Advances in Biological Functions and Clinical Studies of FGF21

Introduction

Fibroblast growth factors (FGFs) are widely expressed in the human body and have numerous and complicated physiological functions. FGFs regulate cell growth, proliferation, differentiation, and metabolic modulation, tissue repair, and inflammatory response.^1,2 FGFs can be divided into three types (classic, intracellular and hormone-like types) based on their action modes.³ Classic and intracellular FGFs mostly act in an autocrine or paracrine way,⁴ while hormone-like FGFs mainly act in the endocrine way.⁵ Most autocrine and paracrine FGFs have a high affinity for the heparin glucosamine sulfate (HSGAG), which promotes the binding of the FGFs to the tyrosine kinase FGF receptor (FGFR1-4) on the cell surface, inducing FGFR activation, dimerization, and activation of downstream signaling pathways.^6–9 HSGAGs can also stabilize FGFs, prevent FGFs degradation, and limit the diffusion range of FGFs.¹⁰

FGF21 is a member of the FGF19 subfamily in the FGFs family and belongs to the hormone-like FGFs. Compared to other FGFs members, FGF21 has three special features: 1. It has no obvious mitogenic or tumor-promoting function;¹¹ 2. The spatial configuration variation of the region that binds to HSGAGs makes it have a weaker affinity for HSGAG, thus not easily bound in the extracellular matrix. However, it enters the circulation in the form of endocrine hormones to regulate metabolism and cross the blood-brain barrier through simple diffusion;¹² 3. It does not directly bind to cell receptors, and it needs β-Klotho protein to form a stable combination to play its physiological role. Herein, the latest research progress on FGF21 is summarized.

Receptor Characteristics of FGF21

Unlike the classical FGFs, FGF21 binds to FGF receptors (FGFRs) and the co-receptor protein β-Klotho (a single transmembrane protein expressed during the differentiation of adipose precursor cells into adipocytes). Besides, FGF21 activates the signal transduction downstream only when FGFRs and β-Klotho are dimerized and autophosphorylated.^13,14 Neither β-Klotho nor FGFRs can be activated by FGF21 alone.¹⁵ In the FGF21-FGFRs-β-Klotho complex, β-Klotho, a “zip code”-like receptor, is the main high-affinity receptor of FGF21, providing the targeted signals for FGF21. At the same time, FGFR acts as a catalytic subunit that mediates receptor dimerization and intracellular signal transduction.¹⁶ Studies have also shown that the C-terminus and N-terminus are involved in activating FGF21 receptors, and any deletion of the terminus greatly reduces FGF21 activity. The C-terminus of FGF21 has a sugar-mimicking Ser-pro-Ser motif, which can be recognized and bound by β-Klotho. Besides, the C-terminus mutation of FGF21 is associated with an affinity decrease of β-Klotho, indicating that the C-terminal also mediates the binding of FGF21 and β-Klotho. Although the N-terminal mutation of FGF21 is also associated with decreased activity, it can still bind to β-Klotho, suggesting that the N-terminal only participates in the receptor activation process.^16–19 Therefore, complete C-terminal and N-terminal structure and simultaneous binding to β-Klotho and FGFRs promote the physiological functions of FGF21.

Regulation of FGF21 Expression Level

Studies have shown that FGF21 is highly expressed in the liver, skeletal muscle, kidney, heart, fat, and blood vessels.²⁰ FGF21 (mainly produced by liver cells) is also expressed in the blood circulation due to its hormone-like characteristics,²¹ targeting the heart, bones, kidneys, small intestine, and brain because of its strong diffusion and distribution ability.¹³ However, FGF21 produced in adipose tissue most acts in an autocrine or paracrine manner on the metabolic regulation of itself and adjacent tissues.²² Moreover, the expression level of FGF21 varies greatly in different tissues and under different conditions. FGF21 expression level can be regulated in the following ways;

