Our research team previously found that fibroblast growth factor (FGF) 21, a circulating hormone, was significantly associated with atherosclerosis in human and animal models. The relationship between FGF21 and blood pressure (BP) is rarely studied in the Asian population. Therefore, we aimed to explore the relationship of FGF21 with BP in a Chinese population.

We analysed data on 1051 participants from the Shenzhen-Hong Kong United Network on Cardiovascular Disease (SHUN-CVD) study.

The medians of FGF21 level were 355.1 pg/mL (IQR 234.3-574.8 pg/mL) for hypertensive patients and 253.5 (IQR 136.9-403.3 pg/mL) for non-hypertensive participants. Ln-transformed FGF21 level was associated with both systolic and diastolic BP (systolic BP: B = 4.45 [95% CI 3.41-5.49]; p < .001; diastolic BP: B = 2.72 [95% CI 2.03-3.42]; p < .001). After adjusting for sex, age, body mass index, hypercholesterolaemia, diabetes, alcohol consumption, smoking and physical activity, the association remained significant (systolic BP: B = 1.99 [95% CI 1.01-2.97]; p < .001; diastolic BP: B = 1.36 [95% CI 0.69-2.04]; p < .001). Serum FGF21 level was associated with hypertension (quartile 4 vs. quartile 1, OR = 4.19 [95% CI 2.65-6.61]; p for trend < .001).

This is the first study to elucidate the relationship of FGF21 with BP in the Asian population. FGF21 is significantly associated with BP. Besides its use as a biomarker, FGF21 may be a new drug target for hypertension treatment.

Fibroblast growth factor (FGF) 21 is a hormone produced mainly by the liver but also other organs, including the heart. Although FGF21 analogs are used for treating obesity and metabolic syndrome in humans, preclinical and clinical studies have elicited mixed results about whether prolonged FGF21 signaling is protective or detrimental for cardiac function. Based on our findings, showing elevated serum and cardiac FGF21 levels in humans with increased left ventricular afterload, we explore the involvement of FGF21 in cardiac hypertrophy. Our mouse studies reveal interorgan liver-heart crosstalk, which is controlled by an initial hepatic FGF21 release followed by the induction of cardiomyocyte (CM) FGF21 expression. Tissue-specific genetic ablation or anti-sense oligonucleotide-based inhibition of FGF21 shows that, in response to pressure overload, CM FGF21 upregulation is a critical event that is stimulated by liver-derived FGF21 and drives cardiac hypertrophy likely by interfering with cardioprotective oxytocin signaling. Conclusively, the hepato-cardiac FGF21-based signaling axis governs cardiac hypertrophy.

Sotagliflozin, a dual SGLT1/2 inhibitor, enhances glucagon like peptide-1 (GLP-1) levels and GLP-1 receptor agonists are used to manage non-alcoholic fatty liver disease (NAFLD). Study investigates the effects of sotagliflozin on NAFLD, alone and combined with linagliptin, comparing outcomes in normoglycemic and hyperglycemic animal models.Obese fatty liver disease (FLD) model was induced by high-fat diet (HFD) feeding, while a diabetic non-alcoholic steatohepatitis (NASH) model was developed by administering a single dose of streptozotocin to neonatal mice, followed by HFD feeding post-weaning. At termination of the study, parameters including biochemical markers, inflammatory cytokines, hepatic lipid content, and histopathology were assessed.In NASH mice, sotagliflozin and linagliptin reduced hepatic triglycerides by 60% and 44%, respectively, and cholesterol by 46% and 49%. Their combination further decreased triglycerides by 68.5% and cholesterol by 83.9%. In FLD mice, sotagliflozin and linagliptin reduced triglycerides by 33% and 17%, respectively, and cholesterol by 46% and 21%. Combination treatment offered no benefit, reducing triglycerides by 38% and cholesterol by 27%. Both the treatments improved plasma fibroblast growth factor 21, hepatic interlukin-6, glucose tolerance, steatosis and mitigated fat pad weight, but their combination did not show additional benefit. However, combination treatment demonstrated added benefit in modulating NAFLD activity score, liver enzymes, glycogenated hepatic nuclei, plasma glucose and active GLP-1 levels.Study underscores sotagliflozin's potential to mitigate NAFLD and highlights the benefit of combining it with linagliptin in hyperglycemic NASH model, which showed limited efficacy in normoglycemic FLD mice.

Alzheimer's disease (AD) is a neurodegenerative disease caused by the progressive deposition of extracellular amyloid beta (Aβ) and intracellular neurofibrillary tangles (NFTs). Of note, metabolic disorders such as insulin resistance (IR) and type 2 diabetes (T2D) are associated with the development of brain IR and associated neurodegeneration. In addition, AD neuropathology and linked cognitive impairment accelerate the development of peripheral IR and the progression of T2D. Therefore, there is a bidirectional relationship between T2D and AD. It has been demonstrated that AD and T2D induce dysregulation of peroxisome proliferator-activated receptor alpha (PPAR-α) leading to the central and peripheral metabolic disturbances. Hence, dysregulated PPAR-α could be a shared mechanism in both AD and T2D, and restoration of PPAR-α signalling by PPAR-α agonist fenofibrate (FN) may alleviate T2D and AD. Therefore, this review aims to shed light on the potential involvement of PPAR-α in T2D and AD, and how FN could be effective in the management of AD. FN seems to be effective in both AD and T2D by dual neuroprotective and antidiabetic effects that can mitigate AD neuropathology and T2D-related complications by modulating various cellular processes and inflammatory signalling pathways. In conclusion, FN could be a possible candidate in the management of AD and T2D by modulating different signalling pathways involved in the pathogenesis of these conditions.

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.

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.

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.

