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Query Topic: FGF21

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type 2 diabetes(128)

Liraglutide Decreases Liver Fat Content and Serum Fibroblast Growth Factor 21 Levels in Newly Diagnosed Overweight Patients with Type 2 Diabetes and Nonalcoholic Fatty Liver Disease.
In this study, we aimed to verify plasma fibroblast growth factor 21 (FGF21) elevation in newly diagnosed overweight patients with type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD) and to evaluate the effectiveness of liraglutide on reducing liver fat content and serum (FGF21) levels in those patients. A 12-week, single-center, prospective study was conducted. Twenty newly diagnosed overweight patients with T2DM and NAFLD were recruited. Twenty healthy age, sex, and body mass index (BMI) matched subjects were enrolled as the control group. Enzyme-linked immunosorbent assay was used to measure serum FGF21 levels. Liver fat content was determined using the 3.0 T whole-body MRI scanner. Those newly diagnosed overweight patients with T2DM and NAFLD had a BMI of 27.6 ± 0.5 kg/m Liraglutide treatment reduced both liver fat content and FGF21 levels in newly diagnosed overweight patients with T2DM and NAFLD. FGF21 may be a potential biomarker for evaluating the effects of liraglutide treatment on hepatic fat and glucose metabolism.
Publication Date: 2021-10-19
Journal: Journal of diabetes research

serum fgf21 levels(118)

Elevated serum FGF21 predicts the major adverse cardiovascular events in STEMI patients after emergency percutaneous coronary intervention.
Although there have been several studies related to serum fibroblast growth factor 21 (FGF21) levels and acute myocardial infarction, the value of serum FGF21 levels in ST-segment elevation myocardial infarction (STEMI) patients after emergency percutaneous coronary intervention (PCI) has not been previously investigated. A total of 348 STEMI patients who underwent emergency PCI were enrolled from January 2016 to December 2018. The primary endpoint was the occurrence of major adverse cardiovascular events (MACEs), with a median follow-up of 24 months. Eighty patients with stable angina (SA) who underwent selective PCI served as the control group. Serum FGF21 levels were measured by ELISA. Serum FGF21 levels were significantly higher in the STEMI group than in the SA group (225.03 ± 37.98 vs. 135.51 ±  34.48, Elevated FGF21 levels on admission have been shown to be a powerful predictor of MACEs for STEMI patients after emergency PCI.
Publication Date: 2021-10-28
Journal: PeerJ

peroxisome proliferator-activated receptor(66)

PPARα agonist WY-14,643 induces adipose atrophy and fails to blunt chronic ethanol-induced hepatic fat accumulation in mice lacking adipose FGFR1.
Fibroblast growth factor 21 (FGF21) is mainly regulated by peroxisome proliferator-activated receptor α (PPARα) in liver. The PPARα-FGF21 axis protects against alcohol-related liver disease (ALD). FGF21 exerts its effect via FGF receptor 1 (FGFR1). However, liver specific FGFR1 abrogation had no effect on ALD. Adipose tissues highly express FGFR1. When adipocyte specific FGFR1 knockout (fgfr1
Publication Date: 2021-07-16
Journal: Biochemical pharmacology

white adipose tissue(64)

Potential of Hibiscus sabdariffa Linn. in managing FGF21 resistance in diet-induced-obesity rats via miR-34a regulation.
Obesity is a cause of FGF21 resistance, which affects the browning and thermogenesis process of the adipose tissue. Decreased receptor expression is influenced by miR-34a, whose expression is increased in obesity. While FGF21-based therapies have been widely investigated, the potential activity of Hibiscus sabdariffa Linn. extract (HSE) against FGF21 resistance is unknown. This study aims to determine the effects of HSE on the expression of miR-34a and FGF21 receptors in white adipose tissue. This experimental study used 24 male Sprague-Dawley rats and divided into four groups: Control (N); diet-induced-obesity rats (DIO); DIO rats with HSE 200 mg/kgBW/day and DIO rats with HSE 400 mg/kgBW/day. Rats were fed a high-fat diet for 17 weeks. HSE was administered daily for 5 weeks. The administration of HSE 400 mg/kgBW/day resulted in the equivalent expression of miR-34a to that of the control (p > 0.05). FGFR1 receptor expression was also similar to controls (p > 0.05). Beta-klotho expression was significantly lower than that of control (p < 0.05) but equivalent to that of DIO rats (p < 0.05). H. sabdariffa has the potential to reduce FGF21 resistance in DIO rats through the suppression of miR-34a expression and an increase in the number of FGFR1 and beta-klotho receptors in adipose tissue.
Publication Date: 2021-10-24
Journal: Veterinary medicine and science

circulating fgf21 levels(63)

Circulating fibroblast growth factor 21 links hemodynamics with kidney function in middle-aged and older adults: A mediation analysis.
Altered hemodynamics are commonly observed in individuals with declining renal function; however, the pathophysiological mechanisms linking renal dysfunction and hemodynamics have not been fully elucidated. Fibroblast growth factor 21 (FGF21), which upregulates sympathetic nerve activity, can alter systemic hemodynamics, and its level can increase as renal function declines. This study aimed to determine the associations among circulating FGF21 levels, hemodynamics, and renal function in middle-aged and older adults. In a total of 272 middle-aged and older adults (age range: 46-83 years), estimated glomerular filtration rate (eGFR), hemodynamics (brachial and aortic blood pressure and aortic pulse wave velocity [PWV]), and serum FGF21 levels were measured. For mediation analysis, hemodynamic parameters were entered as outcomes. eGFR or log-transformed urinary albumin and creatinine ratio (UACR) and log-transformed serum FGF21 levels were set as the predictors and mediator, respectively. According to multivariable regression models after adjusting for potential covariates, serum FGF21 levels were significantly associated with brachial systolic blood pressure (β = 0.140), pulse pressure (β = 0.136), and aortic PWV (β = 0.144). Mediation analyses showed that serum FGF21 levels significantly mediated the relationship of eGFR with brachial systolic blood pressure (indirect effect [95% confidence interval]: -0.032 [-0.071, -0.002]), pulse pressure (-0.019 [-0.041, -0.001]), and aortic PWV (-0.457 [-1.053, -0.021]) and the relationship of UACR with aortic PWV (7.600 [0.011, 21.148]). These findings suggest that elevated circulating FGF21 levels partially mediate the association of elevated blood pressure and/or aortic stiffness with renal dysfunction in middle-aged and older adults.
Publication Date: 2021-10-26
Journal: Hypertension research : official journal of the Japanese Society of Hypertension

plasma fgf21 levels(53)

Association of plasma FGF21 levels with muscle mass and muscle strength in a national multicentre cohort study: Korean Frailty and Aging Cohort Study.
despite of the beneficial effects of fibroblast growth factor (FGF) 21 in several metabolic diseases, the association of plasma FGF21 with muscle mass and muscle strength is still unclear. a total of 386 community-dwelling older adults aged 70-84 years were analysed. Appendicular skeletal muscle mass was measured using dual-energy X-ray absorptiometry and normalised to the square of height (ASM/ht2). Muscle strength was assessed using the hand grip strength (HGS) test. The definitions of low muscle mass (LMM) and low muscle strength (LMS) were based on the Asian Working Group for Sarcopenia. plasma FGF21 was significantly lower in participants with LMM than in those with normal muscle mass (289.7 [192.4-448.3] vs. 345.6 [238.6-503.2] pg/ml, P = 0.008). In contrast, the LMS group had a significantly higher plasma FGF21 level than the normal muscle strength group (369.7 [244.4-591.1] vs. 309.7 [205.3-444.8] pg/ml, P = 0.006). In the partial correlation analysis, following adjustment for age, sex and body mass index, FGF21 levels had no significant association with ASM/ht2, but were negatively associated with HGS (r = -0.112, P = 0.029). Furthermore, after multivariate adjustment for confounding variables, the odds ratio for the risk of LMS was 2.32 (95% confidence interval 1.20-4.46) when comparing the highest with the lowest FGF21 quartile. circulating FGF21 levels are negatively associated with muscle strength but are not independently correlated with muscle mass.
Publication Date: 2021-10-01
Journal: Age and ageing

brown adipose tissue(41)

A pyrexic effect of FGF21 independent of energy expenditure and UCP1.
Administration of FGF21 to mice reduces body weight and increases body temperature. The increase in body temperature is generally interpreted as hyperthermia, i.e. a condition secondary to the increase in energy expenditure (heat production). Here, we examine an alternative hypothesis: that FGF21 has a direct pyrexic effect, i.e. FGF21 increases body temperature independently of any effect on energy expenditure. We studied the effects of FGF21 treatment on body temperature and energy expenditure in high-fat-diet-fed and chow-fed mice exposed acutely to various ambient temperatures, in high-fat diet-fed mice housed at 30 °C (i.e. at thermoneutrality), and in mice lacking uncoupling protein 1 (UCP1). In every model studied, FGF21 increased body temperature, but energy expenditure was increased only in some models. The effect of FGF21 on body temperature was more (not less, as expected in hyperthermia) pronounced at lower ambient temperatures. Effects on body temperature and energy expenditure were temporally distinct (daytime versus nighttime). FGF21 enhanced UCP1 protein content in brown adipose tissue (BAT); there was no measurable UCP1 protein in inguinal brite/beige adipose tissue. FGF21 increased energy expenditure through adrenergic stimulation of BAT. In mice lacking UCP1, FGF21 did not increase energy expenditure but increased body temperature by reducing heat loss, e.g. a reduced tail surface temperature. The effect of FGF21 on body temperature is independent of UCP1 and can be achieved in the absence of any change in energy expenditure. Since elevated body temperature is a primary effect of FGF21 and can be achieved without increasing energy expenditure, only limited body weight-lowering effects of FGF21 may be expected.
Publication Date: 2021-08-22
Journal: Molecular metabolism

2 diabetes mellitus(41)

Diagnostic Performance of Serum Biomarkers Fibroblast Growth Factor 21, Galectin-3 and Copeptin for Heart Failure with Preserved Ejection Fraction in a Sample of Patients with Type 2 Diabetes Mellitus.
More than half of the patients with heart failure have preserved ejection fraction (HFpEF), however evidence shows a mortality rate comparable to those with reduced ejection fraction. The aim of this study was to evaluate whether FGF21, galectin-3 and copeptin can be used as biomarkers to identify HFpEF in patients with confirmed type 2 diabetes mellitus (DM). Sixty-nine diabetic patients were enrolled and divided into two groups: patients with HFpEF (
Publication Date: 2021-09-29
Journal: Diagnostics (Basel, Switzerland)

hepatic fgf21 expression(39)