Regulation by Transcription Factors

Numerous transcription regulators can also regulate the FGF21 expression level. For instance, peroxisome proliferator-activated receptor (PPAR) can regulate FGF21 expression by binding to the transcriptional regulatory element at the beginning of the FGF21 promoter region, and FGF21 and PPAR can regulate each other. PPAR contains three subtypes: PPARα, PPARβ/δ, and PPARγ. PPARα and PPARγ can induce FGF21 expression. PPARα can induce FGF21 expression in the liver,²³ and FGF21 level in the liver of mice was significantly increased after the administration of PPARα agonist fenofibrate, indicating the effect of PPARα on promoting FGF21 expression. Similarly, PPARγ can regulate the expression and function of FGF21 in adipose tissue. Muise et al²⁴ found that the PPARγ agonist rosiglitazone can activate PPARγ, promoting fat cells to produce FGF21 and synergistically regulating FGF21 to accelerate glucose uptake and utilization. Conversely, FGF21 in the tissue can also activate PPAR α and PPAR γ. Dutchak et al²⁵ indicated that FGF21 induced by PPARγ in adipose tissue can increase its transcription by inhibiting PPARγ ubiquitination. These processes form a cyclic loop of PPARα, PPARγ, and FGF21 and feed-forward to regulate FGF21 expression.

Regulation by microRNAs

Recent studies have indicated that microRNAs (miRNAs) are associated with the regulation of metabolism and metabolic disorders.²⁶ MiRNAs primarily bind to the 3’-untranslated region (3’UTR) of mRNAs, inhibiting mRNAs translation and regulating the expression of related genes. The activity of the 3’UTR of FGF21 mRNA in the liver can be inhibited by circulating exosomal miRNAs, in which miR-99b is the identified regulatory factor.²⁷ Furthermore, anti-miR-577 therapy can protect and restore the insulin regulation of FGF21 and improve the survival and function of diabetic pancreatic β-cells.^28,29 MiR-212 can inhibit FGF21 expression in HepG2 cells in non-alcoholic fatty liver disease (NAFLD), while miR-212 inhibitors can increase FGF21 protein level and reduce lipid synthesis. Si-FGF-21 silences the expression of FGF21, significantly increasing the lipid content in HepG2 cells, thus hindering the anti-lipid effect of miR-212 inhibitors in these cells.³⁰ Collectively, these suggest that miR-212 targets FGF21, thus regulating FGF21 expression.

Regulation by Dietary

Fasting, ketogenic diet, high-sugar diet, and high-fat diet are all important transcription inducers for FGF21 expression. Fasting can strongly induce FGF21 expression.³¹ A ketogenic diet or fasting can significantly increase FGF21 expression by recruiting PPARα in the region near the FGF21 transcriptional promoter.^23,32 Notably, neither the ketogenic diet (up to 3 months) nor short-term fasting (up to 48 hours) can increase serum FGF21 levels in humans.²³ However, prolonged fasting (7–10 days) can increase serum FGF21 levels in humans, possibly due to the different metabolic rates and fasting tolerances among different species.³³ A high-fat diet induces excessive unsaturated fatty acids and bile acids, increasing the transcription and secretion of FGF21 in the liver by activating the farnesoid X receptor (FXR) and PPARα.³⁴ Lundsgaard et al³⁵ found that a high-carbohydrate diet can also induce FGF21 gene expression in the liver.

FGF21 can also be highly expressed under oxidative stress, energy stress, endoplasmic reticulum stress, cold stress, and mitochondrial dysfunction, and its expression is also regulated by sodium butyrate, metformin, glucocorticoids, etc.^36–38 Animal studies have shown that one-time acute exercise (60 minutes on a treadmill or until repeated electrical stimulation rendered normal running impossible) promotes gene expression in the liver of mice and increases serum levels of FGF21. Clinical trials have also shown that 30 minutes of acute aerobic exercise can also increase circulating FGF21 levels.³⁹ FGF21 expression level in skeletal muscle is very low in healthy conditions, and circulating FGF21 mainly comes from the liver. However, the expression of myogenic FGF21 significantly increases in some stress states, such as hunger, endoplasmic reticulum stress, mitochondrial dysfunction, etc.^40,41 Kim et al⁴² found that the FGF21 content significantly increased in the soleus muscle of Zucker diabetic obese rats after 12 weeks of resistance exercise. However, the phenomenon was not observed in the gastrocnemius muscle.