Hepatic lipogenesis, marked by GCKR-modulated triglycerides, is significantly associated with increased serum FGF-21 in children/adolescents with obesity.

Although primarily secreted by the liver, Fibroblast Growth Factor 21 (FGF21) is also expressed in the pancreas, where its function remains unclear. This study aims to elucidate the role of the glucagon-FGF21 interaction in the metabolic benefits of SGLT2 inhibition (SGLT2i) and hypothesizes it is key to enhancing glucose and lipid metabolism in individuals with glucose intolerance or type 2 diabetes (T2D).

FGF21, FGF1R, and β-klotho expression in human pancreas was analysed by RNAscope, qPCR and immunofluorescent techniques. Glucose-stimulated insulin secretion (GSIS) assay was used to investigate the effects of recombinant FGF21 (rFGF21) on islets from donors with glucose intolerance or T2D. To explore the role of the glucagon-FGF21 axis in the benefits of SGLT2i, we used WT and Sglt2 knockout (KO) mice fed a chow diet (CD) or a high-fat diet (HFD) and chronically treated with vehicle or dapagliflozin.

Chronic rFGF21 treatment enhanced GSIS in islets from donors with glucose intolerance, with increased FGFR1 expression, suggesting FGF21's greater efficacy in the early stages of disease. In diet-induced insulin-resistant mice, dapagliflozin reduced postprandial glycaemia and elevated plasma glucagon and FGF21 levels. Sglt2 KO mice on a CD showed increased fasting plasma glucagon without changes in FGF21. In diet-induced insulin-resistant Sglt2 KO mice, elevated glucagon and FGF21 levels paralleled chronic dapagliflozin treatment, indicating similar metabolic adaptations in both models.

Our findings indicate FGF21 as a crucial mediator in liver-pancreas crosstalk, improving lipid and glucose metabolism, enhancing pancreatic function, and potentiating the therapeutic efficacy of SGLT2i, thereby representing a target for prediabetes treatment.

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).

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.

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.

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.

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.

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.

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).

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.

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.

Introduction: Circuit training is a form of body conditioning with endurance and resistance components. Given the function of skeletal muscle as an endocrine organ secreting various myokines involved in maintaining glucose metabolism homeostasis, our study focused on estimating the impact of the implemented training program on the direction of changes in myokines such as interleukin (IL)-6, IL-10, fibroblast growth factor 21 (FGF21), and irisin in women newly diagnosed with insulin resistance. Methods: This prospective controlled trial randomly divided 42 women into two groups. The training group performed circuit training combining strength (50%-80% of one-repetition maximum) and endurance (50%-75% of heart rate reserve) exercises for 3 months, three 33-min sessions weekly. Exercises were performed on five weight and two cardio machines. The control nontraining group did not change their previous activity. Body composition indicators and IL-6, IL-10, FGF21, and irisin levels were measured before and after the intervention. The data for 27 patients were analysed using two-way repeated measures analyses of variance. Results: The pattern of change in serum IL-6 levels over time differed significantly between the groups (p < 0.05). The patterns of change did not differ significantly between groups for IL-10, FGF21, and irisin. Conclusion: The circuit training program implemented in women newly diagnosed with insulin resistance significantly increased their serum IL-6 and not their IL-10, FGF21, and irisin levels. Trial Registration: ClinicalTrials.gov: NCT04528693.

Glucose metabolism disturbances may result in diabetes-associated cognitive decline (DACI). Methionine restriction (MR) diet has emerged as a potential dietary strategy for managing glucose homeostasis. However, the effects and underlying mechanisms of MR on DACI have not been fully elucidated. Here, we found that a 13-week MR (0.17 % methionine, w/w) intervention starting at 8 weeks of age improved peripheral insulin sensitivity in male db/db mice, a model for type 2 diabetes. Notably, MR significantly improved working as well as long-term memory in db/db mice, accompanied by increased PSD-95 level and reduced neuroinflammatory factors, malondialdehyde (MDA), and 8-hydroxy-2'-deoxyguanosine (8-OHdG). We speculate that this effect may be mediated by MR activating hepatic fibroblast growth factor 21 (FGF21) and the brain FGFR1/AMPK/GLUT4 signaling pathway to enhance brain glucose metabolism. To further delineate the mechanism, we used intracerebroventricular injection of adeno-associated virus to specifically knock down FGFR1 in the brain to verify the role of FGFR1 in MR-mediated DACI. It was found that the positive effects of MR on DACI were offset, reflected in decreased cognitive function, impaired synaptic plasticity, upregulated neuroinflammation, and balanced enzymes regulating reactive oxygen species (Sod1, Sod2, Nox4). Of note, the FGFR1/AMPK/GLUT4 signaling pathway and brain glucose metabolism were inhibited. In summary, our study demonstrated that MR increased peripheral insulin sensitivity, activated brain FGFR1/AMPK/GLUT4 signaling through FGF21, maintained normal glucose metabolism and redox balance in the brain, and thereby alleviated DACI. These results provide new insights into the effects of MR diet on cognitive dysfunction caused by impaired brain energy metabolism.

Hormone therapy, especially androgen deprivation therapy (ADT), is effective against prostate cancer (PC), whereas long-term ADT is a risk for metabolic/cardiovascular disorders including diabetes (DM), hypertension (HT) and dyslipidemia (DL), and might result in progression to castration-resistant prostate cancer (CRPC). We thus conducted a multicenter retrospective cohort study to ask whether CRPC progression would be associated positively with HT, DM or DL and negatively with statins prescribed for treatment of DL. In this study, 1,112 nonmetastatic PC patients undergoing ADT were enrolled. Univariate statistical analyses clearly showed significant association of HT or DM developing after ADT onset, though not preexisting HT or DM, with early CRPC progression. On the other hand, preexisting DL or statin use, but not newly developed DL or started statin prescriptions following ADT, was negatively associated with CRPC progression. Multivariate analysis revealed significant independent association of the newly developed DM or HT, or preexisting statin use with CRPC progression [adjusted hazard ratios (95% confidence intervals): 3.85 (1.65-8.98), p = 0.002; 2.75 (1.36-5.59), p = 0.005; 0.25 (0.09-0.72), p = 0.010, respectively]. Together, ADT-related development of HT or DM and preexisting statin use are considered to have positive and negative impact on CRPC progression, respectively.