Effect of nighttime light exposure on glucose metabolism in protein-restricted mice.
Disruption of biological rhythms due exposure to artificial light at night (ALAN) has been emerged as new risk factor for metabolic diseases. However, it remains largely unexplored the effects induced by exposure to ALAN on energy metabolism with concomitant misalignment in the circadian system caused by nutritional imbalance. Objective: Here we evaluate whether low-protein diet could enhance the effects induced by exposure to ALAN on the energy metabolism and consequently predispose to metabolic disorders. Male C57BL6/J mice were weaned on a normal protein (NP) or a low-protein (LP) diet and housed on 12h light/dark (L/D) cycle. After 6 weeks, mice maintained on their respective diets were subdivided into normal light/dark cycle or exposed to ALAN for 8 weeks. We observed that exposure to ALAN concomitant to LP diet disrupts the behavioral rhythms, without shifting the timing of food intake. Furthermore, exposure to ALAN lead to increased body and fat pad weights, higher levels of fast and fed glycemia and glucose intolerance independent of the diet consumed. Importantly the insulin resistance developed in mice exposed to ALAN was diet-dependent. At the molecular level, exposure to ALAN concurrent with LP diet increased the expression of Phosphoenolpyruvate carboxykinase 1 in both periods analyzed and inverted the pattern of Fibroblast growth factor 21 (Fgf21) expression in the liver. Our data suggest that dietary protein restriction modulates the effects induced by nighttime light exposure on glucose metabolism, which could be partially related with the dysregulation on hepatic Fgf21 expression.
Publication Date: 2021-10-15
Journal: The Journal of endocrinology

recombinant human fgf21(31)

FGF21 Attenuated LPS-Induced Depressive-Like Behavior
Major depressive disorder is a serious neuropsychiatric disorder with high rates of recurrence and mortality. Many studies have supported that inflammatory processes play a central role in the etiology of depression. Fibroblast growth factor 21 (FGF21), a member of the fibroblast growth factors (FGFs) family, regulates a variety of pharmacological activities, including energy metabolism, glucose and lipid metabolism, and insulin sensitivity. In addition, recent studies showed that the administration of FGF21, a regulator of metabolic function, had therapeutic effects on mood stabilizers, indicating that FGF21 could be a common regulator of the mood response. However, few studies have highlighted the antidepressant effects of FGF21 on lipopolysaccharide (LPS)-induced mice, and the anti-inflammatory mechanism of FGF21 in depression has not yet been elucidated. The purpose of the current study was to determine the antidepressant effects of recombinant human FGF21 (rhFGF21). The effects of rhFGF21 on depression-like behaviors and the inflammatory signaling pathway were investigated in both an LPS-induced mouse model and primary microglia
Publication Date: 2020-03-19
Journal: Frontiers in pharmacology

body mass index(31)

Fibroblast growth factor 21 is associated with increased serum total antioxidant capacity and oxidized lipoproteins in humans with different stages of chronic kidney disease.
Oxidative stress (OS) induces the production of fibroblast growth factor 21 (FGF21). Previous data have revealed that FGF21 protects cells from OS injury and death, making it a potential therapeutic option for many diseases with increased OS. However, the association of this growth factor with OS markers in humans with chronic kidney disease (CKD) remains unknown. This study aims to evaluate the association of serum FGF21 with serum total antioxidant capacity (TAC) and oxidized low-density lipoproteins (OxLDL) in subjects in different stages of kidney disease. This is a cross-sectional study that included 382 subjects with different stages of CKD, irrespective of type 2 diabetes (T2D) diagnosis. Associations of serum FGF21 with OxLDL, TAC, sex, age, body mass index (BMI), fasting plasma glucose, estimated glomerular filtration rate (eGFR), T2D, and smoking, were evaluated through bivariate and partial correlation analyses. Independent associations of these variables with serum FGF21 were evaluated using multiple linear regression analysis. Serum FGF21 was significantly and positively correlated with age ( A positive association between serum FGF21 and OS has been found independently of renal function in humans. Results from the present study provide novel information for deeper understanding of the role of FGF21 in OS in humans with CKD and T2D; mechanistic studies to explain the association of serum FGF21 with oxidative stress in CKD are needed.
Publication Date: 2021-04-16
Journal: Therapeutic advances in endocrinology and metabolism

insulin resistance(109)

Hepatocyte-specific fibroblast growth factor 21 overexpression ameliorates high-fat diet-induced obesity and liver steatosis in mice.
Fibroblast growth factor (FGF) 21 is an endocrine growth factor mainly secreted by the liver in response to a ketogenic diet and alcohol consumption. FGF21 signaling requires co-receptor β-klotho (KLB) co-acting with FGF receptors, which has pleiotropic metabolic effects, including induced hepatic fatty acid oxidation and ketogenesis, in human and animal models of obesity. We examined the hepatocyte-specific enhancer/promoter of FGF21 expression plasmids in high-fat diet-fed mice for 12 weeks. Hydrodynamic injection for FGF21 delivery every 6 weeks sustained high circulating levels of FGF21, resulting in marked reductions in body weight, epididymal fat mass, insulin resistance, and liver steatosis. FGF21-induced lipolysis in the adipose tissue enabled the liver to be flooded with fat-derived FFAs. The hepatic expression of Glut2 and Bdh1 was upregulated, whereas that of gluconeogenesis-related genes, G6p and Pepck, and lipogenesis-related genes, Srebp-1 and Srebp-2, was significantly suppressed. FGF21 induced the phosphorylation of AMPK at Thr172 and Raptor at ser792 and suppressed that of mTOR at ser2448, which downregulated mTORC1 signaling and reduced IRS-1 phosphorylation at ser1101. Finally, in the skeletal muscle, FGF21 increased Glut4 and Mct2, a membrane protein that acts as a carrier for ketone bodies. Enzymes for ketone body catabolism (Scot) and citrate cycle (Cs, Idh3a), and a marker of regenerating muscle (myogenin) were also upregulated via increased KLB expression. Thus, FGF21-induced lipolysis was continuously induced by a high-fat diet and fat-derived FFAs might cause liver damage. Hepatic fatty acid oxidation and ketone body synthesis may act as hepatic FFAs' disposal mechanisms and contribute to improved liver steatosis. Liver-derived ketone bodies might be used for energy in the skeletal muscle. The potential FGF21-related crosstalk between the liver and extraliver organs is a promising strategy to prevent and treat metabolic syndrome-related nonalcoholic steatohepatitis.
Publication Date: 2021-11-05
Journal: Laboratory investigation; a journal of technical methods and pathology

body weight(103)

Fibroblast Growth Factor 21 as a Potential Biomarker for Improved Locomotion and Olfaction Detection Ability after Weight Reduction in Obese Mice.
Obesity is one of the most challenging diseases of the 21st century and is accompanied by behavioural disorders. Exercise, dietary adjustments, or time-restricted feeding are the only successful long-term treatments to date. Fibroblast growth factor 21 (FGF21) plays a key role in dietary regulation, but FGF21 resistance is prevalent in obesity. The aim of this study was to investigate in obese mice whether weight reduction leads to improved behaviour and whether these behavioural changes are associated with decreased plasma FGF21 levels. After establishing a model for diet-induced obesity, mice were subjected to three different interventions for weight reduction, namely dietary change, treadmill exercise, or time-restricted feeding. In this study, we demonstrated that only the combination of dietary change and treadmill exercise affected all parameters leading to a reduction in weight, fat, and FGF21, as well as less anxious behaviour, higher overall activity, and improved olfactory detection abilities. To investigate the interrelationship between FGF21 and behavioural parameters, feature selection algorithms were applied designating FGF21 and body weight as one of five highly weighted features. In conclusion, we concluded from the complementary methods that FGF21 can be considered as a potential biomarker for improved behaviour in obese mice after weight reduction.
Publication Date: 2021-09-29
Journal: Nutrients

fatty acid(103)

Hepatic P38 Activation Modulates Systemic Metabolism Through Fgf21-Mediated Interorgan Communication.
The mechanisms underlying the pathogenesis of steatosis and insulin resistance in nonalcoholic fatty liver disease remain elusive. Increased phosphorylation of hepatic p38 has long been noticed in fatty liver; however, whether the activation of hepatic p38 is a cause or consequence of liver steatosis is unclear. Here, we demonstrate that hepatic p38 activation by MKK6 overexpression in the liver of mice induces severe liver steatosis, reduces fat mass, and elevates circulating fatty acid levels in a hepatic p38α- and FGF21-dependent manner. Mechanistically, through increasing the FGF21 production from liver, hepatic p38 activation increases the influx of fatty acids from adipose tissue to liver, leading to hepatic ectopic lipid accumulation and insulin resistance. Although hepatic p38 activation exhibits favorable effects in peripheral tissues, it impairs the hepatic FGF21 action by facilitating the ubiquitination and degradation of FGF21 receptor cofactor β-Klotho. Consistently, we show that p38 phosphorylation and FGF21 expffression are increased, β-Klotho protein levels are decreased in the fatty liver of either mice or patients. In conclusion, our study reveals previously undescribed effects of hepatic p38 activation on systemic metabolism and provides new insights into the roles of hepatic p38α, FGF21, and β-Klotho in the pathogenesis of nonalcoholic fatty liver disease.
Publication Date: 2021-10-23
Journal: Diabetes

insulin sensitivity(92)

The adverse metabolic effects of branched-chain amino acids are mediated by isoleucine and valine.
Low-protein diets promote metabolic health in rodents and humans, and the benefits of low-protein diets are recapitulated by specifically reducing dietary levels of the three branched-chain amino acids (BCAAs), leucine, isoleucine, and valine. Here, we demonstrate that each BCAA has distinct metabolic effects. A low isoleucine diet reprograms liver and adipose metabolism, increasing hepatic insulin sensitivity and ketogenesis and increasing energy expenditure, activating the FGF21-UCP1 axis. Reducing valine induces similar but more modest metabolic effects, whereas these effects are absent with low leucine. Reducing isoleucine or valine rapidly restores metabolic health to diet-induced obese mice. Finally, we demonstrate that variation in dietary isoleucine levels helps explain body mass index differences in humans. Our results reveal isoleucine as a key regulator of metabolic health and the adverse metabolic response to dietary BCAAs and suggest reducing dietary isoleucine as a new approach to treating and preventing obesity and diabetes.
Publication Date: 2021-04-23
Journal: Cell metabolism

beneficial effects(81)

