Plasma Fibroblast Growth Factor 21 Research Articles

Distinct genetic signals at the FGF21 locus complicate studies of FGF21's role in diet regulation using human cohort data

ObjectivesExperimental 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. MethodsWe 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. ResultsWe 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. ConclusionsThese findings support the feedback diet-regulatory mechanism of FGF21 in humans, but highlights the need for mechanistic characterization of the complex FGF21 genetic region.

Association of brown adipose tissue activity with circulating sex hormones and fibroblast growth factor 21 in the follicular and luteal phases in young women

BackgroundThermogenesis is influenced by fluctuations in sex hormones during the menstrual cycle in premenopausal women. The thermogenic activity and mass of brown adipose tissue (BAT) are regulated by endocrine factors, including sex hormones and fibroblast growth factor 21 (FGF21). However, the relationship between human BAT and these endocrine fluctuations within individuals remains to be elucidated. This study aimed to assess variations in BAT activity between the luteal and follicular phases and identify correlations with circulating levels of sex hormones and FGF21.MethodsHealthy young women were enrolled in an observational study. Measurement of BAT activity and blood analyses were performed in both the follicular and luteal phases. BAT activity was analyzed using thermography with 2-h cold exposure. Plasma 17β-estradiol, progesterone, and FGF21 levels were determined by enzyme-linked immunosorbent assay. A comparative analysis within individuals was conducted in 13 women to compare the follicular and luteal phases. Furthermore, sensitivity analysis was carried out in 21 women during the follicular phase only.ResultsPlasma 17β-estradiol and progesterone levels were significantly higher in the luteal phase, whereas plasma FGF21 level was significantly higher in the follicular phase. Comparison analysis found no significant differences in cold-induced BAT activity between the follicular and luteal phases in young women. Correlation analysis in both comparison and sensitivity analyses found that plasma 17β-estradiol and progesterone levels were not associated with BAT activity, whereas plasma FGF21 levels were significantly and positively correlated with BAT activity only in the follicular phase. In addition, plasma 17β-estradiol levels in the follicular phase were significantly and positively associated with plasma FGF21 levels in both the comparison and sensitivity analyses.ConclusionsThe thermogenic activity of BAT during cold exposure was comparable between the follicular and luteal phases in young women. Higher BAT activity was associated with elevated levels of plasma FGF21 only in the follicular phase, which is related to increased plasma 17β-estradiol levels.

Diosmin and Hesperidin Have a Protective Effect in Diabetic Neuropathy via the FGF21 and Galectin-3 Pathway.

Background and Objectives: This study aimed to investigate the protective effect of diosmin and hesperidin in diabetic neuropathy using a rat model, focusing on their impact on nerve regeneration through the fibroblast growth factor 21 (FGF21) and galectin-3 (gal3) pathway. Materials and Methods: Forty adult male Wistar rats were used in this study. Diabetes was induced using streptozotocin (STZ), and the rats were divided into control, diabetes and saline-treated, diabetes and diosmin + hesperidin (150 mg/kg) treated, and diabetes and diosmin + hesperidin (300 mg/kg) treated groups. Electromyography (EMG) and inclined plane testing were performed to assess nerve function and motor performance. Sciatic nerve sections were examined histopathologically. Plasma levels of FGF21, galectin-3, and malondialdehyde (MDA) were measured as markers of oxidative stress and inflammation. Results: Diabetic rats treated with saline displayed reduced nerve conduction parameters and impaired motor performance compared to controls. Treatment with diosmin and hesperidin significantly improved compound muscle action potential (CMAP) amplitude, distal latency, and motor performance in a dose-dependent manner. Histopathological examination revealed decreased perineural thickness in treated groups. Additionally, treatment with diosmin and hesperidin resulted in increased plasma FGF21 levels and reduced plasma levels of galectin-3 and MDA, indicating decreased oxidative stress and inflammation. Conclusions: Diosmin and hesperidin exhibited protective effects in diabetic neuropathy by promoting nerve regeneration, enhancing nerve conduction, and improving motor performance. These effects were associated with modulation of the FGF21 and galectin-3 pathway. These findings suggest that diosmin and hesperidin may hold potential as adjunctive therapies for diabetic neuropathy.

Plasma FGF21 Concentration in Kidney Transplant Patients-Results from Prospective and Cross-Sectional Studies.

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.