Fibroblast growth factor 21 (FGF-21) has been suggested as a potential therapeutic target for insulin resistance in health-related metabolic disorders such as type 2 diabetes. Despite the metabolic effects of resistance (RT) and aerobic training (AT) on diabetes symptoms, uncertainty exists regarding the superiority of effects manifested through these training approaches on FGF-21 and biochemical and physiological variables associated with metabolic disorders in men diagnosed with type 2 diabetes. This study aimed to investigate the impact of a 12-week RT and AT on FGF-21 levels and symptoms associated with metabolic disorders in male individuals diagnosed with type 2 diabetes. Thirty-six sedentary obese diabetic men (40 to 45 years old) were matched based on the level of FGF-1. They and were randomly divided into two training groups (RT, n = 12 and AT, n = 12) performing three days per week of moderate-intensity RT or AT for 12 weeks and an inactive control group (n = 12). Both training interventions significantly improved FGF-21, glucose metabolism, lipid profile, hormonal changes, strength, and aerobic capacity. Subgroup analysis revealed that RT had greater adaptive responses (p < 0.01) in fasting blood sugar (ES = -0.52), HOMA-IR (ES = -0.87), testosterone (ES = 0.52), cortisol (ES = -0.82), FGF-21 (ES = 0.61), and maximal strength (ES = 1.19) compared to AT. Conversely, AT showed greater changes (p < 0.01) in cholesterol (ES = -0.28), triglyceride (ES = -0.64), HDL (ES = 0.46), LDL (ES = -0.73), and aerobic capacity (ES = 1.18) compared to RT. Overall, both RT and AT interventions yielded significant moderate to large ES in FGF-21 levels and enhanced the management of biochemical variables. RT is an effective method for controlling FGF-21 levels and glucose balance, as well as for inducing hormonal changes. On the other hand, AT is more suitable for improving lipid profiles in overweight men with type 2 diabetes mellitus.

X-linked hypophosphatemia (XLH) is characterized by increased concentrations of circulating fibroblast growth factor 23 (FGF-23) resulting in phosphate wasting, hypophosphatemia, atypical growth plate and bone matrix mineralization. Epidemiologic studies suggest a relationship between FGF-23, obesity, and metabolic dysfunction. The prevalence of overweight and obesity is high in children with XLH. We aimed to evaluate the prevalence of obesity and metabolic complications in adults with XLH.

We conducted a prospective cohort study in adult XLH patients from a single tertiary referral center. The proportion of patients with a BMI >25 kg/m2 was the main outcome measure. Body fat mass percentage (FM%) and adipose tissue surfaces were secondary outcome measures. Glucose homeostasis (plasma glucose and insulin concentrations after fasting and 2 hours after an oral glucose tolerance test) was explored in a subgroup of patients and compared with age-, sex-, and BMI-matched healthy controls.

Among 113 evaluated patients, 85 (75%) were female and 110 (97%) carried a PHEX mutation. Sixty-three (56%) patients were overweight or obese, with a median BMI of 25.3 [IQR, 22.7; 29.2] kg/m2. BMI was correlated with FM%, abdominal and thigh subcutaneous and intra-abdominal adipose tissue surfaces. The prevalence of impaired fasting glucose, impaired glucose tolerance, and diabetes was not different between XLH patients and matched controls.

The prevalence of overweight and obesity is high among XLH patients and is associated with excess fat mass. However, the prevalence of glucose homeostasis abnormalities is not increased in patients compared to healthy controls, suggesting that metabolically healthy overweight or obesity predominates.

Background/Objectives: Fibroblast growth factor 21 (FGF21) is a protein hormone involved in physiological conditions in the regulation of energy expenditure and several metabolic processes. The aim of this present study was to analyze the effect of successful kidney transplantations on the plasma FGF21 concentration and to study the factors which may influence plasma FGF21 concentration in patients in long time after kidney transplantation. Methods: This study consisted of two independent parts. The first part was a prospective observation of CKD patients in stage 5 before and then on the 14th and 30th day and 6 months after kidney transplantation. The second part of this study was the cross-sectional study completed in patients at least one year after kidney transplantation and the control group. In CKD patients directly before and during the early period after KTx, plasma FGF21 concentrations were measured four times (immediately before and 14 and 30 days and 6 months after KTx). In patients long time after kidney transplantation and in healthy subjects, plasma FGF21 concentration was measured once. Results: Forty patients with chronic kidney disease (CKD) who were either directly before or within the early period after kidney transplantation (KTx), 184 patients longtime after KTx and 50 healthy subjects were enrolled into this study. In CKD patients at the stage directly before receiving a KTx, the mean plasma FGF21 concentration was significantly higher than in the healthy subjects [1013.0 pg/mL versus 239.5 pg/mL, p < 0.001]. At 14, 30 days, and 6 months after the KTx, a significant decrease of plasma FGF21 was observed, with values of 322.5 pg/mL; 355.0 pg/mL; and 344.0 pg/mL (p < 0.001), respectively]. In patients long time after KTx, a negative correlation was found between the plasma FGF21 concentration and the estimated glomerular filtration rate and a positive correlation was found between the plasma FGF21 concentration and the BMI, the serum concentration of triglycerides, insulin, interleukin-6, CRP, and cystatin C. Conclusions: The plasma FGF21 concentration in patients with end-stage renal disease is higher than in healthy subjects and significantly decreases after a successful KTx. The plasma FGF21 concentration measured by ELISA in patients long time after kidney transplantation seems to be related to the degree of kidney function impairment and their metabolic status. The kidneys appear to be one of the main organs involved in the biodegradation and/or elimination of FGF21.