The Role of Fibroblast Growth Factor 21 in Diabetic Cardiovascular Complications and Related Epigenetic Mechanisms.
Fibroblast growth factor 21 (FGF21), is an emerging metabolic regulator mediates multiple beneficial effects in the treatment of metabolic disorders and related complications. Recent studies showed that FGF21 acts as an important inhibitor in the onset and progression of cardiovascular complications of diabetes mellitus (DM). Furthermore, evidences discussed so far demonstrate that epigenetic modifications exert a crucial role in the initiation and development of DM-related cardiovascular complications. Thus, epigenetic modifications may involve in the function of FGF21 on DM-induced cardiovascular complications. Therefore, this review mainly interprets and delineates the recent advances of role of FGF21 in DM cardiovascular complications. Then, the possible changes of epigenetics related to the role of FGF21 on DM-induced cardiovascular complications are discussed. Thus, this article not only implies deeper understanding of the pathological mechanism of DM-related cardiovascular complications, but also provides the possible novel therapeutic strategy for DM-induced cardiovascular complications by targeting FGF21 and related epigenetic mechanism.
Publication Date: 2021-08-06
Journal: Frontiers in endocrinology

significantly higher(80)

Postprandial dynamics and response of fibroblast growth factor 21 in older adults.
Fibroblast growth factor 21 (FGF21) plays a pivotal role in glucose and lipid metabolism and has been proposed as a longevity hormone. However, elevated plasma FGF21 concentrations are paradoxically associated with mortality in higher age and little is known about the postprandial regulation of FGF21 in older adults. In this parallel group study, we investigated postprandial FGF21 dynamics and response in older (65-85 years) compared to younger (18-35 years) adults following test meals with varying macronutrient composition. Participants (n = 60 older; n = 60 younger) were randomized to one of four test meals: dextrose, high carbohydrate (HC), high fat (HF) or high protein (HP). Blood was drawn before and 15, 30, 60, 120, 240 min after meal ingestion. Postprandial dynamics were evaluated using repeated measures ANCOVA. FGF21 response was assessed by incremental area under the curve. Fasting FGF21 concentrations were significantly higher in older adults. FGF21 dynamics were affected by test meal (p < 0.001) and age (p = 0.013), when adjusted for BMI and fasting FGF21. Postprandial FGF21 concentrations steadily declined over 240 min in both age groups after HF and HP, but not after dextrose or HC ingestion. At 240 min, FGF21 concentrations were significantly higher in older than in younger adults following dextrose (133 pg/mL, 95%CI: 103, 172 versus 91.2 pg/mL, 95%CI: 70.4, 118; p = 0.044), HC (109 pg/mL, 95%CI: 85.1, 141 versus 70.3 pg/mL, 95%CI: 55.2, 89.6; p = 0.014) and HP ingestion (45.4 pg/mL, 95%CI: 34.4, 59.9 versus 27.9 pg/mL 95%CI: 20.9, 37.1; p = 0.018). FGF21 dynamics and response to HF were similar for both age groups. The age-specific differences in postprandial FGF21 dynamics and response in healthy adults, potentially explain higher FGF21 concentrations in older age. Furthermore, there appears to be a significant impact of acute and recent protein intake on FGF21 secretion.
Publication Date: 2021-06-16
Journal: Clinical nutrition (Edinburgh, Scotland)

energy expenditure(75)

Protein-carbohydrate interaction effects on energy balance, FGF21, IGF-1, and hypothalamic gene expression in rats.
Amino acids are involved in energy homeostasis, just as are carbohydrates and lipids. Therefore, mechanisms controlling protein intake should operate independently and in combination with systems controlling overall energy intake to coordinate appropriate metabolic and behavioral responses. The objective of this study was to quantify the respective roles of dietary protein and carbohydrate levels on energy balance, plasma fibroblast growth factor 21 (FGF21) and insulin growth factor 1 (IGF-1) concentrations, and hypothalamic neurotransmitters (POMC, NPY, AgRP, and CART). In a simplified geometric framework, 7-wk-old male Wistar rats were fed 12 diets containing 3%-30% protein for 3 wk, in which carbohydrates accounted for 30%-75% of the carbohydrate and fat part of the diet. As a result of this study, most of the studied parameters (body composition, energy expenditure, plasma FGF21 and IGF-1 concentrations, and
Publication Date: 2021-09-28
Journal: American journal of physiology. Endocrinology and metabolism

factor-21 fgf21(69)

Long-term adjustment of hepatic lipid metabolism after chronic stress and the role of FGF21.
Chronic stress leads to post-traumatic stress disorder (PTSD) and metabolic disorders including fatty liver. We hypothesized that stress-induced molecular mechanisms alter energy metabolism, thereby promoting hepatic lipid accumulation even after a stress-free recovery period. In this context, we investigated fibroblast growth factor-21 (FGF21) as protective for energy and glucose homeostasis. FGF21 knockout mice (B6.129S6(SJL)-Fgf21tm1.2Djm; FGF21KO) and control mice (C57BL6; WT) were subjected to chronic variable stress. Mice were examined directly after acute intervention (Cvs) and long-term after 3 months of recovery (3mCvs). In WT, Cvs reduced insulin sensitivity and hepatic lipid accumulation, whilst fatty acid uptake increased. FGF21KO mice responded to Cvs with improved glucose tolerance, insulin resistance but liver triglycerides and plasma lipids were unaltered. Hepatic gene expression was specifically altered by genotype and stress e.g. by PPARa and SREBP-1 regulated genes. The stress-induced alteration of hepatic metabolism persisted after stress recovery. In hepatocytes at 3mCvs, differential gene regulation and secreted proteins indicated a genotype specific progression of liver dysfunction. Overall, at 3mCvs FGF21 was involved in maintaining mitochondrial activity, attenuating de novo lipogenesis, increased fatty acid uptake and histone acetyltransferase activity. Glucocorticoid release and binding to the FGF21 promoter may contribute to prolonged FGF21 release and protection against hepatic lipid accumulation. In conclusion, we showed that stress favors fatty liver disease and FGF21 protected against hepatic lipid accumulation after previous chronic stress loading by i) restored physiological function, ii) modulated gene expression via DNA-modifying enzymes, and iii) maintained energy metabolism.
Publication Date: 2021-10-09
Journal: Biochimica et biophysica acta. Molecular basis of disease

fgf21 concentrations(69)

Roles of fibroblast growth factor 21 in the control of depression-like behaviours after social defeat stress in male rodents.
Fibroblast growth factor 21 (FGF21) modulates energy metabolism and neuroendocrine stress responses. FGF21 synthesis is increased after environmental or metabolic challenges. Detailed roles of FGF21 in the control of behavioural disturbances under stressful conditions remain to be clarified. Here, we examined the roles of FGF21 in the control of behavioural changes after social defeat stress in male rodents. Central administration of FGF21 increased the number of tyrosine hydroxylase-positive catecholaminergic cells expressing c-Fos protein, an activity marker of neurones, in the nucleus tractus solitarius and area postrema. Double in situ hybridisation showed that some catecholaminergic neurones in the dorsal medulla oblongata expressed β-Klotho, an essential co-receptor for FGF21, in male mice. Social defeat stress increased FGF21 concentrations in the plasma of male mice. FGF21-deficient male mice showed social avoidance in a social avoidance test with C57BL/6J mice (background strain of FGF21-deficient mice) and augmented immobility behaviour in a forced swimming test after social defeat stress. On the other hand, overexpression of FGF21 by adeno-associated virus vectors did not significantly change behaviours either in wild-type male mice or FGF21-deficient male mice. The present data are consistent with the view that endogenous FGF21, possibly during the developmental period, has an inhibitory action on stress-induced depression-like behaviour in male rodents.
Publication Date: 2021-09-03
Journal: Journal of neuroendocrinology

fgf21 mrna(68)

Transmembrane G protein-coupled receptor 5 signaling stimulates fibroblast growth factor 21 expression concomitant with up-regulation of the transcription factor nuclear receptor Nr4a1.
Fibroblast growth factor 21 (FGF21) acts as an endocrine factor, playing important roles in the regulation of energy homeostasis, glucose and lipid metabolism. It is induced by diverse metabolic and cellular stresses, such as starvation and cold challenge, which in turn facilitate adaptation to the stress environment. The pharmacological action of FGF21 has received much attention, because the administration of FGF21 or its analogs has been shown to have an anti-obesity effect in rodent models. In the present study, we found that 3-O-acetyloleanolic acid, an active constituent isolated from the fruits of Forsythia suspensa, stimulated FGF21 production concomitant with the up-regulation of a transcription factor, nuclear receptor Nr4a1, in C2C12 myotubes. Additionally, significant increases in mFgf21 promoter activity were observed in C2C12 cells overexpressing TGR5 receptor in response to 3-O-acetyloleanolic acid treatment. Treatment with the p38 MAPK inhibitor SB203580 was effective at suppressing these stimulatory effects of 3-O-acetyloleanolic acid. Pretreatment with SB203580 also significantly repressed FGF21 mRNA abundance and FGF21 secretion in C2C12 myotubes after 3-O-acetyloleanolic acid stimulation, suggesting that p38 activation is required for the induction of FGF21 by ligand-activated TGR5 in C2C12 myotubes. These findings collectively indicated that TGR5 receptor signaling drives FGF21 expression via p38 activation, at least partly, by mediating Nr4a1 expression. Thus, the novel biological function of 3-O-acetyloleanolic acid as an agent having anti-obesity effects is likely to be mediated through the activation of TGR5 receptors.
Publication Date: 2021-08-28
Journal: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie

significantly increased(64)