Mice Regulate Dietary Amino Acid Balance and Energy Intake by Selecting between Complementary Protein Sources

BackgroundA balanced intake of protein and constituent amino acids (AAs) requires adjustments to total food intake (protein leverage [PL]) and food selection to balance deficits and excesses (complementary feeding). We provided mice with choices of casein and whey, 2 protein sources that are complementary in AA balance, across a range of protein concentrations (P%) of digestible energy (DE). ObjectivesWe aimed to determine if: 1) PL operates similarly for casein and whey; 2) one protein source is preferred at control P%; 3) the preference changes as P% falls; and 4) AA intakes under control and low P% levels identify AAs that drive changes in protein selection. MethodsFood intake and plasma fibroblast growth factor-21 (FGF21) concentrations were measured in mice at various P% (P7.5%–P33%). For direct comparisons, defined diets were used in which the protein source was either casein or whey. In food choice studies, mice had access to foods in which both casein and whey were provided at the same P% level at the same time. ResultsPL operated at different P% thresholds in casein (13%)- and whey (10%)-based diets, and the magnitude of PL was greater for casein. Although mice preferred casein under control conditions (P23%), a pronounced preference shift to whey occurred as P% fell to P13% and P10%. At low P%, increases in food intake were accompanied by increases in plasma FGF21, a protein hunger signal. Among AAs deficient in casein and enriched in whey, the intake of Cys was the most invariant as P% changed between P23% and P10%, appearing to drive the switch in protein preference. ConclusionsMice selected between complementary protein sources, casein and whey, achieving stable total energy intake and regulated intake of AAs as P% varied. Supplementation of low P% casein diets with one whey-enriched AA, Cys, suppressed plasma FGF21 and total food intake.

The dual GCGR/GLP-1R agonist survodutide: Biomarkers and pharmacological profiling for clinical candidate selection.

To describe the biomarker strategy that was applied to select survodutide (BI 456906), BI 456908 and BI 456897 from 19 dual glucagon receptor (GCGR)/ glucagon-like peptide-1 receptor (GLP-1R) agonists for in-depth pharmacological profiling, which led to the qualification of survodutide as the clinical development candidate. Potencies to increase cyclic adenosine monophosphate (cAMP) were determined in Chinese hamster ovary (CHO)-K1 cells stably expressing human GCGR and GLP-1R. Agonism for endogenously expressed receptors was investigated in insulinoma cells (MIN6) for mouse GLP-1R, and in rat primary hepatocytes for the GCGR. In vivo potencies to engage the GLP-1R or GCGR were determined, measuring improvement in oral glucose tolerance (30 nmol/kg) and increase in plasma fibroblast growth factor-21 (FGF21) and liver nicotinamide N-methyltransferase (NNMT) mRNA expression (100 nmol/kg), respectively. Body weight- and glucose-lowering efficacies were investigated in diet-induced obese (DIO) mice and diabetic db/db mice, respectively. Upon acute dosing in lean mice, target engagement biomarkers for the GCGR and GLP-1R demonstrated a significant correlation (Spearman correlation coefficient with p < 0.05) to the in vitro GCGR and GLP-1R potencies for the 19 dual agonists investigated. Survodutide, BI 456908 and BI 456897 were selected for in-depth pharmacological profiling based on the significant improvement in acute oral glucose tolerance achieved (area under the curve [AUC] of 54%, 57% and 60% vs. vehicle) that was comparable to semaglutide (AUC of 45% vs. vehicle), while showing different degrees of in vivo GCGR engagement, as determined by hepatic NNMT mRNA expression (increased by 15- to 17-fold vs. vehicle) and plasma FGF21 concentrations (increased by up to sevenfold vs. vehicle). In DIO mice, survodutide (30 nmol/kg/once daily), BI 456908 (30 nmol/kg/once daily) and BI 456897 (10 nmol/kg/once daily) achieved a body weight-lowering efficacy from baseline of 25%, 27% and 26%, respectively. In db/db mice, survodutide and BI 456908 (10 and 20 nmol/kg/once daily) significantly lowered glycated haemoglobin (0.4%-0.6%); no significant effect was observed for BI 456897 (3 and 7 nmol/kg/once daily). Survodutide was selected as the clinical candidate based on its balanced dual GCGR/GLP-1R pharmacology, engaging the GCGR for robust body weight-lowering efficacy exceeding that of selective GLP-1R agonists, while achieving antidiabetic efficacy that was comparable to selective GLP-1R agonism. Survodutide is currently being investigated in Phase 3 clinical trials in people living with obesity.