While the high-dose streptozotocin (STZ; 100 mg/kg) rodent model is the gold standard in modeling Type I diabetes, models for Type II diabetes are needed for this more common form of diabetes. We investigated the retinal, cognitive, and metabolic alterations in a Type II diabetic model induced by high-fat diet (HFD) and low-dose STZ (30 mg/kg). Long Evans rats were assigned to naïve control, HFD, or HFD+STZ groups. Diabetic rats were further stratified into Type I and Type II based on metabolic assessments. Optomotor response (OMR, visual function), electroretinograms (retinal function), and Y-maze (cognitive function) were tested. Serum was analyzed for 12 metabolic markers using a multiplex panel. Type I rats showed severe increases in blood glucose accompanied by impairments in insulin and glucose tolerance, reduced bodyweight, and low insulin levels. In contrast, Type II rats showed moderate changes in blood glucose and insulin and glucose tolerance with weights and insulin levels similar to naïve controls. Type I and II rats showed OMR deficits (p<0.05) and electroretinogram changes (p<0.05). No cognitive deficits were observed. Type I rats displayed reduced serum levels of brain-derived neurotrophic factor (BDNF), C-Peptide, and leptin (p<0.05), and alterations in C-Peptide, PYY, and glucagon levels correlated with retinal function changes (p<0.05). Type II rats exhibited a moderate diabetic state while still developing retinal and visual deficits, which recapitulates phenotypes reported in patients.

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease for which therapeutic options are limited, with an unmet need to identify new therapeutic targets. IPF is thought to be the consequence of repeated microlesions of the alveolar epithelium, leading to aberrant epithelial-mesenchymal communication and the accumulation of extracellular matrix proteins. The reactivation of developmental pathways, such as Fibroblast Growth Factors (FGFs), is a well-described mechanism during lung fibrogenesis. Secreted FGFs with local paracrine effects can either exert an anti-fibrotic or a pro-fibrotic action during this pathological process through their FGF receptors (FGFRs) and heparan sulfate residues as co-receptors. Among FGFs, endocrine FGFs (FGF29, FGF21, and FGF23) play a central role in the control of metabolism and tissue homeostasis. They are characterized by a low affinity for heparan sulfate, present in the cell vicinity, allowing them to have endocrine activity. Nevertheless, their interaction with FGFRs requires the presence of mandatory co-receptors, alpha and beta Klotho proteins (KLA and KLB). Endocrine FGFs are of growing interest for their anti-fibrotic action during liver, kidney, or myocardial fibrosis. Innovative therapies based on FGF19 or FGF21 analogs are currently being studied in humans during liver fibrosis. Recent data report a similar anti-fibrotic action of endocrine FGFs in the lung, suggesting a systemic regulation of the pulmonary fibrotic process. In this review, we summarize the current knowledge on the protective effect of endocrine FGFs during the fibrotic processes, with a focus on pulmonary fibrosis.

Glucagon receptor agonism is currently explored for the treatment of obesity and metabolic dysfunction-associated steatotic liver disease (MASLD). The metabolic effects of glucagon receptor agonism may in part be mediated by increases in circulating levels of Fibroblast Growth Factor 21 (FGF21) and Growth Differentiation Factor 15 (GDF15). The effect of glucagon agonism on FGF21 and GDF15 levels remains uncertain, especially in the context of elevated insulin levels commonly observed in metabolic diseases.

We investigated the effect of a single bolus of glucagon and a continuous infusion of glucagon on plasma concentrations of FGF21 and GDF15 in conditions of endogenous low or high insulin levels. The studies included individuals with overweight with and without MASLD, healthy controls (CON) and individuals with type 1 diabetes (T1D). The direct effect of glucagon on FGF21 and GDF15 was evaluated using our in-house developed isolated perfused mouse liver model.

FGF21 and GDF15 correlated with plasma levels of insulin, but not glucagon, and their secretion was highly increased in MASLD compared with CON and T1D. Furthermore, FGF21 levels in individuals with overweight with or without MASLD did not increase after glucagon stimulation when insulin levels were kept constant. FGF21 and GDF15 levels were unaffected by direct stimulation with glucagon in the isolated perfused mouse liver.

The glucagon-induced secretion of FGF21 and GDF15 is augmented in MASLD and may depend on insulin. Thus, glucagon receptor agonism may augment its metabolic benefits in patients with MASLD through enhanced secretion of FGF21 and GDF15.

Substantial weight loss in people living with type 2 diabetes (T2D) can reduce the need for glucose-lowering medications while concurrently lowering glycemia below the diagnostic threshold for the disease. Furthermore, weight-loss interventions have also been demonstrated to improve aspects of underlying T2D pathophysiology related to ectopic fat in the liver and pancreatic beta-cell function. As such, the purpose of this secondary analysis was to explore the extent to which a low-carbohydrate and energy-restricted (LCER) diet intervention improves markers of beta-cell stress/function, liver fat accumulation, and metabolic related liver function in people with type 2 diabetes.