The Physiological Function of FGF21

Earlier research on FGF21 function mainly focused on reducing blood sugar and lipids, lowering body weight, improving insulin resistance (IR), and cardiovascular diseases related to abnormal glucose and lipid metabolism, such as coronary heart disease, heart remodeling.^12,43 In recent years, the functions of FGF21 in inhibiting inflammation, reducing oxidative stress levels,^44,45 and inhibiting apoptosis of endothelial cells⁴⁶ and cardiomyocytes⁴⁷ have been studied. The regulatory effects of FGF21 on metabolic diseases, such as obesity, hyperlipidemia, and hyperglycemia, the damage repair effects on inflammation and apoptosis, and the blocking effects on some cancers indicate that FGF21 has a broad prospect for development. Studies have shown that FGF21 mainly participates in the processes of material metabolism, heart and brain damage by activating Adenosine 5’-monophosphate (AMP)-activated protein kinase (AMPK), serine/threonine protein kinase (Akt), and extracellular-regulated protein kinases (ERK) and other downstream factors. FGF21 plays metabolic regulation functions, such as promoting glucose uptake, gluconeogenesis, increasing the oxidation of free fatty acids, promoting ketogenesis, increasing energy production and utilization.^48,49 FGF21 also has the effect of apoptosis protection and neurocognitive function recovery.

FGF21 and Glucose Metabolism

Insulin, as one of the most important humoral factors regulating glucose metabolism, enhances glucose absorption by activating the Phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway and promoting the expression of glucose transporter 4 (GLUT4).⁵⁰ FGF21 can also activate the PI3K signaling pathway and regulate Akt activation. However, FGF21 mainly inhibits the expression of related gluconeogenesis and glucose production by inducing phosphorylation of atypical protein kinase C (PKC) I/L and exerts insulin-like hypoglycemic effect to control blood glucose balance.⁵¹ Ge et al⁵² found that glucose transporter-1 (GLUT1) promoter is highly conserved in serum response element (SRE) and E-26 (ETS) binding motifs. FGF21 binds to the receptor to activate the downstream factor extracellular signal-regulated kinases (ERK1/2)), and then activate ETS-like protein-1 (ELK-1) and serum response factor (SRF, the downstream target of ERK1/2), enhancing glucose uptake and reducing blood glucose concentration by combining the promoter sequence of GLUT1 gene, trans-activating GLUT1 gene and inducing GLUT1 expression. Furthermore, there can be a synergistic effect between insulin and FGF21. Insulin can activate PKC, enhancing the FGF21 regulation effect on the GLUT1 expression through the ERK1/2-SRF/Elk-1 pathway.⁵³ FGF21 can also improve insulin sensitivity and enhance the hypoglycemic effect of insulin. The mammalian target of rapamycin complex 1 (mTORC1) and its downstream effector, ribosomal protein S6 kinase 1 (S6K1), are the key regulators of nutritional overload-induced insulin resistance and the pathogenesis of type 2 diabetes mellitus (T2DM).⁵⁴ S6K1 phosphorylates insulin receptor substrate 1 (IRS-1), thereby destroying PI3K, a key molecular basis for inducing IR. FGF21 binds to the receptor complex, downregulating mTORC1 in a tuberous sclerosis complex (TSC)-dependent manner, thus activating downstream pathways to improve insulin resistance and increase insulin sensitivity.⁵⁵ Notably, FGF21 has a two-way regulatory role in lowering and raising blood sugar levels. Besides, animal experiments and clinical trials have shown different functions of FGF21 and the body regulation mechanism of normal and abnormal metabolism.

Rat experiments showed FGF21 improves IR, increases insulin sensitivity, and reduces blood insulin concentration.¹² FGF21 analogues also improve IR, reduces blood glucose and insulin levels, and improve glucose tolerance in primates.⁵⁶ Moreover, scholars have discovered that adipose tissue is a key target of FGF21 for glucose metabolism regulation, and a certain amount of adipose tissue in mice is the guarantee for FGF21 to regulate blood sugar.⁵⁷ Clinical trials have shown that FGF21 analogues (LY2405319, PF-05231023, BMS-986036, etc.) also lower blood glucose. However, their effect on lowering blood glucose was not significant.^17,58,59 Further studies have shown that FGF21 also promotes gluconeogenesis and maintains blood glucose balance, preventing hypoglycemia occurrence.¹²

FGF21 reduces blood glucose by promoting the phosphorylation of Akt via insulin, thereby upregulating the number of insulin receptors, increasing insulin sensitivity, and alleviating chronic inflammatory response, thus improving IR, thus regulating glucose metabolism.^60–62 Second, FGF21 can upregulate adiponectin expression in adipocytes by activating the PPARγ signaling pathway to promote GLUT4 migration from cytoplasm to cell membrane, or directly promoting GLUT1 expression, increasing glucose transport and lowering blood glucose.^22,63,64 FGF21 can also act on pancreatic islets and indirectly induce a hypoglycemic effect. FGF21 can inhibit islet α cells to reduce glucagon secretion,¹² inhibiting the synergistic toxicity of glycolipid and cytokine-induced β cell apoptosis, reducing the damage of islet β cells and enhancing the function of islet β cells, thereby improving blood sugar level.⁶⁵