Association of circulating fibroblast growth factor 21 levels with all-cause and cardiovascular mortality: The multi-ethnic study of atherosclerosis

BackgroundFibroblast 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. MethodsA 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. ResultsFGF21 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. ConclusionsIn 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.

Fructose-induced FGF21 secretion does not activate brown adipose tissue in Japanese young men: randomized cross-over and randomized controlled trials

BackgroundHuman brown adipose tissue (BAT) activity is associated with lower body fatness and favorable glucose metabolism. Previous studies reported that oral fructose loading induces postprandial fibroblast growth factor 21 (FGF21) secretion. FGF21 is a known inducer of adipose tissue thermogenesis; however, the effects of diet-induced FGF21 secretion on BAT thermogenesis remain to be elucidated.MethodsThe effects of both single load and daily consumption of fructose on BAT activity were examined using a randomized cross-over trial and a 2-week randomized controlled trial (RCT), respectively. In the cross-over trial, 15 young men consumed a single dose of fructose solution or water and then consumed the other on a subsequent day. The RCT enrolled 22 young men, and the participants were allocated to a group that consumed fructose and a group that consumed water daily for 2 weeks. BAT activity was analyzed using thermography with cold exposure. Plasma FGF21 level was determined by enzyme-linked immunosorbent assay.ResultsIn the cross-over single-load trial, plasma FGF21 levels were significantly increased at 2 h after oral fructose load (p < 0.01); however, there was no significant difference in BAT activity between the fructose load and drinking water. The 2-week RCT revealed that both plasma FGF21 levels and BAT activity were not significantly increased by daily fructose consumption compared to water. Correlation analyses revealed that BAT activity at the baseline and the final measurements were strongly and positively associated with the RCT (r = 0.869, p < 0.001). Changes in BAT activity were significantly and negatively correlated with changes in plasma glucose levels during the 2-week intervention (r = − 0.497, p = 0.022).ConclusionsOral fructose load induces a temporary increase in circulating FGF21 levels; however, this does not activate BAT thermogenesis in healthy young men. Further studies are needed to elucidate the effect of endogenous FGF21 on physiological function.Trial registrationThis study is registered with the University Hospital Medical Information Network in Japan (number 000051761, registered 1 August 2023, retrospectively registered, https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000052680).

Fibroblast Growth Factor 21: A More Effective Biomarker Than Free Fatty Acids and Other Insulin Sensitivity Measures for Predicting Non-alcoholic Fatty Liver Disease in Saudi Arabian Type 2 Diabetes Patients.

Background Non-alcoholic fatty liver disease (NAFLD) is more prevalent among individuals with type 2 diabetes (T2DM), elevating their risk of cardiovascular diseases (CVDs) and premature mortality. There is a need to modify treatment strategies to prevent or delay these adverse outcomes. Currently, there are no sensitive or specific biomarkers for predicting NAFLD in Saudi T2DM patients. Therefore, we aimed to explore the possibility of using fibroblast growth factor 21 (FGF-21), free fatty acids (FFAs), homeostatic model assessment for insulin resistance (HOMA-IR), and quantitative insulin sensitivity check index (QUICKI) as possible markers. Methodology In this study, a total of 67 T2DM patients were recruited. NAFLD was detected by ultrasonography in 28 patients. Plasma glucose, FFAs, FGF-21, and serum insulin were measured in fasting blood samples. HOMA-IR and QUICKI were calculated. The means of the two groups with and without NAFLD were statistically compared. The receiver operating characteristics (ROC) curve and the area under the curve (AUC) were used to assess the ability to identify NAFLD. Results The mean levels of FGF-21 and HOMA-IR were significantly higher and that of QUICKI was significantly lower in patients with NAFLD than in those without (p < 0.001, p = 0.023, and p = 0.018, respectively). FGF-21 had the highest AUC to identify NAFLD (AUC = 0.981, 95% confidence interval = 0.954-1, P < 0.001). The AUCs for HOMA-IR, QUICKI, and FFA were <0.7. The highest sensitivity, specificity, positive likelihood ratio, and the lowest negative likelihood ratio were found when FGF-21 was used to predict NAFLD. Conclusions FGF-21 may be used as a biomarker to predict NAFLD in people with T2DM due to its high sensitivity and specificity compared to the other markers.