Sulforaphane ameliorates non-alcoholic fatty liver disease in mice by promoting FGF21/FGFR1 signaling pathway.
Most studies regarding the beneficial effect of sulforaphane (SFN) on non-alcoholic fatty liver disease (NAFLD) have focused on nuclear factor E2-related factor 2 (Nrf2). But the molecular mechanisms underlying the beneficial effect of SFN in the treatment of NAFLD remain controversial. Fibroblast growth factor (FGF) 21 is a member of the FGF family expressed mainly in liver but also in adipose tissue, muscle and pancreas, which functions as an endocrine factor and has been considered as a promising therapeutic candidate for the treatment of NAFLD. In the present study we investigated whether FGF21 was involved in the therapeutic effect of SFN against NAFLD. C57BL/6J mice were fed a high-fat diet (HFD) for 12 weeks to generate NAFLD and continued on the HFD for additional 6 weeks with or without SFN treatment. We showed that administration of SFN (0.56 g/kg) significantly ameliorated hepatic steatosis and inflammation in NAFLD mice, along with the improved glucose tolerance and insulin sensitivity, through suppressing the expression of proteins responsible for hepatic lipogenesis, while enhancing proteins for hepatic lipolysis and fatty acids oxidation. SFN administration significantly increased hepatic expression of FGFR1 and fibroblast growth factor 21 (FGF21) in NAFLD mice, along with decreased phosphorylation of p38 MAPK (the downstream of FGF21). HepG2 cells were treated in vitro with FFAs (palmitic acid and oleic acid) followed by different concentrations of SFN. We showed that the effects of SFN on FGF21 and FGFR1 protein expression were replicated in FFAs-treated HepG2 cells. Moreover, the increased FGFR1 protein occurred earlier than increased FGF21 protein. Interestingly, the rapid effect of SFN on FGFR1 protein was not regulated by the FGFR1 gene transcription. Knockdown of FGFR1 and p38 genes weakened SFN-reduced lipid deposition in FFAs-treated HepG2 cells. SFN administration in combination with rmFGF21 (1.5 mg/kg, i.p., every other day) for 3 weeks further suppressed hepatic steatosis in NAFLD mice. In conclusion, SFN ameliorates lipid metabolism disorders in NAFLD mice by upregulating FGF21/FGFR1 pathway. Our results verify that SFN may become a promising intervention to treat or relieve NAFLD.
Publication Date: 2021-10-17
Journal: Acta pharmacologica Sinica

weight loss(63)

Liver-Specific Nonviral Gene Delivery of Fibroblast Growth Factor 21 Protein Expression in Mice Regulates Body Mass and White/Brown Fat Respiration.
Viral-mediated in vivo gene delivery methods currently dominate among therapeutic strategies within the clinical and experimental settings, albeit with well documented limitations arising from immunologic constraints. In this study, we demonstrate the utility of nonviral hepatotropic in vivo gene delivery of unpackaged expression constructs, including one encoding fibroblast growth factor 21 (FGF21). FGF21 is an important hepatokine whose expression positively correlates with therapeutic outcomes across various animal models of obesity. Our data demonstrate that FGF21 expression can be restored into the livers of immunocompetent FGF21 knockout mice for at least 2 weeks after a single injection with an FGF21 expression plasmid. In wild-type C57BL6/J mice, in vivo transfection with an FGF21-expressing plasmid induced weight loss, decreased adiposity, and activated thermogenesis in white fat within 2 weeks. Furthermore, in vivo FGF21 gene delivery protected C57BL6/J mice against diet-induced obesity by decreasing adiposity and increasing uncoupling protein 1-dependent thermogenesis in brown fat and by boosting respiratory capacity in subcutaneous and perigonadal white fat. Together, the data illustrate a facile and effective methodology for delivering prolonged protein expression specifically to the liver. We contend that this method will find utility in basic science research as a practical means to enhance in vivo studies characterizing liver protein function. We further believe our data provide a rationale for further exploring the potential clinical utility of nonviral gene therapy in mouse models of disease. SIGNIFICANCE STATEMENT: This study presents a valuable method for nonviral gene delivery in mice that improves upon existing techniques. The data provide a rationale for further exploring the potential clinical utility of nonviral gene therapy in mouse models of disease and will likely enhance in vivo studies characterizing liver protein function.
Publication Date: 2021-06-03
Journal: The Journal of pharmacology and experimental therapeutics

fgf21 treatment(52)

Fibroblast growth factor 21 (FGF21) alleviates senescence, apoptosis, and extracellular matrix degradation in osteoarthritis via the SIRT1-mTOR signaling pathway.
Osteoarthritis (OA) is a complex condition that involves both apoptosis and senescence and currently cannot be cured. Fibroblast growth factor 21 (FGF21), known for its role as a potent regulator of glucose and energy metabolism, protects from various diseases, possibly by mediating autophagy. In the present study, the role of FGF21 in the progression of OA was investigated in both in vitro and in vivo experiments. In vitro, the results revealed that FGF21 administration alleviated apoptosis, senescence, and extracellular matrix (ECM) catabolism of the chondrocytes induced by tert-butyl hydroperoxide (TBHP) by mediating autophagy flux. Furthermore, CQ, an autophagy flux inhibitor, could reverse the protective effect of FGF21. It was observed that the FGF21-induced autophagy flux enhancement was mediated by the nuclear translocation of TFEB, which occurs due to the activation of the SIRT1-mTOR signaling pathway. The in vivo experiments demonstrated that FGF21 treatment could reduce OA in the DMM model. Taken together, these findings suggest that FGF21 protects chondrocytes from apoptosis, senescence, and ECM catabolism via autophagy flux upregulation and also reduces OA development in vivo, demonstrating its potential as a therapeutic agent in OA.
Publication Date: 2021-09-25
Journal: Cell death & disease

blood glucose(44)

Therapeutic effect and mechanism of combined use of FGF21 and insulin on diabetic nephropathy.
Although FGF21 ameliorates diabetic nephropathy (DN), the efficacy is not satisfactory. Studies demonstrate that FGF21 combined with Insulin exhibits reciprocal sensitization on glucose and lipid metabolism in mice with type 2 diabetes. However, therapeutic effect of combined use of FGF21 and Insulin on DN has not been reported. Therefore, this study explored therapeutic effect and mechanism of combined use of FGF21 and Insulin on DN. Our results showed that compared with Insulin or FGF21 alone, FGF21 combined with Insulin further ameliorated blood glucose, HbAlc, OGTT, renal function, liver function, blood lipid, histopathological changes, oxidative stress and AGEs in the mice of DN (BKS-Lepr
Publication Date: 2021-10-26
Journal: Archives of biochemistry and biophysics

fgf19 fgf21(43)

The Saga of Endocrine FGFs.
Fibroblast growth factors (FGFs) are cell-signaling proteins with diverse functions in cell development, repair, and metabolism. The human FGF family consists of 22 structurally related members, which can be classified into three separate groups based on their action of mechanisms, namely: intracrine, paracrine/autocrine, and endocrine FGF subfamilies. FGF19, FGF21, and FGF23 belong to the hormone-like/endocrine FGF subfamily. These endocrine FGFs are mainly associated with the regulation of cell metabolic activities such as homeostasis of lipids, glucose, energy, bile acids, and minerals (phosphate/active vitamin D). Endocrine FGFs function through a unique protein family called klotho. Two members of this family, α-klotho, or β-klotho, act as main cofactors which can scaffold to tether FGF19/21/23 to their receptor(s) (FGFRs) to form an active complex. There are ongoing studies pertaining to the structure and mechanism of these individual ternary complexes. These studies aim to provide potential insights into the physiological and pathophysiological roles and therapeutic strategies for metabolic diseases. Herein, we provide a comprehensive review of the history, structure-function relationship(s), downstream signaling, physiological roles, and future perspectives on endocrine FGFs.
Publication Date: 2021-09-29
Journal: Cells

fgf21 resistance(32)

Integration of FGF21 Signaling and Metabolomics in High-Fat Diet-Induced Obesity.
Sex differences in obesity have been well established, but the metabolic mechanism underlying these differences remains unclear. In the present study, we determined the expression levels of endogenous fibroblast growth factor 21 (FGF21) and its related receptors in male and female mice that were fed a high-fat diet (HFD) for 12 weeks. We also analyzed the metabolic changes in serum and livers using a nuclear magnetic resonance-based metabolomics approach. Reverse transcription polymerase chain reaction and western blotting results revealed that the levels of FGFR1, FGFR2, and co-factor β-klotho were upregulated in female mice to alleviate FGF21 resistance induced by HFD. The metabolomics results demonstrated that the serum and liver metabolic patterns of HFD-fed male mice were significantly separated from those of the female HFD-fed group and the normal diet group. Furthermore, low-density lipoprotein/very low density lipoprotein and betaine levels were associated with the resistance of exogenous HFD in female mice. These findings imply that sex-based differences in metabolism and susceptibility to obesity might be mediated by the FGF21 signaling pathway.
Publication Date: 2021-07-10
Journal: Journal of proteome research

fgf21 plays(25)

FGF21 promotes migration and differentiation of epidermal cells during wound healing via SIRT1 dependent autophagy.
Migration and differentiation of epidermal cells are essential for epidermal regeneration during wound healing. Fibroblast growth factor 21 (FGF21) plays key roles in mediating a variety of biological activities. However, its role in skin wound healing remains unknown. Fgf21 knockout (Fgf21 KO) mice were used to determine the effect of FGF21 on wound healing. The source of FGF21 and its target cells were determined by immunohistochemistry, immunoblotting, and ELISA assay. Moreover, Sirt1 FGF21 was active in fibroblasts and promoted migration and differentiation of keratinocytes following injury. After wounding, SIRT1 expression and autophagosome synthesis were lower in Fgf21 KO mice. Depletion of ATG7 in keratinocytes counteracted the FGF21-induced increases in migration and differentiation, suggesting that autophagy is required for the FGF21-mediated pro-healing effects. Furthermore, epithelial-specific Sirt1 knockout abolished the FGF21-mediated improvements of autophagy and wound healing. Silencing of SIRT1 in keratinocytes, which decreased deacetylation of p53 and autophagy-related proteins, revealed that FGF21-induced autophagy during wound healing was SIRT1-dependent. Our findings reveal that FGF21 is a key regulator of keratinocyte migration and differentiation during wound healing.
Publication Date: 2021-10-06
Journal: British journal of pharmacology

disease nafld(23)

Dose-response relationship between serum fibroblast growth factor 21 and liver fat content in non-alcoholic fatty liver disease.
Although serum fibroblast growth factor 21 (FGF21) levels are associated with liver fat content in non-alcoholic liver fat disease (NAFLD), the precise nature of the association remains undetermined. Therefore, this study aimed to explore the potential dose-response relationship between FGF21 and liver fat content in NAFLD. For this exploratory study from a randomized trial, 220 NAFLD patients with central obesity were recruited via community-based screening and randomly assigned to either control, moderate or vigorous-moderate exercise groups for 12 months. After this exercise intervention, patients were followed-up for a further 12 months. Serum FGF21 levels were measured by ELISA. Intrahepatic triglyceride (IHTG) content was determined by proton magnetic resonance spectroscopy. Of the 220 patients, 149 (67.7%) were female; mean age was 53.9 ± 7.1 years and mean BMI was 28.0 ± 2.9 kg/m Serum FGF21 is strongly associated with liver fat content in a dose-response manner in centrally obese NAFLD patients. These findings support the use of serum FGF21 as a biomarker of liver fat content in NAFLD.
Publication Date: 2020-12-30
Journal: Diabetes & metabolism