In terms of gluconeogenesis, studies have shown that FGF21 can increase and maintain blood sugar under fasting or starvation.⁶⁶ FGF21 secreted by tissue cells can cross the blood-brain barrier and directly act on the hypothalamus through the hypothalamic-pituitary-adrenal axis, stimulating the synthesis and release of adrenal corticosterone increasing blood glucose via liver gluconeogenesis.⁶⁷ Furthermore, FGF21 can bind to FGFRs in the liver to activate the downstream RAS-RAF-MAPK signaling pathway via the β-Klotho, resulting in a cascade reaction. FGF21 then induces the expression of early liver genes, such as PPARγ coactivator-activated receptor-γ coactivator 1α (PGC1α) gene, which increases the transcriptional activity of PPARα. It upregulates the expression of gluconeogenesis-related genes, thereby regulating gluconeogenesis.^68,69

FGF21 and Lipid Metabolism

FGF21 is an “adipokine”, which regulates blood lipid. It can significantly reduce the plasma levels of total cholesterol (TC), low-density lipoprotein (LDL), and triglyceride (TG) and increase the plasma levels of high-density lipoprotein (HDL) and adiponectin in normal subjects.⁷⁰ A study indicated that diet-induced obese mice and hereditary db/db obese mice have weight loss, reversal of liver steatosis, and reduction in plasma TG levels changes after several weeks of continuous FGF21 administration. Plasma TC and LDL levels decrease, while HDL level increases in a dose-dependent manner in mice administered with different FGF21 doses.^71,72 Similar findings were found in diabetic monkeys. Besides the decrease in blood glucose to the normal level, the decrease of blood insulin level, and the enhancement of the body’s sensitivity to insulin, blood lipid also decreased, especially the selective decrease of TG and LDL. At the same time, HDL showed an upward trend after long-term injection of FGF21 in diabetic monkeys.⁷³

FGF21 also plays an important role in liver fat metabolism. Liu et al⁷⁴ indicated that long-term alcohol exposure induces liver damage and steatosis, inducing the body to upregulate FGF21 as compensation. Knockout of the FGF21 gene inhibits β-oxidation of liver fatty acids, aggravating alcoholic steatohepatitis (ASH). However, recombinant FGF21 alleviates liver steatosis and inflammation induced by ASH. Furthermore, the treatment of rodent and non-human primate model animals of NAFLD, FGF21 analog, and B1344 showed an inhibited liver inflammation and natural immune cell infiltration, reduced liver injury and hepatocyte death, significantly improved liver lipid accumulation, liver fibrosis, and prevented further development of non-alcoholic steatohepatitis (NASH).⁷⁵ However, B1344 has greater potency, higher maximum response, and lower immunogenicity than FGF21.

FGF21 and Energy Metabolism

Humans and animals have white adipose tissue (WAT) and brown adipose tissue (BAT). The WAT mainly stores metabolic surplus energy in the form of TG, which causes weight gain.⁷⁶ Unlike WAT, BAT is rich in multi-crystal mitochondria, which is the main source of non-shivering thermogenesis. BAT maintains the body temperature and energy balance by increasing the uptake of glycolipids and using uncoupling protein 1 (UCP1) to decouple biological oxidation from ATP synthesis, thus converting energy released via biological oxidation into heat, reducing ATP synthesis.^77,78 FGF21 can upregulate the expression of UCP1 and other thermogenesis genes, promoting the “Browning” of WAT, thus regulating the balance between body temperature and energy.⁷⁹ However, scholars have also found that FGF21 regulates energy metabolism only in mice with abnormal metabolism.^79,80 Furthermore, Liver kinase B1 (LKB1) phosphorylation activates AMPK, thereby increasing the content of NAD+ in cells, activating Sirtuin 1 (SIRT1), thus promoting mitochondrial energy transformation in skeletal muscles.^81–83 FGF21 in skeletal muscle is also transported to adipose tissue through blood circulation, increasing the level of FGF21 in WAT and further inducing the expression of silent mating type information regulation 2 homolog 1 (SIRT1), PGC1 α, UCP1 and other factors, thus promoting the “Browning” of WAT and increasing energy consumption.⁸⁴ Collectively, the above studies indicate that FGF21 maintains the energy balance of the body with abnormal metabolism through the regulation of glucose and lipid metabolism, which does not affect the normal metabolism in the body.