Dietary protein restriction modulates ‘dessert’ intake after a meal, via fibroblast growth factor 21 (FGF21)

Pharmacological administration of fibroblast growth factor 21 (FGF21) alters food choice, including that it decreases the consumption of sucrose and other sweet tastants. Conversely, endogenous secretion of FGF21 by the liver is modulated by diet, such that plasma FGF21 is increased after eating foods that have a low dietary protein: total energy (P: E) ratio. Together, these findings suggest a strategy to promote healthy eating, in which the macronutrient content of a pre-load diet could reduce the consumption of sweet desserts in sated mice. Here, we tested the prediction that individuals maintained on a low P: E diet, and offered a highly palatable sweet ‘dessert’ following a pre-load meal, would eat less of the sugary snack compared to controls—due to increased FGF21 signaling. In addition to decreasing sweet intake, FGF21 increases the consumption of dietary protein. Thus, we predicted that individuals maintained on the low P: E diet, and offered a very high-protein pellet as ‘dessert’ or snack after a meal, would eat more of the high protein pellet compared to controls, and that this depends on FGF21. We tested this in C57Bl/6J, and liver-specific FGF21-null (FGF21ΔL) null male and female mice and littermate controls. Contrary to expectation, eating a low protein pre-load did not reduce the later consumption of a sweet solution in either males or females, despite robustly increasing plasma FGF21. Rather, eating the low protein pre-load increased later consumption of a high protein pellet. This was more apparent among males and was abrogated in the FGF21ΔL mice. We conclude that physiologic induction of hepatic FGF21 by a low protein pre-load diet is not sufficient to reduce the consumption of sweet desserts, though it effectively increases the subsequent intake of dietary protein in male mice.

3-Month Post-Operative Increase in FGF21 is Predictive of One-Year Weight Loss After Bariatric Surgery.

The association between bariatric surgery outcome and blood levels of fibroblast growth factor 21 (FGF21) remains controversial. Many patients displayed stable or decreased FGF21 one year after bariatric surgery. Nevertheless, there is often an early increase FGF21 concentration in the post-surgery period. The aim of this study was to investigate the relationship between 3-month FGF21 response and percentage total weight loss at one year after bariatric surgery. In this prospective monocentric study, a total of 144 patients with obesity grade 2-3 were included; 61% of them underwent a sleeve gastrectomy and 39% a Roux-en-Y gastric bypass. Data analysis was carried out to determine the relation between 3-month plasma FGF21 response and weight loss one year after bariatric surgery. Multiple adjustments were done including degree of weight loss after 3months. FGF21 significantly increased between baseline and Month 3 (n = 144, p < 10-3), then decreased between Month 3 and Month 6 (n = 142, p = 0.047) and was not different from baseline at Month 12 (n = 142, p = 0.86). The 3-month-FGF21 response adjusted to body weight loss was not different between types of bariatric surgery. The 3-month-FGF21 response was associated to body weight loss at Month 6 (r = -0.19, p = 0.02) and Month 12 (r = -0.34, p < 10-4). After multiple regression analysis, only Month 12 body weight loss remained associated to 3-month FGF21 response (r = -0.3, p = 0.02). This study showed that the magnitude of changes in FGF21 at 3months after bariatric surgery emerged as an independent predictor of one-year body weight loss irrespective of the type of surgery.

FGF21 Depletion Attenuates Colitis through Intestinal Epithelial IL-22-STAT3 Activation in Mice.

Fibroblast growth factor 21 (FGF21) is a glucose and lipid metabolic regulator. Recent research revealed that FGF21 was also induced by inflammatory stimuli. Its role in inflammatory bowel disease (IBD) has not been investigated. In this study, an experimental IBD model was established in FGF21 knockout (KO) and wild-type (WT) mice by adding 2.5% (wt/vol) dextran sodium sulfate (DSS) to their drinking water for 7 days. The severity of the colitis and the inflammation of the mouse colon tissues were analyzed. In WT mice, acute DSS treatment induced an elevation in plasma FGF21 and a significant loss of body weight in a time-dependent manner. Surprisingly, the loss of body weight and the severity of the colitis induced by DSS treatment in WT mice were significantly attenuated in FGF21 KO mice. Colon and circulating pro-inflammatory factors were significantly lower in the FGF21 KO mice compared to the WT mice. As shown by BrdU staining, the FGF21 KO mice demonstrated increased colonic epithelial cell proliferation. DSS treatment reduced intestinal Paneth cell and goblet cell numbers in the WT mice, and this effect was attenuated in the FGF21 KO mice. Mechanistically, FGF21 deficiency significantly increased the signal transducer and activator of transcription (STAT)-3 activation in intestinal epithelial cells and increased the expression of IL-22. Further study showed that the expression of suppressor of cytokine signaling-2/3 (SOCS 2/3), a known feedback inhibitor of STAT3, was significantly inhibited in the DSS-treated FGF2 KO mice compared to the WT mice. We conclude that FGF21 deficiency attenuated the severity of DSS-induced acute colitis, which is likely mediated by enhancing the activation of the IL-22-STAT3 signaling pathway in intestinal epithelial cells.