95 ci(19)

Association between FGF19, FGF21 and lipocalin-2, and diabetes progression in PCOS.
Women with polycystic ovary syndrome (PCOS) have an increased risk of developing type 2 diabetes. FGF19, FGF21 and lipocalin-2 have emerged as important markers of metabolic risk. This study aims to compare the levels of FGF19, FGF21 and lipocalin-2 between subjects with or without PCOS, and to investigate the relationship between proteins and diabetes progression. In this nested case-control cohort study, 128 Chinese PCOS women and 128 controls were recruited and followed-up. All subjects underwent the oral glucose tolerance test for the evaluation of glycaemic status. Baseline serum protein levels were measured using ELISA. Compared with controls, PCOS subjects had higher levels of FGF19 (P < 0.001) and FGF21 (P = 0.022), but had lower lipocalin-2 (P < 0.001). In total, 20.8% of PCOS and 9.2% of controls developed diabetes over a mean duration of 10.4 ± 1.2 and 11.3 ± 0.5 years, respectively. Logistic regression analyses suggested FGF19 was positively associated with diabetes progression in controls, after adjusting for age, follow-up duration, waist and fasting glucose (P = 0.026, odds ratio (OR) (95% CI): 7.4 (1.3-43.6)), and the positive relationship between FGF21 and diabetes progression in controls was attenuated by adjusting for age and follow-up duration (P = 0.183). Lipocalin-2 was positively correlated with diabetes progression in PCOS group (P = 0.026, OR (95% CI)): 2.5 (1.1-5.6)); however, this became attenuated after adjusting for waist and fasting glucose (P = 0.081). In conclusion, there is differential expression of FGF19, FGF21, and lipocalin-2 in PCOS. The serum level of FGF19, and FGF21 is associated with diabetes progression in women without PCOS, while lipocalin-2 was related to diabetes progression in PCOS women.
Publication Date: 2021-09-03
Journal: Endocrine connections

kinase ampk(18)

Liraglutide regulates lipid metabolism via FGF21- LKB1- AMPK- ACC1 pathway in white adipose tissues and macrophage of type 2 diabetic mice.
Liraglutide (LRG), a glucagon-like peptide 1 analogue (GLP1A), could decrease body mass of type 2 diabetes (T2DM), but the exact molecular mechanism of LRG has not been elucidated. This study was performed to explore whether LRG regulated TG synthesis via secretion of FGF21 and modulating AMP-dependent protein kinase (AMPK) pathway in an autocrine mode. Two-month-old male C57BL/6 mice were fed high-fat diet (HFD) for 4 months followed by injection of 30 mg/kg streptozotocin (STZ) to induce state of T2DM. Then DM mice were given LRG (0.4 mg/kg/d) for 4 months. Body mass, serum lipids and FGF21 levels, related gene expression were analyzed. Lipopolysaccharide (LPS)-induced RAW264.7 cells were treated with palmitic acid and different concentrations of LRG. Then Exendin (9-39), siRNA targeted to liver kinase B1 (LKB1) and Compound C were used to confirm the signaling pathway. LRG decreased adipocyte size, increased secretion of FGF21, and promoted phosphorylation of LKB1, AMPK and Acetyl coenzyme A carboxylase 1 (ACC1) in white adipose tissue (WAT) of DM mice. LRG also increased phosphorylation of fibroblast growth factor receptor 3 (FGFR3), LKB1, AMPK and ACC1 via FGF21 secretion, which ultimately inhibited synthesis of TG in macrophage. In conclusion, FGF21 is induced to be expressed in macrophage by LRG, which then activates LKB1-AMPK-ACC1 pathway in an autocrine manner.
Publication Date: 2021-03-01
Journal: Biochemical and biophysical research communications


Regulation and Potential Biological Role of Fibroblast Growth Factor 21 in Chronic Kidney Disease.
Chronic kidney disease (CKD) is an incurable progressive disease with the progressive impairment of kidney function, which can accelerate the progression of cardiovascular disease, increase the risk of infection, and lead to related complications such as anemia and bone disease. CKD is to a great extent preventable and treatable, and it is particularly important to improve the early diagnosis, strengthen the research underlying the mechanism of disease occurrence and development, and innovate new intervention measures. Fibroblast growth factor 21 (FGF21) belongs to one of members of endocrine FGF subfamily with evolutionarily conserved functions and performs a vital role in the regulation of energy balance and adipose metabolism. FGF21 needs to rely on β-Klotho protein to specifically bind to FGF receptor (FGFR), which activates the FGF21 signaling exerting the biological function. FGF21 is deemed as an important regulatory factor extensively modulating many cellular functions under physiologic and pathologic conditions. Although the metabolic effect of FGF21 has been extensively studied, its potential biological role in the kidney has not been generally investigated. In this review, we summarize the biological characteristics, regulation and biological function of FGF21 based on the current studies, and briefly discuss the potential relationship with chronic kidney disease.
Publication Date: 2021-10-23
Journal: Frontiers in physiology


Fibroblast Growth Factor 21 Ameliorates Na
Infarcted myocardium is predisposed to cause lethal ventricular arrhythmias that remain the main cause of death in patients suffering myocardial ischemia. Liver-derived fibroblast growth factor 21 (FGF21) is an endocrine regulator, which exerts metabolic actions by favoring glucose and lipids metabolism. Emerging evidence has shown a beneficial effect of FGF21 on cardiovascular diseases, but the role of FGF21 on ventricular arrhythmias following myocardial infarction (MI) in humans has never been addressed. This study was conducted to investigate the pharmacological effects of FGF21 on cardiomyocytes after MI in humans. Patients with arrhythmia in acute MI and healthy volunteers were enrolled in this study. Serum samples were collected from these subjects on day 1 and days 7-10 after the onset of MI for measuring FGF21 levels using ELISA. Here, we found that the serum level of FGF21 was significantly increased on day 1 after the onset of MI and it returned to normal on days 7-10, relative to the Control samples. In order to clarify the regulation of FGF21 on arrhythmia, two kinds of arrhythmia animal models were established in this study, including ischemic arrhythmia model (MI rat model) and nonischemic arrhythmia model (ouabain-induced guinea pig arrhythmia model). The results showed that the incidence and duration time of ischemic arrhythmias in rhbFGF21-treated MI rats were significantly reduced at different time point after MI compared with normal saline-treated MI rats. Moreover, the onset of the first ventricular arrhythmias was delayed and the numbers of VF and maintenance were attenuated by FGF21 compared to the rhbFGF21-untreated group in the ouabain model. Consistently,
Publication Date: 2021-10-12
Journal: Frontiers in pharmacology


The Same Metabolic Response to FGF21 Administration in Male and Female Obese Mice Is Accompanied by Sex-Specific Changes in Adipose Tissue Gene Expression.
The preference for high-calorie foods depends on sex and contributes to obesity development. Fibroblast growth factor 21 (FGF21) beneficially affects taste preferences and obesity, but its action has mainly been studied in males. The aim of this study was to compare the effects of FGF21 on food preferences and glucose and lipid metabolism in C57Bl/6J male and female mice with diet-induced obesity. Mice were injected with FGF21 or vehicle for 7 days. Body weight, choice between standard (SD) and high-fat (HFD) diets, blood parameters, and gene expression in white (WAT) and brown (BAT) adipose tissues, liver, muscles, and the hypothalamus were assessed. Compared to males, females had a greater preference for HFD; less WAT; lower levels of cholesterol, glucose, and insulin; and higher expression of
Publication Date: 2021-10-14
Journal: International journal of molecular sciences


Pemafibrate Prevents Retinal Dysfunction in a Mouse Model of Unilateral Common Carotid Artery Occlusion.
Cardiovascular diseases lead to retinal ischemia, one of the leading causes of blindness. Retinal ischemia triggers pathological retinal glial responses and functional deficits. Therefore, maintaining retinal neuronal activities and modulating pathological gliosis may prevent loss of vision. Previously, pemafibrate, a selective peroxisome proliferator-activated receptor alpha modulator, was nominated as a promising drug in retinal ischemia. However, a protective role of pemafibrate remains untouched in cardiovascular diseases-mediated retinal ischemia. Therefore, we aimed to unravel systemic and retinal alterations by treating pemafibrate in a new murine model of retinal ischemia caused by cardiovascular diseases. Adult C57BL/6 mice were orally administered pemafibrate (0.5 mg/kg) for 4 days, followed by unilateral common carotid artery occlusion (UCCAO). After UCCAO, pemafibrate was continuously supplied to mice until the end of experiments. Retinal function (a-and b-waves and the oscillatory potentials) was measured using electroretinography on day 5 and 12 after UCCAO. Moreover, the retina, liver, and serum were subjected to qPCR, immunohistochemistry, or ELISA analysis. We found that pemafibrate enhanced liver function, elevated serum levels of fibroblast growth factor 21 (FGF21), one of the neuroprotective molecules in the eye, and protected against UCCAO-induced retinal dysfunction, observed with modulation of retinal gliosis and preservation of oscillatory potentials. Our current data suggest a promising pemafibrate therapy for the suppression of retinal dysfunction in cardiovascular diseases.
Publication Date: 2021-09-11
Journal: International journal of molecular sciences


Fibroblast growth factor 21 in dairy cows: current knowledge and potential relevance.
Fibroblast growth factor 21 (FGF21) has been identified as an important regulator of carbohydrate and lipid metabolism, which plays an important role for metabolic regulation, particularly under conditions of energy deprivation or stress conditions. Dairy cows are subjected to a negative energy balance and various kinds of stress particularly during the periparturient phase and during early lactation. It has been shown that the plasma concentration of FGF21 in dairy cows is dramatically increased at parturition and remains high during the first weeks of lactation. This finding suggests that FGF21 might exert similar functions in dairy cows than in other species, such as mice or humans. However, the role of FGF21 in dairy cows has been less investigated so far. Following a brief summary of the previous findings about the function of FGF21 in humans and mice, the present review aims to present the current state of knowledge about the role of FGF21 in dairy cows. The first part of the review deals with the tissue localization of FGF21 and with conditions leading to an upregulation of FGF21 expression in the liver of dairy cows. In the second part, the influence of nutrition on FGF21 expression and the role of FGF21 for metabolic diseases in dairy cows is addressed. In the third part, findings of exogenous FGF21 application on metabolism in dairy cows are reported. Finally, the potential relevance of FGF21 in dairy cows is discussed. It is concluded that FGF21 might be of great importance for metabolic adaptation to negative energy balance and stress conditions in dairy cows. However, further studies are needed for a better understanding of the functions of FGF21 in dairy cows.
Publication Date: 2021-09-15
Journal: Journal of animal science and biotechnology


