration of Non-Alcoholic Fatty Liver Cells Using Chimeric FGF21/HGFR: A Novel Therapeutic Approach.

Non-alcoholic fatty liver disease (NAFLD) has emerged as a significant liver ailment attributed to factors like obesity and diabetes. While ongoing research explores treatments for NAFLD, further investigation is imperative to address this escalating health concern. NAFLD manifests as hepatic steatosis, precipitating insulin resistance and metabolic syndrome. This study aims to validate the regenerative potential of chimeric fibroblast growth factor 21 (FGF21) and Hepatocyte Growth Factor Receptor (HGFR) in NAFLD-afflicted liver cells. AML12, a murine hepatocyte cell line, was utilized to gauge the regenerative effects of chimeric FGF21/HGFR expression. Polysaccharide accumulation was affirmed through Periodic acid-Schiff (PAS) staining, while LDL uptake was microscopically observed with labeled LDL. The expression of FGF21/HGFR and NAFLD markers was analyzed by mRNA analysis with RT-PCR, which showed a decreased expression in acetyl-CoA carboxylase 1 (ACC1) and sterol regulatory element binding protein (SREBP) cleavage-activating protein (SCAP) with increased expression of hepatocellular growth factor (HGF), hepatocellular nuclear factor 4 alpha (HNF4A), and albumin (ALB). These findings affirm the hepato-regenerative properties of chimeric FGF21/HGFR within AML12 cells, opening novel avenues for therapeutic exploration in NAFLD.

Safety and Efficacy of Efruxifermin in Combination With a GLP-1 Receptor Agonist in Patients With NASH/MASH and Type 2 Diabetes in a Randomized Phase 2 Study.

BACKGROUND & AIMS: In phase 2 studies, efruxifermin, an Fc-FGF21 analog, significantly reduced steatohepatitis and fibrosis in patients with non-alcoholic steatohepatitis, now called metabolic dysfunction-associated steatohepatitis (MASH), for which there is no approved treatment. Type 2 diabetes (T2D) and obesity are prevalent among patients with MASH and increasingly treated with glucagon-like peptide-1 receptor agonists (GLP-1RAs). This study evaluated the safety and efficacy of efruxifermin in patients with MASH, fibrosis, and T2D taking a GLP-1RA. METHODS: Cohort D was a double-blind, placebo-controlled, phase 2b study in adults with T2D and MASH with fibrosis (F1-F3) on stable GLP-1RA therapy randomized (2:1) to receive efruxifermin 50 mg or placebo, once weekly for 12 weeks. The primary endpoint was safety and tolerability of efruxifermin added to a stable dose of GLP-1RA. Secondary endpoints included changes in hepatic fat fraction (HFF), markers of liver injury and fibrosis, and metabolic parameters. RESULTS: Adults (N = 31) with T2D and MASH fibrosis (F1-F3) on a stable GLP-1RA (semaglutide, 48.4%; dulaglutide, 45.2%; liraglutide, 6.5%) received efruxifermin 50 mg (n = 21) or placebo (n = 10) for 12 weeks. The addition of efruxifermin to a GLP-1RA appeared safe and well-tolerated. The most frequent efruxifermin-related adverse events were mild to moderate gastrointestinal events. One patient receiving efruxifermin discontinued due to nausea, and another withdrew consent. There were no treatment-related serious adverse events. After 12 weeks, efruxifermin reduced HFF by 65% (P < .0001 vs placebo) compared with a 10% reduction for placebo (GLP-1RA alone). Efruxifermin also improved noninvasive markers of liver injury, fibrosis, glucose, and lipid metabolism while maintaining GLP-1RA-mediated weight loss. CONCLUSIONS: The tolerability profile of efruxifermin added to GLP-1RA appeared comparable to that of either drug alone, while also significantly reducing HFF and noninvasive markers of fibrosis in patients with MASH and T2D. Liver health in patients already on a GLP-1RA may be further improved by addition of efruxifermin. CLINICALTRIALS: gov, Number: NCT05039450.

Critical role of FGF21 in diabetic kidney disease: from energy metabolism to innate immunity.

Diabetic kidney disease (DKD) stands as the predominant cause of chronic kidney disease (CKD) on a global scale, with its incidence witnessing a consistent annual rise, thereby imposing a substantial burden on public health. The pathogenesis of DKD is primarily rooted in metabolic disorders and inflammation. Recent years have seen a surge in studies highlighting the regulatory impact of energy metabolism on innate immunity, forging a significant area of research interest. Within this context, fibroblast growth factor 21 (FGF21), recognized as an energy metabolism regulator, assumes a pivotal role. Beyond its role in maintaining glucose and lipid metabolism homeostasis, FGF21 exerts regulatory influence on innate immunity, concurrently inhibiting inflammation and fibrosis. Serving as a nexus between energy metabolism and innate immunity, FGF21 has evolved into a therapeutic target for diabetes, nonalcoholic steatohepatitis, and cardiovascular diseases. While the relationship between FGF21 and DKD has garnered increased attention in recent studies, a comprehensive exploration of this association has yet to be systematically addressed. This paper seeks to fill this gap by summarizing the mechanisms through which FGF21 operates in DKD, encompassing facets of energy metabolism and innate immunity. Additionally, we aim to assess the diagnostic and prognostic value of FGF21 in DKD and explore its potential role as a treatment modality for the condition.