Abstract 365: Targeting FGF21 inhibits tumor growth and attenuates cachexia in experimental colorectal cancer

Abstract Background: Colorectal cancer (CRC) is frequently accompanied by cachexia, an uncured multi-organ wasting syndrome, debilitating musculoskeletal health, physical function, and overall survival. Fibroblast growth factor 21 (FGF21) is a modulator of musculoskeletal health and metabolism and has been associated with CRC risk and progression. Here, we investigated the effects of tumor derived FGF21 on musculoskeletal health in CRC. Methods: Plasma from CRC patients and preclinical models of CRC (C26, MC38) were assessed for circulating FGF21 levels, and CRC cell lines (C26, MC38, HCT116) were screened for FGF21 expression. Using CRISPR/Cas9 technology, FGF21 was deleted from MC38 cells (KO-MC38). 8-week-old male C57BL/6J mice were subcutaneously injected (1.0x106) with wild-type (WT-MC38) or FGF21-/- (KO-MC38) MC38 tumor cells, while experimental control animals received saline (n = 10-13/group). Animals underwent electrophysiological testing to obtain motor unit number estimation (MUNE) 48 hours prior to euthanasia and were assessed for maximum plantarflexion torque 24 hours prior to euthanasia. At the time of euthanasia, plasma was collected for assessment of systemic FGF21, while tumors and skeletal muscles (gastrocnemius, quadriceps, and tibialis anterior) were excised and weighed. Femur bones were processed for microcomputed tomography (µCT) imaging and analysis. Results: CRC patients and MC38 tumor hosts demonstrated elevated circulating plasma FGF21 (p&amp;lt;0.05) compared to controls. Gene expression of CRC cells revealed an 11-fold increase of FGF21 in MC38 compared to C26 and HCT116 cells. WT-MC38 tumor hosts had elevated plasma FGF21 (4-fold; p&amp;lt;0.05) compared to control, which was unchanged in KO-MC38 hosts. In line with the development of cachexia, WT-MC38 hosts displayed reductions in muscle mass (gastrocnemius: -5%; p&amp;lt;0.05, quadriceps: -10%; p&amp;lt;0.01, tibialis anterior: -8%; p&amp;lt;0.01), MUNE (-31%; p&amp;lt;0.01), and plantarflexion torque (-10%; p&amp;lt;0.05). Meanwhile, µCT of femur bones demonstrated reductions in trabecular bone volume fraction (BV/TV: -30%; p&amp;lt;0.05) and cortical cross-sectional thickness (Cs.Th: -14%; p&amp;lt;0.05) in WT-MC38 hosts compared to experimental controls. Conversely, when compared to WT-MC38, KO-MC38 hosts had preserved skeletal muscle mass (gastrocnemius: +7%; p&amp;lt;0.01, quadriceps: +13%; p&amp;lt;0.001, tibialis anterior: +8%; p&amp;lt;0.001), MUNE (+47%; p&amp;lt;0.01), plantarflexion torque (+8%; p&amp;lt;0.05), and bone mass (BV/TV: +69%; p&amp;lt;0.001, Cs.Th: +23%; p&amp;lt;0.001). Strikingly, the mass of KO-MC38 tumors was reduced 75% (p&amp;lt;0.01) compared to WT-MC38 tumors. Conclusion: Our data suggest that targeting CRC-derived FGF21 halts tumor growth, resulting in preservation of musculoskeletal health and function. Thus, counteracting tumor-derived FGF21 may serve as a therapeutic intervention against the progression of cancer and cancer-associated cachexia. Citation Format: Fabrizio Pin, Anika Shimonty, Joshua Robert Huot. Targeting FGF21 inhibits tumor growth and attenuates cachexia in experimental colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 365.