Acute sleep loss alters circulating fibroblast growth factor 21 levels in humans: A randomised crossover trial.
The hormone fibroblast growth factor 21 (FGF21) modulates tissue metabolism and circulates at higher levels in metabolic conditions associated with chronic sleep-wake disruption, such as type 2 diabetes and obesity. In the present study, we investigated whether acute sleep loss impacts circulating levels of FGF21 and tissue-specific production, and response pathways linked to FGF21. A total of 15 healthy normal-weight young men participated in a randomised crossover study with two conditions, sleep loss versus an 8.5-hr sleep window. The evening before each intervention, fasting blood was collected. Fasting, post-intervention morning skeletal muscle and adipose tissue samples underwent quantitative polymerase chain reaction and DNA methylation analyses, and serum FGF21 levels were measured before and after an oral glucose tolerance test. Serum levels of FGF21 were higher after sleep loss compared with sleep, both under fasting conditions and following glucose intake (~27%-30%, p = 0.023). Fasting circulating levels of fibroblast activation protein, a protein which can degrade circulating FGF21, were not altered by sleep loss, whereas DNA methylation in the FGF21 promoter region increased only in adipose tissue. However, even though specifically the muscle exhibited transcriptional changes indicating adverse alterations to redox and metabolic homeostasis, no tissue-based changes were observed in expression of FGF21, its receptors, or selected signalling targets, in response to sleep loss. In summary, we found that acute sleep loss resulted in increased circulating levels of FGF21 in healthy young men, which may occur independent of a tissue-based stress response in metabolic peripheral tissues. Further studies may decipher whether changes in FGF21 signalling after sleep loss modulate metabolic outcomes associated with sleep or circadian disruption.
Publication Date: 2021-09-04
Journal: Journal of sleep research


Beneficial effects of dietary polyphenols in the prevention and treatment of NAFLD: cell-signaling pathways underlying health effects.
Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic accretion of triacylglycerides in the absence of alcohol intake that may progress to steatohepatitis, fibrosis and cirrhosis, becoming the main cause of chronic liver disease. This article discusses recent data concerning the use of dietary polyphenols in the prevention and treatment of NAFLD in vitro, in vivo, and in clinical trials. Study searches were performed using the PubMed database from the National Library of Medicine-National Institutes of Health. Polyphenols exert beneficial effects in NAFLD, with positive outcomes being related to body weight gain, insulin resistance, liver fat accumulation, oxidative stress, pro-inflammatory status, mitochondrial dysfunction and ER stress. Data reported for hydroxytyrosol suggest that the activation of the hepatic PPAR-α-FGF21-AMPK-PGC-1α signaling cascade is associated with fatty acid oxidation enhancement, de novo lipogenesis diminution and recovery of mitochondrial function, a contention that is supported by the actions of several polyphenols on specific components of this signaling pathway. Besides, polyphenols downregulate NF-κB, suppressing the pro-inflammatory state developed in NAFLD and upregulate liver Nrf2, increasing the cellular antioxidant potential. The latter feature of polyphenols is contributed by chelation of pro-oxidant trace elements, reduction of free radicals to stable forms and inhibition of free radical generating systems. Polyphenols are relevant bioactive compounds in terms of prevention and treatment of NAFLD, which exhibit low bioavailability and instability in biological systems that could limit their health effects. These drawbacks reinforce the necessity of further studies to improve the efficacy of polyphenol formulations for human interventions.
Publication Date: 2021-09-17
Journal: Current medicinal chemistry


Postnatal exercise protects offspring from high-fat diet-induced reductions in subcutaneous adipocyte beiging in C57Bl6/J mice.
Maternal low-protein and postnatal high-fat (HF) diets program offspring obesity and type 2 diabetes mellitus (T2DM) risk by epigenetically reducing beige adipocytes (BAs) via increased G9a protein expression (Histone3 Lysine9 dimethyl transferase), an inhibitor of the BA marker fibroblast growth factor 21 (FGF21). Conversely, offspring exercise reduces fat mass and white adipocytes, but the mechanisms are not yet understood. This work investigated whether exercise reduces offspring obesity and T2DM risk caused by a maternal HF diet via regulation of G9a and FGF21 expression that would convert white to BA. Two-month-old female C57Bl/6J mice (F0) were fed a 16% (normal fat; NF) or a 45% HF diet for 3 months prior to breeding, and subsequent gestation and lactation. Male offspring (F1) were fed the same NF and HF diets and further divided into either sedentary (S) or voluntary wheel running (Ex) groups for an additional 3 months yielding eight groups: NF (maternal treatment condition)-NF-S (postweaning treatment conditions), NF-HF-S, NF-NF-Ex, NF-HF-Ex, HF-NF-S, HF-HF-S, HF-NF-Ex, and HF-HF-Ex. Subcutaneous adipose tissue was collected for protein and mRNA analysis of FGF21, peroxisome proliferator-activated receptor-gamma coactivator (PGC-1 alpha, inducer of FGF21), G9a, E4BP4 (G9a coactivator), and protein expression of H3K9 demethylases (KDM4C). Postnatal HF diet decreased FGF21 positive BA numbers regardless of maternal diets and postnatal exercise. Under sedentary conditions, postnatal HF diet increased protein expression of FGF21 transcription inhibitors G9a and E4BP4 compared to NF diet resulting in decreased FGF21 expression. In contrast, postnatal HF diet and exercise decreased G9a and E4BP4 protein expression while decreasing FGF21 expression compared to NF diet. Under exercised condition, postnatal HF diet-induced KDM4C protein expression while no changes in KDM4C protein expression were induced by postnatal HF diet under sedentary conditions. These findings suggest that the postnatal diet exerts a greater impact on offspring adiposity and BA numbers than maternal diets. These data also suggest that offspring exercise induces KDM4C to counter the increase in G9a that was triggered by maternal and postnatal HF diets. Future studies need to determine whether KDM4C induces methylation status of G9a to alter thermogenic function of BA.
Publication Date: 2021-09-14
Journal: The Journal of nutritional biochemistry


Circulating fibroblast growth factor 21 as a potential biomarker for missed abortion in humans.
To investigate whether serum levels of fibroblast growth factor 21 (FGF21) and fatty acid-binding protein-4 (FABP4) are associated with missed abortion (MA) in humans. Cross-sectional study. University-affiliated hospital. Patients with MA at 8-12 weeks of gestation. None. Serum levels of FGF21 and FABP4 were tested by enzyme-linked immunosorbent assay. Placental samples were collected during dilation and curettage surgery, and the expression of FGF21 and its related genes were measured using quantitative polymerase chain reaction. In the discovery cohort, 78 patients with MA and 79 healthy pregnant women matched for maternal age and body mass index were nested from a prospective cohort. Circulating levels of FGF21 and FABP4 were significantly and independently elevated in patients with MA relative to the levels in the healthy controls. A single measurement of FGF21 serum level effectively discriminated MA with an area under the receiver operating characteristics curve of 0.80 (95% confidence interval: 0.73-0.87). Importantly, in our external validation cohort that comprised subjects with MA (n = 34) or induced abortion (n = 27), the FGF21 serum levels achieved an area under the receiver operating characteristics curve of 0.85 (95% confidence interval: 0.75-0.96) when identifying those with MA. Nevertheless, expression of FGF21 in the placenta was not associated with its serum concentration. Placental tissues from patients with MA exhibited impaired FGF21 signaling. Our results suggested that serum levels of FGF21 and FABP4 were associated with MA. Circulating FGF21 may serve as a potential biomarker for the recognition of MA.
Publication Date: 2021-06-26
Journal: Fertility and sterility


Hepatic FGF21 preserves thermoregulation and cardiovascular function during bacterial inflammation.
Sickness behaviors, including anorexia, are evolutionarily conserved responses to acute infections. Inflammation-induced anorexia causes dramatic metabolic changes, of which components critical to survival are unique depending on the type of inflammation. Glucose supplementation during the anorectic period induced by bacterial inflammation suppresses adaptive fasting metabolic pathways, including fibroblast growth factor 21 (FGF21), and decreases survival. Consistent with this observation, FGF21-deficient mice are more susceptible to mortality from endotoxemia and polybacterial peritonitis. Here, we report that increased circulating FGF21 during bacterial inflammation is hepatic derived and required for survival through the maintenance of thermogenesis, energy expenditure, and cardiac function. FGF21 signaling downstream of its obligate coreceptor, β-Klotho (KLB), is required in bacterial sepsis. However, FGF21 modulates thermogenesis and chronotropy independent of the adipose, forebrain, and hypothalamus, which are operative in cold adaptation, suggesting that in bacterial inflammation, either FGF21 signals through a novel, undescribed target tissue or concurrent signaling of multiple KLB-expressing tissues is required.
Publication Date: 2021-08-19
Journal: The Journal of experimental medicine


Hepatic CPT1A Facilitates Liver-Adipose Cross-Talk
Hepatosteatosis, defined as excessive intrahepatic lipid accumulation, represents the first step of NAFLD. When combined with additional cellular stress, this benign status progresses to local and systemic pathological conditions such as NASH and insulin resistance. However, the molecular events directly caused by hepatic lipid build-up, in terms of its impact on liver biology and peripheral organs, remain unclear. Carnitine palmitoyltransferase 1A (CPT1A) is the rate limiting enzyme for long chain fatty acid beta-oxidation in the liver. Here we utilise hepatocyte-specific Compared to the wild-type (WT) littermates, high fat diet (HFD)-fed LKO mice displayed more severe hepatosteatosis but were otherwise protected against diet-induced weight gain, insulin resistance, hepatic ER stress, inflammation and damage. Interestingly, increased energy expenditure was observed in LKO mice, accompanied by enhanced adipose tissue browning. RNAseq analysis revealed that the peroxisome proliferator activator alpha (PPARα)- fibroblast growth factor 21 (FGF21) axis was activated in liver of LKO mice. Importantly, antibody-mediated neutralization of FGF21 abolished the healthier metabolic phenotype and adipose browning in LKO mice, indicating that the elevation of FGF21 contributes to the improved liver pathology and adipose browning in HFD-treated LKO mice. Liver with deficient CPT1A expression adopts a healthy steatotic status that protects against HFD-evoked liver damage and potentiates adipose browning in an FGF21-dependent manner. Inhibition of hepatic CPT1A may serve as a viable strategy for the treatment of obesity and NAFLD.
Publication Date: 2021-10-23
Journal: Diabetes