We conducted secondary analyses of blood samples from a larger pragmatic community-based parallel-group randomized controlled trial involving a 12-week pharmacist implemented LCER diet (Pharm-TCR: <50 g carbohydrates; ~850-1100 kcal/day; n = 20) versus treatment-as-usual (TAU; n = 16). Participants were people with T2D, using ≥ 1 glucose-lowering medication, and a body mass index of ≥ 30 kg/m2. Main outcomes were C-peptide to proinsulin ratio, circulating microRNA 375 (miR375), homeostatic model assessment (HOMA) beta-cell function (B), fatty liver index (FLI), hepatic steatosis index (HSI), HOMA insulin resistance (IR), and circulating fetuin-A and fibroblast growth factor 21 (FGF21). Data were analysed using linear regression with baseline as a covariate.

There was no observed change in miR375 (p = 0.42), C-peptide to proinsulin ratio (p = 0.17) or HOMA B (p = 0.15). FLI and HSI were reduced by -25.1 (p < 0.0001) and - 4.9 (p < 0.0001), respectively. HOMA IR was reduced by -46.5% (p = 0.011). FGF21 was reduced by -161.2pg/mL (p = 0.035) with a similar tendency found for fetuin-A (mean difference: -16.7ng/mL; p = 0.11). These improvements in markers of hepatic function were accompanied by reductions in circulating metabolites linked to hepatic insulin resistance (e.g., diacylglycerols, ceramides) in the Pharm TCR group.

The Pharm-TCR intervention did not improve fasting indices of beta-cell stress; however, markers of liver fat accumulation and and liver function were improved, suggesting that a LCER diet can improve some aspects of the underlying pathophysiology of T2D.

Clinicaltrials.gov (NCT03181165).

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.

Protein leverage (PL) is the phenomenon of consuming food until absolute intake of protein approaches a 'target value', such that total energy intake (TEI) varies passively with the ratio of protein: non-protein energy (fat + carbohydrate) in the diet. The PL hypothesis (PLH) suggests that the dilution of protein in energy-dense foods, particularly those rich in carbohydrates and fats, combines with protein leverage to contribute to the global obesity epidemic. Evidence for PL has been reported in younger adults, children and adolescents. This study aimed to test for PL and the protein leverage hypothesis (PLH) in a cohort of older adults.

We conducted a retrospective analysis of dietary intake in a cohort of 1699 community-dwelling older adults aged 67-84 years from the NuAge cohort. We computed TEI and the energy contribution (EC) from each macronutrient. The strength of leverage of macronutrients was assessed through power functions ( TEI = μ * EC L ). Body mass index (BMI) was calculated, and mixture models were fitted to predict TEI and BMI from macronutrients' ECs.

In this cohort of older adults, 53% of individuals had obesity and 1.5% had severe cases. The mean TEI was 7673 kJ and macronutrients' ECs were 50.4%, 33.2% and 16.4%, respectively for carbohydrates, fat, and protein. There was a strong negative association (L = -0.37; p < 0.001) between the protein EC and TEI. Each percent of energy intake from protein reduced TEI by 77 kJ on average, ceteris paribus. However, BMI was unassociated with TEI in this cohort.

Findings indicate clear evidence for PL on TEI, but not on BMI, likely because of aging, body composition, sarcopenia, or protein wasting.

The effectiveness of ketogenic diet (KD) in ameliorating fatty liver has been established, although its mechanism is under investigation. Fibroblast growth factor 21 (FGF21) positively regulates obesity-associated metabolic disorders and is elevated by KD. FGF21 conventionally initiates its intracellular signaling via receptor β-klotho (KLB). However, the mechanistic role of FGF21-KLB signaling for KD-ameliorated fatty liver remains unknown. This study aimed to delineate the critical role of FGF21 signaling in the ameliorative effects of KD on hepatic steatosis.

Eight-week-old C57BL/6 J mice were fed a chow diet (CD), a high-fat diet (HFD), or a KD for 16 weeks. Adeno-associated virus-mediated liver-specific KLB knockdown mice and control mice were fed a KD for 16 weeks. Phenotypic assessments were conducted during and after the intervention. We investigated the mechanism underlying KD-alleviated hepatic steatosis using multi-omics and validated the expression of key genes.

KD improved hepatic steatosis by upregulating fatty acid oxidation and downregulating lipogenesis. Transcriptional analysis revealed that KD dramatically activated FGF21 pathway, including KLB and fibroblast growth factor receptor 1 (FGFR1). Impairing liver FGF21 signaling via KLB knockdown diminished the beneficial effects of KD on ameliorating fatty liver, insulin resistance, and regulating lipid metabolism.

KD demonstrates beneficial effects on diet-induced metabolic disorders, particularly on hepatic steatosis. Liver FGF21-KLB signaling plays a critical role in the KD-induced amelioration of hepatic steatosis.

Non-alcoholic fatty liver disease (NAFLD), also known as metabolically associated fatty liver disease (MAFLD), is a systemic metabolic disease characterized by lipid accumulation in the liver, lipid toxicity, insulin resistance, intestinal dysbiosis, and inflammation that can progress from simple steatosis to nonalcoholic steatohepatitis (NASH) and even cirrhosis or cancer. It is the most prevalent illness threatening world health. Currently, there are almost no approved drug interventions for MAFLD, mainly dietary changes and exercise to control weight and regulate metabolic disorders. Meanwhile, the metabolic pathway involved in amino acid metabolism also influences the onset and development of MAFLD in the body, and most amino acid metabolism takes place in the liver. Essential amino acids are those amino acids that must be supplemented from outside the diet and that cannot be synthesized in the body or cannot be synthesized at a rate sufficient to meet the body's needs, including leucine, isoleucine, valine (collectively known as branched-chain amino acids), tryptophan, phenylalanine (which are aromatic amino acids), histidine, methionine, threonine and lysine. The metabolic balance of the body is closely linked to these essential amino acids, and essential amino acids are closely linked to the pathophysiological process of MAFLD. In this paper, we will focus on the metabolism of essential amino acids in the body and further explore the therapeutic strategies for MAFLD based on the studies conducted in recent years.