Iron-fortified klutuk banana (Musa balbisiana Colla) flour supplementation prevented growth failure by suppressing FGF21 in malnourished rats

PurposeMalnutrition during childhood precedes growth failure and affects the child’s well-being later in life. This study aims to investigate the potency of iron-fortified klutuk banana (Musa balbisiana Colla) flour on growth parameters and fibroblast growth factor 21 (FGF21) expression in malnourished rat model.Design/methodology/approachRats were allocated into normal control (NC), untreated malnutrition (MC), malnutrition + iron-fortified klutuk banana flour (IBF) and malnutrition + Indonesian Government-issued biscuit (GB). Malnutrition was induced by an isoenergetic low-protein diet for five weeks. The IBF and GB groups were supplemented with IBF 1.2 g/200 gBW and GB 1.2 g/200 gBW, respectively, via gavage daily for three weeks. The body weight and length, the levels of plasma and liver FGF21 and red blood cell indices were analyzed.FindingsAfter three weeks of supplementation, the IBF group showed higher body weight (245 ± 13.6 g vs 201.8 ± 16.3 g; p = 0.0004) and length (20.9 ± 0.5 cm vs 19.8 ± 0.5 cm; p = 0.021) compared with the untreated group. The plasma FGF21 level decreased in the IBF group (p = 0.034). The IBF group altered mean corpuscular volume and mean corpuscular hemoglobin, suggesting the IBF might attenuate malnutrition-induced anemia. Overall, the IBF prevented growth failure in malnourished condition. This might be mediated by the suppression of FGF21 expression, along with the prevention of malnutrition and anemia.Originality/valueThis study provides preliminary information about the potential use of rarely consumed banana, klutuk banana, as a supplement to treat malnutrition. This study might help the developing countries to eliminate the widespread malnutrition in economically challenged communities.

Association between Plasma FGF21 Levels and Body Composition in Patients with Gastric Cancer

Background Accumulating evidence has suggested that Fibroblast growth factor 21 (FGF21) plays an important role in metabolic diseases. This study aimed to investigate the relationship between plasma FGF21 levels and body composition parameters in gastric cancer (GC) patients. Methods This study was cross-sectional based on a prospective cohort of GC patients in a single center. Computer tomography (CT) and bioelectrical impedance analysis (BIA) were used to estimate skeletal muscle and adipose tissue mass. Blood samples were collected and plasma concentrations of FGF21 were measured by ELISA. Spearman’s rank correlation test and logistic regression analysis were performed to assess associations between plasma FGF21 levels and these body composition parameters. Results A total of 66 GC patients were enrolled in this study. Plasma FGF21 levels were significantly higher in women compared with men. The plasma FGF21 levels were positively correlated with fat mass index (FMI), fat mass percentage (FM%), and subcutaneous adipose tissue index (SATI). Furthermore, after adjustment for confounders, the lower plasma FGF21 levels were remain associated with increased odds for low SATI. Conclusions Plasma FGF21 levels were positively associated with FMI, FM%, and SATI in GC patients, suggesting a potential mechanistic link between FGF21 and subcutaneous adipose tissue in GC.

Plasma FGF21 Levels Are Not Associated with Weight Loss or Improvements in Metabolic Health Markers upon 12 Weeks of Energy Restriction: Secondary Analysis of an RCT.

Recent studies suggest that circulating fibroblast growth factor 21 (FGF21) may be a marker of metabolic health status. We performed a secondary analysis of a 12-week randomized controlled trial to investigate the effects of two energy restriction (ER) diets on fasting and postprandial plasma FGF21 levels, as well as to explore correlations of plasma FGF21 with metabolic health markers, (macro)nutrient intake and sweet-taste preference. Abdominally obese subjects aged 40-70 years (n = 110) were randomized to one of two 25% ER diets (high-nutrient-quality diet or low-nutrient-quality diet) or a control group. Plasma FGF21 was measured in the fasting state and 120 min after a mixed meal. Both ER diets did not affect fasting or postprandial plasma FGF21 levels despite weight loss and accompanying health improvements. At baseline, the postprandial FGF21 response was inversely correlated to fasting plasma glucose (ρ = -0.24, p = 0.020) and insulin (ρ = -0.32, p = 0.001), HOMA-IR (ρ = -0.34, p = 0.001), visceral adipose tissue (ρ = -0.24, p = 0.046), and the liver enzyme aspartate aminotransferase (ρ = -0.23, p = 0.021). Diet-induced changes in these markers did not correlate to changes in plasma FGF21 levels upon intervention. Baseline higher habitual polysaccharide intake, but not mono- and disaccharide intake or sweet-taste preference, was related to lower fasting plasma FGF21 (p = 0.022). In conclusion, we found no clear evidence that fasting plasma FGF21 is a marker for metabolic health status. Circulating FGF21 dynamics in response to an acute nutritional challenge may reflect metabolic health status better than fasting levels.