FGF21 and Heart

Recent studies have shown that FGF21 has an important protective effect on the heart, reflected by reducing myocardial cell apoptosis, antagonism against ischemia-reperfusion injury (IRI), and oxidative stress reaction. Roberts et al⁸⁵ and Cong et al⁸⁶ showed that FGF21 could inhibit the activity of the apoptotic factor C-caspase 3 through the PI3K /Akt signaling pathway, increase cardiac energy supply through the AMPK pathway, thus inhibiting the apoptosis of cardiomyocytes. Moreover, FGF21 interferes with the PER K-eIF2α-ATF4-CHOP signaling axis during endoplasmic reticulum stress, activating the ATF4 signaling pathway and promoting the phosphorylation of c-Jun N-terminal kinase (JNK), thus reducing the accumulation of abnormally folded proteins and inhibiting myocardial cell apoptosis.⁸⁷ FGF21 can also effectively prevent palmitate-induced cardiac apoptosis by upregulating the ERK1/2-dependent p38 mitogen-activated protein kinase (MAPK)-AMPK signaling pathway⁸⁸ and reduce cardiomyocyte IRI and apoptosis after oxidative stress through PI3K/AKT-dependent pathways. 1. FGF21, as an antioxidant factor, induces the expression of antioxidant genes, such as Ucp3, Ucp2, and Sod2 in the heart, thereby preventing the production of reactive oxygen species (ROS).⁸⁹ 2. FGF21 can also activate MAPK to produce a cascade reaction by binding FGFR1c/β-klotho. Therefore, FGF21 can promote the activation of AMPK, the target gene of Liver kinase B1 (LKB1), and reduce the accumulation of ROS, inhibiting apoptosis.⁸⁹ 3. FGF21 promotes transcriptional activation of PPARγ by regulating PPARγ coactivator 1, thus controlling energy metabolism and oxidative stress in multiple tissues,⁹⁰ inducing a protective role on cardiac hypertrophy.

FGF21 and Brain

Although it is unknown whether the brain can directly generate FGF21, it has been proved that FGF21 can move to the brain through the blood-brain barrier via simple diffusion,^91,92 playing a key role in metabolic regulation, neuroprotection, and the potential role of cognition.

FGF21 can bind to FGFRs and β-klotho expressed in the hypothalamus, the suprachiasmatic nucleus (SCN), paraventricular nucleus of the hypothalamus (PVN), and other regions of the brain, and act on the Hypothalamus-pituitary-adrenal axis (HPA) and hypothalamic-pituitary-gonad axis (HPG) to regulate the levels of corticotropin-releasing hormone (CRH) and vasopressin (AVP). The increased release of CRH can promote the substantial release of adrenal cortex hormones, which combine with the liver to induce PGC1α expression. Therefore, FGF21 can upregulate the expression of gluconeogenesis genes, such as glucose 6 phosphatase and phosphoenolpyruvate carboxykinase via PGC1α, increasing liver gluconeogenesis and preventing hypoglycemia.⁶⁷ Moreover, increased CRH in the circulation can increase sympathetic nerve activity in BAT, upregulate UCP1 expression and increase lipolysis in BAT, leading to an increase in energy use and a decrease in weight gain in diet-induced obese mouse models.⁹³ The inhibited release of AVP decreases kisspeptin in the hypothalamus, causing a decrease in the release of luteinizing hormone, affecting ovulation and fertility.⁹⁴

Several studies have shown that FGF21 has an important protective effect on nerve injury and cognitive impairment. Shahror et al⁹⁵ showed that FGF21 can significantly improve the spatial memory deficits, hippocampal nerve damage, and dendritic morphology abnormalities induced by traumatic brain injuries (TBI). Therefore, FGF21 alleviates TBI-induced defects in neurogenesis and maturation of immature hippocampal neurons, thereby restoring the hippocampal independent learning and memory impairment caused by TBI. Sa-Nguanmoo et al⁹⁶ also confirmed that FGF21 enhances hippocampal synaptic plasticity, increases the density of dendritic spines, restoring the function of brain mitochondria. FGF21 can prevent defective neuroprotective molecules in astrocytes, alleviating memory dysfunction and neurodegeneration, such as amyloid plaque pathology and pathological Tau hyperphosphorylation, thus acting as a neuroprotective agent in Alzheimer’s disease (AD).^97,98 FGF21 can also protect the blood-brain barrier after ischemic stroke by activating PPARγ in cerebral blood vessels,⁹⁹ antagonize the M1 polarization of microglia and the accumulation of pro-inflammatory cytokines by inhibiting NF-κB and upregulating PPARγ, and reduce cerebral edema and inflammation after TBI and stroke.^100,101