A two-arm randomized open labeled controlled clinical trial was conducted on 50 patients with non-alcoholic fatty liver disease (NAFLD). Subjects were randomized to either receive two tablets of soy isoflavone (100 mg/day) or placebo. At week 12, the serum levels of alanine amino transferase (ALT), aspartate amino transferase (AST) and controlled attenuation parameter (CAP) score were significantly decreased only in the soy isoflavone group (P < 0.05). A significant decline in the gamma glutamyl transferase (GGT) level was observed only in the placebo group (P = 0.017). A significant increase in the serum level of fetuin A was shown in both groups at the end of the trial with a significantly greater increment in the soy isoflavone group compared to the placebo group (P < 0.05). The changes in the serum level of FGF-21 were not significant in any of the two groups. Steatosis grade significantly improved only in the soy isoflavone group (P = 0.045). There was no significant change in the fibrosis grade in the groups. Soy isoflavone intake led to a decrease in ALT, AST, CAP score, steatosis grade and an increase in the level of fetuin A. However, no significant changes were observed in the fibrosis grade and serum levels of GGT and FGF-21.

Fibroblast growth factor 21 (FGF21) levels are often elevated in cardiovascular disease (CVD). However, no study has assessed its association with cardiovascular and all-cause mortality in a population free of clinically evident CVD.

A total of 5543 Multi-Ethnic Study of Atherosclerosis (MESA) participants (mean age 62.7 years, 47.5 % male), free of clinically evident CVD at baseline, were studied. From baseline (2000-2002), 1606 deaths (including 387 CVD deaths) were observed over a median follow-up of 17.7 years. Multivariable Cox regression analysis was performed to assess the association of plasma FGF21 levels with mortality.

FGF21 levels at baseline were associated with all-cause mortality, even after adjustment for traditional risk factors, including demographic, socioeconomic and cardiovascular risk factors (adjusted hazard ratio 1.08 [95% confidence interval 1.01, 1.16] per 1 SD increase in ln-transformed levels; 1.27 for the highest vs, lowest quartile). Baseline FGF21 levels were significantly associated with both CVD and non-CVD mortality in unadjusted models. However, the association with non-CVD mortality, but not CVD mortality, remained statistically significant after adjusting for covariates. Similar results were obtained in FGF21 quartile analyses and also when using competing risk regression or matched case-control cohort in sensitivity analyses.

In subjects without clinically-evident CVD at baseline, over 17.7 years follow-up there is a modest association of baseline FGF21 levels with all-cause mortality. The finding that this is driven primarily by a significant association with non-CVD mortality over almost two decades merits further investigation.

Obesity, a global health challenge, is a major risk factor for multiple life-threatening diseases, including diabetes, fatty liver, and cancer. There is an ongoing need to identify safe and tolerable therapeutics for obesity management. Herein, we show that treatment with artesunate, an artemisinin derivative approved by the FDA for the treatment of severe malaria, effectively reduces body weight and improves metabolic profiles in preclinical models of obesity, including male mice with overnutrition-induced obesity and male cynomolgus macaques with spontaneous obesity, without inducing nausea and malaise. Artesunate promotes weight loss and reduces food intake in obese mice and cynomolgus macaques by increasing circulating levels of Growth Differentiation Factor 15 (GDF15), an appetite-regulating hormone with a brainstem-restricted receptor, the GDNF family receptor α-like (GFRAL). Mechanistically, artesunate induces the expression of GDF15 in multiple organs, especially the liver, in mice through a C/EBP homologous protein (CHOP)-directed integrated stress response. Inhibition of GDF15/GFRAL signalling by genetic ablation of GFRAL or tissue-specific knockdown of GDF15 abrogates the anti-obesity effect of artesunate in mice with diet-induced obesity, suggesting that artesunate controls bodyweight and appetite in a GDF15/GFRAL signalling-dependent manner. These data highlight the therapeutic benefits of artesunate in the treatment of obesity and related comorbidities.

Fibroblast growth factor 21 (FGF21) is a hepatokine with pleiotropic effects on glucose and lipid metabolic homeostasis. Here, we aimed to elucidate the mechanisms underlying the protective effects of FGF21 on L-lactate homeostasis and liver lesions in a type 1 diabetes mellitus (T1DM) mice model.

Six-week-old male C57BL/6 mice were divided into control, T1DM, and FGF21 groups. We also examined hepatic apoptotic signaling and functional indices in wild-type and hydroxycarboxylic acid receptor 1 (HCA1) knockout mice with T1DM or long-term L-lactate exposure. After preincubation of high glucose- or L-lactate treated hepatic AML12 cells, L-lactate uptake, apoptosis, and monocarboxylic acid transporter 2 (MCT2) expression were investigated.

In a mouse model of T1DM, hepatic FGF21 expression was downregulated by approximately 1.5-fold at 13 weeks after the hyperglycemic insult. In vivo administration of exogenous FGF21 (2 mg/kg) to diabetic or L-lactate-infused mice significantly prevented hepatic oxidative stress and apoptosis by activating extracellular signal-regulated kinase (ERK)1/2, p38 mitogen-activated protein kinase (MAPK) and AMP-activated protein kinase (AMPK) pathways. HCA1-KO mice were less susceptible to diabetes- and L-lactate-induced hepatic apoptosis and dysfunction. In addition, inhibition of PI3K-mTOR activity revealed that FGF21 prevented L-lactate-induced Cori cycle alterations and hepatic apoptosis by upregulating MCT2 protein translation.