Pancreatic alpha cell glucagon–liver FGF21 axis regulates beta cell regeneration in a mouse model of type 2 diabetes

Aims/hypothesisGlucagon receptor (GCGR) antagonism ameliorates hyperglycaemia and promotes beta cell regeneration in mouse models of type 2 diabetes. However, the underlying mechanisms remain unclear. The present study aimed to investigate the mechanism of beta cell regeneration induced by GCGR antagonism in mice.MethodsThe db/db mice and high-fat diet (HFD)+streptozotocin (STZ)-induced mice with type 2 diabetes were treated with antagonistic GCGR monoclonal antibody (mAb), and the metabolic variables and islet cell quantification were evaluated. Plasma cytokine array and liver RNA sequencing data were used to screen possible mediators, including fibroblast growth factor 21 (FGF21). ELISA, quantitative RT-PCR and western blot were applied to verify FGF21 change. Blockage of FGF21 signalling by FGF21-neutralising antibody (nAb) was used to clarify whether FGF21 was involved in the effects of GCGR mAb on the expression of beta cell identity-related genes under plasma-conditional culture and hepatocyte co-culture conditions. FGF21 nAb-treated db/db mice, systemic Fgf21-knockout (Fgf21−/−) diabetic mice and hepatocyte-specific Fgf21-knockout (Fgf21Hep−/−) diabetic mice were used to reveal the involvement of FGF21 in beta cell regeneration. A BrdU tracing study was used to analyse beta cell proliferation in diabetic mice treated with GCGR mAb.ResultsGCGR mAb treatment improved blood glucose control, and increased islet number (db/db 1.6±0.1 vs 0.8±0.1 per mm2, p<0.001; HFD+STZ 1.2±0.1 vs 0.5±0.1 per mm2, p<0.01) and area (db/db 2.5±0.2 vs 1.2±0.2%, p<0.001; HFD+STZ 1.0±0.1 vs 0.3±0.1%, p<0.01) in diabetic mice. The plasma cytokine array and liver RNA sequencing data showed that FGF21 levels in plasma and liver were upregulated by GCGR antagonism. The GCGR mAb induced upregulation of plasma FGF21 levels (db/db 661.5±40.0 vs 466.2±55.7 pg/ml, p<0.05; HFD+STZ 877.0±106.8 vs 445.5±54.0 pg/ml, p<0.05) and the liver levels of Fgf21 mRNA (db/db 3.2±0.5 vs 1.8±0.1, p<0.05; HFD+STZ 2.0±0.3 vs 1.0±0.2, p<0.05) and protein (db/db 2.0±0.2 vs 1.4±0.1, p<0.05; HFD+STZ 1.6±0.1 vs 1.0±0.1, p<0.01). Exposure to plasma or hepatocytes from the GCGR mAb-treated mice upregulated the mRNA levels of characteristic genes associated with beta cell identity in cultured mouse islets and a beta cell line, and blockage of FGF21 activity by an FGF21 nAb diminished this upregulation. Notably, the effects of increased beta cell number induced by GCGR mAb were attenuated in FGF21 nAb-treated db/db mice, Fgf21−/− diabetic mice and Fgf21Hep−/− diabetic mice. Moreover, GCGR mAb treatment enhanced beta cell proliferation in the two groups of diabetic mice, and this effect was weakened in Fgf21−/− and Fgf21Hep−/− mice.Conclusions/interpretationOur findings demonstrate that liver-derived FGF21 is involved in the GCGR antagonism-induced beta cell regeneration in a mouse model of type 2 diabetes.Graphical abstract

Relationship of fibroblast growth factor 21 with the prevalence and progression of vascular and valvular calcification: Multi-ethnic study of atherosclerosis