Clinical Application

The level of FGF21 in normal human circulation is low, while it is significantly increased in patients with atherosclerosis, hypertension, and liver disease.^102–104 Some scholars have also indicated that FGF21 levels in obese or hyperlipidemia patients are 1.5–2 times higher than in normal people. Patients with renal insufficiency may also accumulate FGF21, while FGF21 levels in patients with long-term malnutrition (such as patients with anorexia nervosa) are low.^105–107 FGF21 expression is decreased in patients with type 1 diabetes mellitus (T1DM) and increased in patients with T2DM in individuals with abnormal glucose metabolism, indicating that FGF21 resistance or compensatory increase may exist in patients with T2DM.¹⁰⁸ Similarly, FGF21 up-regulation occurs in patients with metabolic syndrome,¹⁰⁹ possibly because FGF21 plays a compensatory role in the early stage of the disease, promoting the occurrence and development of the disease. Li et al¹¹⁰ found that the plasma FGF21 content and liver FGF21 levels are significantly higher in NAFLD patients than in healthy people. Therefore, FGF21 may be a new biomarker for NAFLD diagnosis. Taken together, these findings indicate that FGF21 has broad prospects as a serum marker in the prevention, diagnosis, treatment, and efficacy evaluation of metabolic abnormalities. Presently, FGF21 has been partially used in clinical practice.

The routine auxiliary examination items, such as serum lactic acid, alanine, creatine kinase have low specificity and sensitivity during the diagnosis of mitochondrial diseases. Recent studies have shown that serum levels of FGF21 are elevated when mitochondrial DNA mutations occur in skeletal muscle but not when similar mutations occur in other organs. Therefore, serum FGF21 is a relatively good biomarker for muscle mitochondrial diseases than other indicators.¹¹¹

Serum FG21 can also be used for early disease detection. For instance, the incidence rate of myocardial ischemia, cardiac hypertrophy, and diabetic cardiomyopathy is positively correlated with serum FGF21 levels.^112–114 Some studies have also indicated that higher serum FGF21 levels are associated with a higher risk of coronary heart disease, NAFLD, and T2DM.^89,115–117 Besides, higher circulating FGF21 levels are associated with higher mortality in patients with end-stage renal disease.¹¹⁰ However, animal experiments and clinical trials have shown different results. Therefore, further studies are necessary to determine whether FGF21 can be used as a molecular marker for the early diagnosis and evaluation of related diseases.

FGF21 also has important clinical significance for disease treatment. Animal experiments have shown that the metabolic phenotypes, such as decreased blood glucose, serum TC and TG levels, increased insulin sensitivity and glucose uptake of two groups of mice overexpressing human and mouse FGF21 are highly similar. However, there are also some differences. For instance, the weight and body fat rate of mice overexpressing human FGF21 decreased, while those overexpressing mouse FGF21 were obese and unresponsive despite having normal metabolism.¹⁷ This study provides a basis for the clinical treatment of FGF21. Clinically, FGF21 levels are elevated in patients with various metabolic abnormalities. In contrast, the findings have shown that FGF21 effectively treats various metabolic abnormalities in animal models. However, it is speculated that the phenomenon is similar to hyperinsulinemia. The increase of FGF21 may be due to “FGF21 resistance” produced by the activation of its compensatory mechanism,¹¹⁸ indicating that the elevated FGF21 is the body’s self-protection mechanism. Therefore, FGF21 can treat metabolic disorders, such as diabetes and lipid metabolism disorders, because it does not possess the classic mitogenic activity of the FGFs.¹¹⁹

Conclusion and Prospect

This article reviews the metabolic regulation, injury protection, and other physiological and pathological functions of FGF21 in various tissues and organs in the body, such as the liver, heart, brain, and adipose tissue, and related regulatory mechanisms. To date, the relevant signal pathways of FGF21 have not been fully elucidated. Therefore, an in-depth study on the systemic biological functions and regulatory pathways of FGF21 can promote the prevention and treatment of metabolic disorders, such as diabetes and obesity, and cardiac and brain diseases, such as myocardial IRI and AD, TBI, and stroke.