These results demonstrate that L-lactate homeostasis may be a therapeutic target for T1DM-related hepatic dysfunction. The protective effects of FGF21 on hepatic damage were associated with its ability to ameliorate MCT2-dependent Cori cycle alterations and prevent HCA1-mediated inhibition of ERK1/2, p38 MAPK, and AMPK signaling.

The liver plays a critical role in several metabolic pathways, including the regulation of glucose and lipid metabolism. Non-alcoholic fatty liver disease (NAFLD), the most common chronic liver disease worldwide, is closely associated with insulin resistance (IR) and metabolic syndrome (MetS). Hepatokines, newly discovered proteins secreted by hepatocytes, have been linked to the induction of these metabolic dysregulations. Polycystic ovary syndrome (PCOS), the most common endocrine disorder in women of reproductive age, has been associated with NAFLD and IR, while hyperandrogenism additionally appears to be implicated in the pathogenesis of the latter. However, the potential role of hepatokines in the development of metabolic disorders in PCOS has not been fully investigated. Therefore, the aim of this review is to critically appraise the current evidence regarding the interplay of hepatokines with NAFLD, hyperandrogenism, and IR in PCOS.

Fibroblast growth factor 21 (FGF21) plays a vital role in normal eukaryotic organism development and homeostatic metabolism under the influence of internal and external factors such as endogenous hormone changes and exogenous stimuli. Over the last few decades, comprehensive studies have revealed the key role of FGF21 in regulating many fundamental metabolic pathways, including the muscle stress response, insulin signaling transmission, and muscle development. By coordinating these metabolic pathways, FGF21 is thought to contribute to acclimating to a stressful environment and the subsequent recovery of cell and tissue homeostasis. With the emphasis on FGF21, we extensively reviewed the research findings on the production and regulation of FGF21 and its role in muscle metabolism. We also emphasize how the FGF21 metabolic networks mediate mitochondrial dysfunction, glycogen consumption, and myogenic development and investigate prospective directions for the functional exploitation of FGF21 and its downstream effectors, such as the mammalian target of rapamycin (mTOR).

Insulin regulates energy metabolism involving multiple organ systems. Insulin resistance (IR) occurs when organs exhibit reduced insulin sensitivity, leading to difficulties in maintaining glucose homeostasis. IR ensures decades prior to development of overt diabetes and can cause silent metabolic derangements. IR is typically seen very early in the course of chronic kidney disease (CKD) and is evident even when the estimated glomerular filtration rate (eGFR) is within the normal range and IR persists at various stages of kidney disease. In this article, we will discuss insulin handling by the kidneys, mechanisms responsible for IR in CKD, measurements and management of IR in patients with CKD, and recent type 2 diabetic trials with implications for improved cardiovascular outcomes in CKD. © 2023 American Physiological Society. Compr Physiol 13:5069-5076, 2023.

This study investigated the relationship between fibroblast growth factor 21 (FGF-21) and newly diagnosed type-2 diabetes mellitus (T2DM).

In this cross-sectional study, FGF-21 and T2DM risk were analyzed using restricted cubic splines with univariate or multivariate logistic regression analysis. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated via logistic regression analysis. Cluster and subgroup analyses were conducted to evaluate the associations between FGF-21 and diabetes in different subpopulations. Nomograms and ROC curves were used to explore the clinical utility of FGF-21 in the diabetes assessment model.

High levels of FGF-21 were significantly associated with a high risk of T2DM after adjusting for confounding factors in both the total population and subpopulations (P for trend < 0.001). In the total population, the ORs of diabetes with increasing FGF-21 quartiles were 1.00 (reference), 1.24 (95% CI 0.56-2.80; quartile 2), 2.47 (95% CI 1.18-5.33; quartile 3), and 3.24 (95% CI 1.53-7.14; quartile 4) in Model 4 (P < 0.001), and the trend was consistent in different subpopulations. In addition, compared with the model constructed with conventional noninvasive indicators, the AUC of the model constructed by adding FGF-21 was increased from 0.668 (95% CI: 0.602-0.733) to 0.715 (95% CI: 0.654-0.777), indicating that FGF-21 could significantly improve the risk-assessment efficiency of type-2 diabetes.

This study demonstrated that a high level of circulating FGF-21 was positively correlated with diabetes, and levels of FGF-21 could be an important biomarker for the assessment of diabetes risk.

Maintaining systemic homeostasis requires the coordination of different organs and tissues in the body. Our bodies rely on complex inter-organ communications to adapt to perturbations or changes in metabolic homeostasis. Consequently, the liver, muscle, and adipose tissues produce and secrete specific organokines such as hepatokines, myokines, and adipokines in response to nutritional and environmental stimuli. Emerging evidence suggests that dysregulation of the interplay of organokines between organs is associated with the pathophysiology of obesity and type 2 diabetes (T2D). Strategies aimed at remodeling organokines may be effective therapeutic interventions. Diet modification and exercise have been established as the first-line therapeutic intervention to prevent or treat metabolic diseases. This review summarizes the current knowledge on organokines secreted by the liver, muscle, and adipose tissues in obesity and T2D. Additionally, we highlighted the effects of diet/nutrition and exercise on the remodeling of organokines in obesity and T2D. Specifically, we investigated the ameliorative effects of caloric restriction, selective nutrients including ω3 PUFAs, selenium, vitamins, and metabolites of vitamins, and acute/chronic exercise on the dysregulation of organokines in obesity and T2D. Finally, this study dissected the underlying molecular mechanisms by which nutrition and exercise regulate the expression and secretion of organokines in specific tissues.

Serum fibroblast growth factor 21 levels in patients with mitochondrial diabetes might be much higher than in those with other diabetes types. The results of this study could lead to the establishment of a simple method for screening mitochondrial diabetes using peripheral blood serum.