BackgroundElevated circulating levels of fibroblast growth factor 21 (FGF21) are associated with cardiovascular disease (CVD). Therefore, we investigated the relationship of plasma FGF21 with calcification at different vascular and valvular sites. MethodsA total of 5786 participants, free of clinically apparent CVD at baseline and with valid data on plasma FGF21 and calcification (Agatston score, volume and density) at coronary arteries, thoracic arteries, mitral and aortic valves, and aortic valve ring, were included in the analysis. Vascular calcification was measured at 2–3 follow-up visits. ResultsAt baseline, higher FGF21 levels were associated with prevalent descending thoracic aortic calcification (DTAC) (prevalence ratio = 1.06 [95% CI 1.01–1.11] per SD increase in log-transformed unit, P = 0.016). Among participants without prevalent calcification, higher FGF21 levels were associated with incident DTAC (relative risk [RR] = 1.13 [95% CI 1.04–1.22], P = 0.002). Among all participants, higher FGF21 levels were also associated with the progression of DTAC score and volume (RR = 1.07 [95% CI 1.03–1.12] and 1.08 [95% CI 1.03–1.12] respectively, both P < 0.01). No significant association of FGF21 was found for prevalence (prevalence ratio = 0.89–1.05), incidence (RR = 0.97–1.16) and progression of calcification (RR = 0.94–1.14) at the other sites. ConclusionHigher FGF21 levels were associated with the presence, incidence and progression of DTAC. However, the magnitude of this association was similar to those of the non-significant associations of FGF21 levels with calcifications at other sites. Further research is needed to assess the potential of FGF21 as a biomarker for vascular calcification.

Protein preference and elevated plasma FGF21 induced by dietary protein restriction is similar in both male and female mice

Animals that are moderately protein restricted respond to this dietary stress by increasing consumption of protein-containing foods. This is true in many species, including rodents. Rodent models of protein restriction have typically relied on only male subjects, and there are plausible reasons why female rodents may respond differently to dietary protein restriction. To address this gap in knowledge, the current experiments examined protein preference after two weeks on a 5% protein diet or 20% protein control diet, in male and female mice. We found that female protein-restricted mice, like male protein-restricted mice, increase consumption of 4% casein (protein) relative to 4% maltodextrin (carbohydrate) when presented with both simultaneously. Interestingly, this increased consumption was due to more bursts in females and more licks per burst in males, indicating possible differences in mechanism by which increased intake is achieved. Stage of the estrous cycle did not affect female responses. Moreover, we measured plasma fibroblast growth factor 21 (FGF21) – a hormone induced by protein restriction and necessary for protein preference – in male and female mice. Here, we found no statistical differences between protein-restricted males, females in diestrus, or females in proestrus. In non-restricted mice FGF21 levels were low, but significantly higher in females in proestrus than females in diestrus or males. Overall, these experiments highlight the importance of including female subjects in studies of food choice and macronutrient restriction.

Fibroblast growth factor 21 is independently associated with long term mortality in metabolic syndrome

Abstract Background Metabolic syndrome (MetS), a cluster of interrelated cardiovascular risk factors, is associated with increased risk of cardiovascular and non-cardiovascular disease. Fibroblast growth factor 21 (FGF21) plays an important role in metabolic regulation and has been shown to be elevated in MetS. However, role of FGF21 in pathogenesis of cardiovascular disease is still controversial. Objective We aimed to identify the association between plasma FGF21 level and long-term mortality in MetS patients. Methods Patients with MetS were enrolled in this study during 2015–2017. Blood samples for FGF21 were collected after 12-hour fasting and plasma FGF21 levels were determined using a human FGF21 enzyme-linked immunosorbent assay (ELISA) at the first time of the enrollment. Clinical parameters, and all-cause mortality were recorded. Cox-proportional hazard regression was used for the analysis of association between plasma FGF21 level and all-cause mortality. Results A total of 202 Mets patients (male 44.6%) with mean age of 64.3±8.3 years and BMI of 27.3±5.4 kg/m2 were enrolled. After a median follow up of 80 months, 32 (15.8%) patients died. Multivariable Cox proportional hazard regression showed that FGF21 level was independently associated with all-cause mortality after adjustment for age, established cardiovascular disease, estimated glomerular filtration rate and left ventricular ejection fraction. Patients with FGF21 level above median (240 pg/ml) had higher risk of all-cause death compared to patients with FGF21 ≤240 pg/ml (hazard ratio [HR], 3.66; 95% confidence interval [CI], 1.24–10.82; p=0.019) (Figure 1). Conclusion FGF21 level is independently associated with long term mortality in metabolic syndrome. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Thailand research fund