Computer-aided engineering of stabilized fibroblast growth factor 21.

FGF21 is an endocrine signaling protein belonging to the family of fibroblast growth factors (FGFs). It has emerged as a molecule of interest for treating various metabolic diseases due to its role in regulating glucogenesis and ketogenesis in the liver. However, FGF21 is prone to heat, proteolytic, and acid-mediated degradation, and its low molecular weight makes it susceptible to kidney clearance, significantly reducing its therapeutic potential. Protein engineering studies addressing these challenges have generally shown that increasing the thermostability of FGF21 led to improved pharmacokinetics. Here, we describe the computer-aided design and experimental characterization of FGF21 variants with enhanced melting temperature up to 15 °C, uncompromised efficacy at activation of MAPK/ERK signaling in Hep G2 cell culture, and ability to stimulate proliferation of Hep G2 and NIH 3T3 fibroblasts cells comparable with FGF21-WT. We propose that stabilizing the FGF21 molecule by rational design should be combined with other reported stabilization strategies to maximize the pharmaceutical potential of FGF21.

Association of hepatokines with markers of endothelial dysfunction and vascular reactivity in obese adolescents.

OBJECTIVES: Obesity-induced insulin resistance (IR) is known to influence hepatic cytokines (hepatokines), including fibroblast growth factor (FGF-21), fetuin-A, and chemerin. This study aimed to investigate the association between hepatokines and markers of endothelial dysfunction and vascular reactivity in obese adolescents. METHODS: A total of 45 obese adolescents were categorized into three groups based on glucose tolerance: normal glucose tolerance (NGT), prediabetes (PD), and type 2 diabetes (T2D). We examined the relationships between FGF-21, fetuin-A, and chemerin with endothelial markers (plasminogen activator inhibitor-1 [PAI-1], intercellular adhesion molecule-1 [ICAM-1], and vascular cell adhesion marker-1 [VCAM-1]) and vascular surrogates (brachial artery reactivity testing [BART] and peak reactive hyperemia [PRH]). RESULTS: Obese adolescents (age 16.2±1.2 years; 62 % female, 65 % Hispanic) with NGT (n=20), PD (n=14), and T2D (n=11) had significant differences between groups in BMI; waist-hip ratio (p=0.05), systolic BP (p=0.008), LDL-C (p=0.02), PAI-1 (p<0.001). FGF-21 pg/mL (mean±SD: NGT vs. PD vs. T2D 54±42; 266±286; 160±126 p=0.006) and fetuin-A ng/mL (266±80; 253±66; 313±50 p=0.018), were significantly different while chemerin ng/mL (26±5; 31±10; 28±2) did not significantly differ between the groups. Positive correlations were found between chemerin and both PAI-1 (r=0.6; p=0.05) and ICAM-1 (r=0.6; p=0.05), FGF-21 and PAI-1 (r=0.6; p<0.001), and fetuin-A with TNFα (r=-0.4; p=0.05). Negative correlations were found between chemerin and PRH (r= -0.5; p=0.017) and fetuin-A and PRH (r=-0.4; p=0.05). CONCLUSIONS: In our cohort, IR predicted higher FGF-21 levels suggesting a linear relationship may exist between the two parameters. Hepatokines can augment alterations in the microvascular milieu in obese adolescents as demonstrated by their associations with the markers PAI-1, ICAM-1, and PRH.

Relation of Sleep Quality to a Panel of Plasma Cardiometabolic Markers in Airline Pilots: A Cross-Sectional Study.

Background Insomnia and poor sleep are leading modifiable risk factors for cardiovascular disease. Given the high susceptibility of airline pilots (APs) to sleep disturbances, we sought to investigate the hypothesis that poor sleep in this professional group correlates with alterations in plasma biochemical markers that would reflect critical aspects in the pathophysiology of cardiometabolic disorders. Methods In this preliminary cross-sectional study, we examined the relation of poor sleep to fourteen plasma biomarkers reflecting multiple cardiometabolic pathways in a convenience sample of 117 male APs. The Pittsburgh Sleep Quality Index (PSQI) was used to categorize the participants into good sleepers (n = 70, 59.8%; PSQI scores from 0 to 4) and poor sleepers (n = 47, 40.2%; PSQI scores of 5 or higher). The concentrations of biomarkers were compared between the two groups using both univariable and multivariable analyses. Results Compared to good sleepers, APs identified as poor sleepers exhibited significantly different levels of four plasma cardiometabolic biochemical markers in univariable analysis. However, in multivariable-adjusted analysis, only three biomarkers, adiponectin, fibroblast growth factor (FGF)-21, and growth differentiation factor (GDF)-15, remained independently associated with poor sleep. Conclusion Poor sleep quality in APs correlates with lower plasma concentrations of adiponectin and elevated levels of FGF-21 and GDF-15. Further longitudinal studies are required to elucidate the role of these biomarkers in the link between sleep disturbances and cardiometabolic risk in this professional group.