Long-term ad libitum dietary restrictions, such as low-protein diets (LPDs), improve metabolic health and extend the life span of mice and humans. However, most studies conducted thus far have focused on the preventive effects of LPDs on metabolic syndromes. To test the therapeutic potential of LPD, we treated a lipodystrophy mouse model IRFKO (adipose-specific insulin receptor knockout) in this study. We have previously shown that IRFKO mice have profound insulin resistance, hyperglycemia, and whitening of interscapular brown adipose tissue (BAT), closely mimicking the phenotypes in lipoatrophic diabetic patients. Here, we demonstrate that 14-day of LPD (5.1% kcal from protein) feeding is sufficient to reduce postprandial blood glucose, improve insulin resistance, and normalize glucose tolerance in the IRFKO mice. This profound metabolic improvement is associated with BAT activation and increase in whole body energy expenditure. To confirm, we showed that surgical denervation of BAT attenuated the beneficial metabolic effects of LPD feeding in IRFKO mice, including the 'browning' effects on BAT and the glucose-ameliorating results. However, BAT denervation failed to affect the body weight-lowering effects of LPD. Together, our results imply a therapeutic potential to use LPD for the treatment of lipoatrophic diabetes.

The mechanisms link obesity and hypertension are not well understood. One possibility is the alterations in adipose-derived adipokines that modulate insulin resistance (IR) and cardiovascular homeostasis. We aimed to assess the associations between hypertension and four adipokine levels in Chinese youth, and to examine to what extent the associations are mediated by IR. We utilized cross-sectional data from the Beijing Children and Adolescents Metabolic Syndrome (BCAMS) Study Cohort (n = 559, mean age = 20.2 years). Plasma leptin, adiponectin, retinol binding protein 4 (RBP4) and fibroblast growth factor 21 (FGF21) levels were assayed. The relationships between adipokines and hypertension and the possible mediation effect of IR were evaluated. Youth with hypertension have lower adiponectin and higher leptin, FGF21 (all P < 0.001) and RBP4 levels (p = 0.06) compared to their counterparts. Moreover, the co-existence of these two or more adipokine abnormalities in youth leads to a 9-fold increased risk for hypertension (OR: 9.19; 95% CI, 4.01-21.08) compared with these without abnormalities. However, in the fully adjusted and BMI-adjusted analyses, only FGF21 was a significant predictor of hypertension (OR: 2.12; 95% CI, 1.34-3.36). Mediation analysis revealed that the associations between leptin, adiponectin, RBP4 and hypertension are totally mediated by IR (proportion: 63.9%, 65.4%, and 31.6%, respectively), while BMI and IR partly mediated the association between FGF21 and hypertension (proportion: 30.6%, 21.2%). Our findings suggest that dysregulation of adipokines might result in hypertension in youth. Leptin, adiponectin and RBP4 may exert their functions in hypertension through adiposity-related IR, whereas FGF21 might be used as an independent marker of hypertension in youth.

Fibroblast growth factor 21 (FGF21) is a peptide hormone mainly synthesized and released from the liver. FGF21 acts on FGF21 receptors (FGFRs) and β-Klotho, which is a transmembrane co-receptor. In type 2 diabetes mellitus (T2DM), inflammatory disorders stimulate the release of FGF21 to overcome insulin resistance (IR). FGF21 improves insulin sensitivity and glucose homeostasis. Metformin which is used in the management of T2DM may increase FGF21 expression. Accordingly, the objective of this review was to clarify the metformin effect on FGF21 in T2DM. FGF21 level and expression of FGF2Rs are dysregulated in T2DM due to the development of FGF21 resistance. Metformin stimulates the hepatic expression of FGF21/FGF2Rs by different signaling pathways. Besides, metformin improves the expression of β-Klotho which improves FGF21 sensitivity. In conclusion, metformin advances FGF21 signaling and decreases FGF21 resistance in T2DM, and this might be an innovative mechanism for metformin in the enhancement of glucose homeostasis and metabolic disorders in T2DM patients.

To assess whether circulating levels of adiponectin, leptin, and fibroblast growth factor 21 (FGF-21) are associated with incident cardiovascular disease (CVD) in rheumatoid arthritis (RA).

Adipokines were measured using banked enrollment serum from patients with RA and dichotomized above/below the median value. Incident CVD events (coronary artery disease [CAD], stroke, heart failure [HF] hospitalization, venous thromboembolism, CVD-related deaths) were identified using administrative data and the National Death Index. Covariates were derived from medical record, biorepository, and registry databases. Multivariable Cox models were generated to quantify associations between adipokine concentrations and CVD incidence. Five-year incidence rates were predicted.

Among 2,598 participants, 639 (25%) had at least 1 CVD event over 19,585 patient-years of follow-up. High adiponectin levels were independently associated with HF hospitalization (hazard ratio [HR] 1.39 [95% confidence interval (95% CI) 1.07-1.79], P = 0.01) and CVD-related death (HR 1.49 [95% CI 1.16-1.92], P = 0.002) but not with other CVD events. High leptin was independently associated with CVD-related death (HR 1.44 [95% CI 1.05-1.97], P = 0.02). High FGF-21 levels were independently associated with lower rates of CAD (HR 0.75 [95% CI 0.58-0.97], P = 0.03). In subgroup analyses, associations between high adiponectin and leptin levels with CVD-related death were driven by strong associations in nonobese patients.

Adipokines are associated with HF hospitalization and CVD-related death in patients with RA, with stronger associations in nonobese participants. These findings suggest that adipokines effectively predict clinically important outcomes in RA perhaps through an association with body composition and metabolic health. Further study is needed to determine whether adipokine measures might augment existing tools to identify RA patients at increased risk of CVD.