Increased glycolysis in skeletal muscle coordinates with adipose tissue in systemic metabolic homeostasis.
Insulin-independent glucose metabolism, including anaerobic glycolysis that is promoted in resistance training, plays critical roles in glucose disposal and systemic metabolic regulation. However, the underlying mechanisms are not completely understood. In this study, through genetically manipulating the glycolytic process by overexpressing human glucose transporter 1 (GLUT1), hexokinase 2 (HK2) and 6-phosphofructo-2-kinase-fructose-2,6-biphosphatase 3 (PFKFB3) in mouse skeletal muscle, we examined the impact of enhanced glycolysis in metabolic homeostasis. Enhanced glycolysis in skeletal muscle promoted accelerated glucose disposal, a lean phenotype and a high metabolic rate in mice despite attenuated lipid metabolism in muscle, even under High-Fat diet (HFD). Further study revealed that the glucose metabolite sensor carbohydrate-response element-binding protein (ChREBP) was activated in the highly glycolytic muscle and stimulated the elevation of plasma fibroblast growth factor 21 (FGF21), possibly mediating enhanced lipid oxidation in adipose tissue and contributing to a systemic effect. PFKFB3 was critically involved in promoting the glucose-sensing mechanism in myocytes. Thus, a high level of glycolysis in skeletal muscle may be intrinsically coupled to distal lipid metabolism through intracellular glucose sensing. This study provides novel insights for the benefit of resistance training and for manipulating insulin-independent glucose metabolism.
Publication Date: 2021-07-07
Journal: Journal of cellular and molecular medicine


FGF21 promotes thermogenic gene expression as an autocrine factor in adipocytes.
The contribution of adipose-derived FGF21 to energy homeostasis is unclear. Here we show that browning of inguinal white adipose tissue (iWAT) by β-adrenergic agonists requires autocrine FGF21 signaling. Adipose-specific deletion of the FGF21 co-receptor β-Klotho renders mice unresponsive to β-adrenergic stimulation. In contrast, mice with liver-specific ablation of FGF21, which eliminates circulating FGF21, remain sensitive to β-adrenergic browning of iWAT. Concordantly, transgenic overexpression of FGF21 in adipocytes promotes browning in a β-Klotho-dependent manner without increasing circulating FGF21. Mechanistically, we show that β-adrenergic stimulation of thermogenic gene expression requires FGF21 in adipocytes to promote phosphorylation of phospholipase C-γ and mobilization of intracellular calcium. Moreover, we find that the β-adrenergic-dependent increase in circulating FGF21 occurs through an indirect mechanism in which fatty acids released by adipocyte lipolysis subsequently activate hepatic PPARα to increase FGF21 expression. These studies identify FGF21 as a cell-autonomous autocrine regulator of adipose tissue function.
Publication Date: 2021-07-01
Journal: Cell reports


Litter expansion alters metabolic homeostasis in a sex specific manner.
Nutritional manipulations early in life have been shown to influence growth rate and elicit long lasting effects which in turn has been found to impact lifespan. Therefore, we studied the long-term effects of pre-weaning dietary restriction implemented by litter expansion (4, 6, 8, 10, and 12 pups per dam: LS4, LS6, LS8, LS10, LS12) on male and female C57BL/6J mice. After weaning, these mice were fed ad libitum a commercial lab chow for the 15-month duration of the study. The male mice from large litter size (LS12) were significantly leaner and had reduced total fat mass compared to the normal size litters (LS 6) starting from weaning through to 15 months of age. Male LS10 & 12 mice also showed significant reduction in their fat depot masses at 15 months of age: gonadal, subcutaneous, and brown fat whereas the females did not mimic these findings. At 9 months of age, only male LS12 mice showed improved glucose tolerance and male LS12 mice also showed improved insulin tolerance starting at 5 months of age. In addition, we found that the male LS8, 10 & 12 mice at 15 months of age showed significantly reduced IGF-1 levels in the serum and various other organs (liver, gastrocnemius and brain cortex). Interestingly, the female LS8, 10, 12 mice showed a different pattern with reduced IGF-1 levels in serum, liver and gastrocnemius but not in the brain cortex. Similarly, the litter expanded mice showed sex specific response to levels of FGF21 and adiponectin with only the male mice showing increased FGF21 and adiponectin levels at 15 months of age. In summary, our data show that, litter expansion results in long-lasting metabolic changes that are age and sex dependent with the male mice showing an early and robust response compared to female mice.
Publication Date: 2021-09-30
Journal: PloS one


The Regulation of Circulating Hepatokines by Fructose Ingestion in Humans.
Fibroblast growth factor 21 (FGF21), follistatin, angiopoietin-like 4 (ANGPTL4), and growth differential factor 15 (GDF15) are regulated by energy metabolism. Recent findings in humans demonstrate that fructose ingestion increases circulating FGF21, with increased response in conditions of insulin resistance. This study examines the acute effect of fructose and somatostatin on circulating FGF21, follistatin, ANGPTL4, and GDF15 in humans. Plasma FGF21, follistatin, ANGPTL4, and GDF15 concentrations were measured in response to oral ingestion of 75 g of fructose in 10 young healthy males with and without a 15-minute infusion of somatostatin to block insulin secretion. A control infusion of somatostatin was also performed in the same subjects. Following fructose ingestion, plasma FGF21 peaked at 3.7-fold higher than basal concentration ( Here we show that in humans (1) the fructose-induced increase in plasma FGF21 was enhanced when somatostatin was infused, suggesting an inhibitory role of insulin on the fructose-induced FGF21 increase; (2) fructose ingestion also increased plasma follistatin, but somatostatin infusion blunted the increase; and (3) fructose ingestion had no stimulating effect on ANGPTL4 and GDF15 levels, demonstrating differences in the hepatokine response to fructose ingestion.
Publication Date: 2021-08-03
Journal: Journal of the Endocrine Society


Stress-induced FGF21 and GDF15 in obesity and obesity resistance.
Fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) are established as stress-responsive cytokines that can modulate energy balance by increasing energy expenditure or suppressing food intake, respectively. Despite their pharmacologically induced beneficial effects on obesity and comorbidities, circulating levels of both cytokines are elevated during obesity and related metabolic complications. On the other hand, endocrine crosstalk via FGF21 and GDF15 was also reported to play a crucial role in genetically modified mouse models of mitochondrial perturbations leading to diet-induced obesity (DIO) resistance. This review aims to dissect the complexities of endogenous FGF21 and GDF15 action in obesity versus DIO resistance for the regulation of energy balance in metabolic health and disease.
Publication Date: 2021-09-17
Journal: Trends in endocrinology and metabolism: TEM


The Role of Reduced Methionine in Mediating the Metabolic Responses to Protein Restriction Using Different Sources of Protein.
Dietary protein restriction and dietary methionine restriction (MR) produce a comparable series of behavioral, physiological, biochemical, and transcriptional responses. Both dietary regimens produce a similar reduction in intake of sulfur amino acids (e.g., methionine and cystine), and both diets increase expression and release of hepatic FGF21. Given that FGF21 is an essential mediator of the metabolic phenotype produced by both diets, an important unresolved question is whether dietary protein restriction represents de facto methionine restriction. Using diets formulated from either casein or soy protein with matched reductions in sulfur amino acids, we compared the ability of the respective diets to recapitulate the metabolic phenotype produced by methionine restriction using elemental diets. Although the soy-based control diets supported faster growth compared to casein-based control diets, casein-based protein restriction and soy-based protein restriction produced comparable reductions in body weight and fat deposition, and similar increases in energy intake, energy expenditure, and water intake. In addition, the prototypical effects of dietary MR on hepatic and adipose tissue target genes were similarly regulated by casein- and soy-based protein restriction. The present findings support the feasibility of using restricted intake of diets from various protein sources to produce therapeutically effective implementation of dietary methionine restriction.
Publication Date: 2021-08-28
Journal: Nutrients


Fibroblast growth factor 21 attenuates iron overload-induced liver injury and fibrosis by inhibiting ferroptosis.
Ferroptosis plays a role in several diseases such as iron overload-induced liver diseases. Manipulation of ferroptosis has been explored as a potential therapeutic strategy to treat related diseases. Numerous antioxidants have been identified to control ferroptosis but the cell-autonomous mechanisms responsible for regulating ferroptosis remain elusive. In the present study, we found that iron overload promoted ferroptosis in hepatocytes by excessively inducing HO-1 expression, which contributed to the progression of liver injury and fibrosis, accompanied by the upregulation of the FGF21 protein level in vitro and in vivo. Interestingly, both recombinant FGF21 and Fgf21 overexpression significantly protected against iron overload-induced hepatocytes mitochondria damage, liver injury and fibrosis by inhibiting ferroptosis. In contrast, the loss of FGF21 aggravated iron overload-induced ferroptosis. Notably, FGF21-induced HO-1 inhibition (via the promotion of HO-1 ubiquitination and degradation) and NRF2 activation provide a mechanistic explanation for this phenomenon. Taken together, we identified FGF21 as a novel ferroptosis suppressor. Thus, FGF21 activation may provide an effective strategy for the potential treatment of iron overload-induced ferroptosis-related diseases, such as hereditary haemochromatosis (HH).
Publication Date: 2021-09-17
Journal: Redox biology


Hepatic AKT orchestrates adipose tissue thermogenesis via FGF21-dependent and -independent mechanisms.
Organismal stressors such as cold exposure require a systemic response to maintain body temperature. Brown adipose tissue (BAT) is a key thermogenic tissue in mammals that protects against hypothermia in response to cold exposure. Defining the complex interplay of multiple organ systems in this response is fundamental to our understanding of adipose tissue thermogenesis. In this study, we identify a role for hepatic insulin signaling via AKT in the adaptive response to cold stress and show that liver AKT is an essential cell-nonautonomous regulator of adipocyte lipolysis and BAT function. Mechanistically, inhibition of forkhead box O1 (FOXO1) by AKT controls BAT thermogenesis by enhancing catecholamine-induced lipolysis in the white adipose tissue (WAT) and increasing circulating fibroblast growth factor 21 (FGF21). Our data identify a role for hepatic insulin signaling via the AKT-FOXO1 axis in regulating WAT lipolysis, promoting BAT thermogenic capacity, and ensuring a proper thermogenic response to acute cold exposure.
Publication Date: 2021-05-20
Journal: Cell reports


Increased Fibroblast Growth Factor 21 (FGF21) Concentration in Early Second Trimester Amniotic Fluid and Its Association with Fetal Growth.
Altered fetal growth, either reduced or exacerbated, is associated with adverse perinatal outcomes. The underlying pathogenetic mechanisms of altered growth remain unclear. Fibroblast growth factor 21 (FGF21) and insulin are both considered to be major regulators of tissue growth and metabolism. The aim of our study was to investigate the association of second trimester amniotic fluid FGF21 and insulin concentrations with fetal growth. The amniotic fluid concentrations of FGF21 and insulin were determined in 80 cases of different fetal growth patterns (SGA-small for gestational age, LGA-large for gestational age, and AGA-appropriate for gestational age fetuses). Both peptides were found to be increased in cases of abnormal fetal growth, reduced growth velocity (SGA), or macrosomia (LGA). Specifically, FGF21 was significantly increased, as higher FGF21 levels were observed in the amniotic fluid of SGA and LGA fetuses compared with AGA fetuses (
Publication Date: 2021-09-27
Journal: Metabolites


Novel mineral regulatory pathways in ovine pregnancy: I. phosphate, klotho signaling, and sodium-dependent phosphate transporters.
Appropriate mineralization of the fetal skeleton requires an excess of phosphate in the fetus compared to the mother. However, mechanisms for placental phosphate transport are poorly understood. This study aimed to identify phosphate regulatory pathways in ovine endometria and placentae throughout gestation. Suffolk ewes were bred with fertile rams upon visual detection of estrus (Day 0). On Days 9, 12, 17, 30, 70, 90, 110, and 125 of pregnancy (n = 3-14/Day), ewes were euthanized and hysterectomized. Phosphate abundance varied across gestational days in uterine flushings, allantoic fluid, and homogenized endometria and placentae (P < 0.05). The expression of mRNAs for sodium-dependent phosphate transporters (SLC20A1 and SLC20A2) and klotho signaling mediators (FGF7, FGF21, FGF23, FGFR1-4, KL, KLB, ADAM10, and ADAM17) were quantified by qPCR. Day 17 conceptus tissue expressed SLC20A1, SLC20A2, KLB, FGF7, FGF21, FGF23, FGFR1, and FGFR2 mRNAs. Both sodium-dependent phosphate transporters and klotho signaling mediators were expressed in endometria and placentae throughout gestation. Gestational day influenced the expression of SLC20A1, ADAM10, ADAM17, FGF21, FGFR1, and FGFR3 mRNAs in both endometria and placentae (P < 0.05). Gestational day influenced endometrial expression of FGF7 (P < 0.001), and placental expression of FGF23 (P < 0.05). Immunohistochemistry confirmed that both FGF23 and KL proteins were expressed in endometria and placentae throughout gestation. The observed spatiotemporal profile of KL-FGF signaling suggests a potential role in the establishment of pregnancy and regulation of fetal growth. This study provides a platform for further mechanistic investigation into the role for KL-FGF signaling in the regulation of phosphate transport at the ovine maternal-conceptus interface.
Publication Date: 2021-02-25
Journal: Biology of reproduction


MiR-21-3p Inhibits Adipose Browning by Targeting FGFR1 and Aggravates Atrial Fibrosis in Diabetes.
A relationship between excess epicardial adipose tissue (EAT) and the risk of atrial fibrillation (AF) has been reported. Browning of EAT may be a novel approach for the prevention or treatment of AF by attenuating atrial fibrosis. Previous studies have identified microRNA-21 (miR-21) as a regulatory factor in atrial fibrosis. The present study examined the role of different subtypes of miR-21 in adipose browning and atrial fibrosis under hyperglycemic conditions. Wild type and miR-21 knockout C57BL/6 mice were used to establish a diabetic model via intraperitoneal injection of streptozotocin. A coculture model of atrial fibroblasts and adipocytes was also established. We identified miR-21-3p as a key regulator that controls adipocyte browning and participates in atrial fibrosis under hyperglycemic conditions. Moreover, fibroblast growth factor receptor (FGFR) 1, a direct target of miR-21-3p, decreased in this setting and controlled adipose browning. Gain and loss-of-function experiments identified a regulatory pathway in adipocytes involving miR-21a-3p, FGFR1, FGF21, and PPAR
Publication Date: 2021-09-07
Journal: Oxidative medicine and cellular longevity


OPA1 deletion in brown adipose tissue improves thermoregulation and systemic metabolism via FGF21.
Adrenergic stimulation of brown adipocytes alters mitochondrial dynamics, including the mitochondrial fusion protein optic atrophy 1 (OPA1). However, direct mechanisms linking OPA1 to brown adipose tissue (BAT) physiology are incompletely understood. We utilized a mouse model of selective OPA1 deletion in BAT (OPA1 BAT KO) to investigate the role of OPA1 in thermogenesis. OPA1 is required for cold-induced activation of thermogenic genes in BAT. Unexpectedly, OPA1 deficiency induced fibroblast growth factor 21 (FGF21) as a BATokine in an activating transcription factor 4 (ATF4)-dependent manner. BAT-derived FGF21 mediates an adaptive response by inducing browning of white adipose tissue, increasing resting metabolic rates, and improving thermoregulation. However, mechanisms independent of FGF21, but dependent on ATF4 induction, promote resistance to diet-induced obesity in OPA1 BAT KO mice. These findings uncover a homeostatic mechanism of BAT-mediated metabolic protection governed in part by an ATF4-FGF21 axis, which is activated independently of BAT thermogenic function.
Publication Date: 2021-05-05
Journal: eLife


Mice with high FGF21 serum levels had a reduced preference for morphine and an attenuated development of acute antinociceptive tolerance and physical dependence.
Because of increased opioid misuse, there is a need to identify new targets for minimizing opioid tolerance, and physical and psychological dependence. Previous studies showed that fibroblast growth factor 21 (FGF21) decreased alcohol and sweet preference in mice. In this study, FGF21-transgenic (FGF21-Tg) mice, expressing high FGF21 serum levels, and wildtype (WT) C57BL/6J littermates were treated with morphine and saline to determine if differences exist in their physiological and behavioral responses to opioids. FGF21-Tg mice displayed reduced preference for morphine in the conditioned place preference assay compared to WT littermates. Similarly, FGF21-Tg mice had an attenuation of the magnitude and rate of acute morphine antinociceptive tolerance development, and acute and chronic morphine physical dependence, but exhibited no change in chronic morphine antinociceptive tolerance. The ED50 values for morphine-induced antinociception in the 55 °C hot plate and the 55 °C warm-water tail withdrawal assays were similar in both strains of mice. Likewise, FGF21-Tg and WT littermates had comparable responses to morphine-induced respiratory depression. Overall, FGF21-Tg mice had a decrease in the development of acute analgesic tolerance, and the development of physical dependence, and morphine preference. FGF21 and its receptor have therapeutic potential for reducing opioid withdrawal symptoms and craving, and augmenting opioid therapeutics for acute pain patients to minimize tolerance development.
Publication Date: 2021-10-30
Journal: Neuropharmacology


Fibroblast growth factor 21 inhibited inflammation and fibrosis after myocardial infarction via EGR1.
Myocardial fibrosis in post-myocardial infarction is a self-healing process of the myocardium, making ventricular remodelling difficult to reverse and develop continuously. Fibroblast growth factor 21 (FGF21) plays an essential role in cardiovascular and metabolic diseases. However, the effect and mechanism of FGF21 action on cardiac inflammation and fibrosis caused by myocardial injury have rarely been reported. Adult male Sprague-Dawley rats administered with or without recombinant human basic FGF21 (rhbFGF21) were assessed using echocardiography and haematoxylin-eosin and Masson's trichrome staining to determine the cardiac function and cardiac inflammation and fibrosis levels. FGF21 might improve cardiac remodelling, as characterised by a decrease in the expression of a series of inflammatory and fibrosis-related factors. Moreover, when FGF receptors (FGFRs) were blocked, the effects of FGF21 disappeared. Mechanistically, we found that oxidative stress induced the downregulation of early growth response protein 1 (EGR1), which contributed to inflammatory factors and fibrosis reduction in cardiomyocytes treated with H
Publication Date: 2021-09-04
Journal: European journal of pharmacology


The potential role of plasma fibroblast growth factor 21 as a diagnostic biomarker for abdominal aortic aneurysm presence and development.
Fibroblast growth factor 21 (FGF21) has been identified as the master hormonal regulator of energy balance, its elevation is observed in a series of metabolic and cardiovascular diseases. Studies have implicated the role of FGF21 signaling in the pathogenesis of abdominal aortic aneurysm (AAA). We will investigate the association of FGF21 and AAA development. In this study, we assayed plasma levels of FGF21 in 82 patients with AAA and 44 control subjects, then analyzed their relationship with clinical, biochemical and histological phenotypes. The expression of β-klotho, an essential co-receptor of FGF21, was assessed with IHC staining and RT-qPCR. Machine learning models incorporate a combination of FGF21 and clinical data were utilized in the prediction of AAA occurrence. FGF21 was statistically higher in patients with AAA (781 pg/ml [533, 1213]) than in control subjects (567 pg/ml [324, 939]). After adjustment for age and BMI, we found a positive association of FGF21 levels with AAA diameters, hypertension rate and hsCRP, and a negative correlation between FGF21 levels and HDL-c. Furthermore, the protein levels of β-klotho in abdominal aorta of AAA were found significantly lower than in control group indicating the presence of FGF21 resistance. Combining FGF21 levels with four clinical characteristics significantly improved the stratification of AAA and control groups with an AUC of 0.778. Combining detection of plasma FGF21 and clinical characteristics may be reliable for identifying the presence of AAA. The role of FGF21 as a therapeutic target of AAA warrants further investigation.
Publication Date: 2021-03-14
Journal: Life sciences