see also:

• cytokines
• Platelet-derived growth factor (PDGF)
• bone physiology

• FGFs are cytokines which may have autocrine, paracrine and endocrine actions
• The fibroblast growth factor (FGF) family is a group of multifunctional signaling molecules that have a wide variety of functions.
• The family comprises of 22 related proteins, each grouped into subfamilies which are based on genetic and functional similarity.
• skeletal muscle secretes a wide variety of molecules like cytokines (including FGF21), miRNA, exosomes, mtDNA during exercise, but also in different acquired and inherited diseases. these mediate communication between distant organs to adapt whole body metabolism to nutritional and environmental pressures.
• some animals such as mouse incisors, grow continuously throughout their life time as a result of active somatic stem cells at the proximal end of the incisor tooth combined with roles of a range of FGFs ¹⁾

• belongs to the FGF19 subfamily (also called endocrine FGF)
• a hormone that regulates important metabolic pathways
• function is complicated due to its different sites of production and actions
• in healthy humans, a large variation level of serum FGF21 is shown between individuals, ranging from 5 pg/mL to 5 ng/mL
• see Front Physiol. 2019 FGF21 as Modulator of Metabolism in Health and Disease

• is expressed in several tissues such as liver (main site of production), adipocytes, pancreas, testes, skeletal muscle, heart, brown adipose tissue, and brain where it passes the blood-brain barrier
• hepatic production is regulated by:
  • the Unfolding Protein Response (UPR)
  • thyroid hormone receptor β, which mediates the action of tri-iodothyronine in the liver, stimulates lipolysis, and hepatic fatty acid oxidation via FGF21 induction
  • PKR-like ER kinase (PERK)–eukaryotic initiation factor 2α (eIF2α)–activating transcription factor 4 (ATF4) pathways
  • RARβ and retinoic acid
  • retinoic acid receptor-related orphan receptor (ROR) α has been implicated in various physiological functions, including the immune system, inflammation, and circadian rhythms
  • the naturally occurring compound baicalein up-regulated FGF21 expression and secretion in C2C12 myotubes
    • it appears baicalein stimulates the ER stress response and FGF21 expression through a RORα-dependent mechanism in C2C12 myotubes, and indicates the potential of baicalein as an effective anti-obesity therapy via its ability to enhance FGF21 production
  • regulated positively or negatively by glucocorticoid receptor (GR), cAMP-responsive element-binding protein H (CREBH), carbohydrate response element-binding protein (ChREBP), PPARγ, farnesoid X receptor (FXR), liver X receptor (LXR)
• extrahepatic tissues, such as skeletal muscle, white adipose, and brown adipose tissue regulate FGF21 via different transcription factors
  • PPARγ activation increases FGF21 production in white adipose tissue where it acts as an autocrine or endocrine factor to improve insulin action
  • in brown adipose tissue (BAT), FGF21 is regulated by ATF2
  • in skeletal muscle it is controlled by ATF4 and by the PI3K–AKT signaling pathway

• FGF21-dependent signaling downstream FGF receptors (FGFr) are extremely complicated
• signaling downstream FGF receptors are tissue specific
  • adipocytes: activates Ras/Raf MAPK and the downstream effector ERK1 and ERK2
  • liver:
    • positively controls the PI3K/AKT, insulin-like growth factor 1 (IGF-1) and mTOR pathways as well as triglyceride homeostasis, glucose uptake, amino acid transport, and energy expenditure
    • inhibits Growth Hormone (GH) action in hepatocytes resulting in STAT5 inhibition, decreased expression, secretion of IGF-I, and the reduction of body size
    • induces the expression of IGFBP1, an inhibitor of IGF1 and suppressor of cytokine signaling 2, which is a negative modulator of GH signaling, furthering blocking the GH-IGF1 axis in the liver
  • brain:
    • acts in the central nervous system and dorsal vagal complex of the hindbrain to regulate circadian rhythm, which is important for the adaptive starvation response
  • heart:
    • plays a key role in cardiac remodeling
    • the heart expresses FGFR1, fibroblast growth factor receptor 1, β-klotho, as well as FGF21
    • in rodents, protects against pathologic cardiac hypertrophy, oxidative stress, and myocardial infarction
    • acts in the manner of an autocrine and controls autophagy in obesity-induced cardiomyopathy
  • skeletal muscle:
    • expressed in response to insulin stimulation, suggesting that FGF21 is an insulin-regulated “myokine”
• FGF21 is activated and released in different conditions such as energy stress, ER stress, mitochondrial dysfunction, and cold-stress
• FGF19 subfamily appears to require additional cofactors to stably bind the FGFRs in the target tissue such as:
  • aging-suppressor gene Klotho and Beta-Klotho with FGF21-Klotho complex binding multiple FGFRs, including FGFR1c, -2c, -3c, and -4
• is a starvation-induced protein that is elevated after 7 days of fasting and regulates the utilization of fuel to adapt metabolism in the late phase of the absence of nutrients
• mediates the adaptive starvation response to induce ketogenesis, gluconeogenesis, lipolysis, and lipid β-oxidation
• stimulates the oxidation of fatty acids, the production of ketone bodies, and the inhibition of lipogenesis
  • administrating FGF21 prevents diet-induced obesity and insulin resistance in mice and humans
  • there is a paradoxically positive correlation with elevated serum FGF21 levels and metabolic disorders like obesity, diabetes, mitochondrial diseases, and aging (all these conditions have muscle loss as a common factor)
• pathophysiological roles:
  • promotion of muscle atrophy, bone loss and reduced bone mineral density
  • acts as a stress-induced myokine, which is released during starvation, ER stress, and mitochondrial dysfunction
• roles in alcohol intoxication:
  • alcohol is one of the most potent inducers of FGF21 hepatic production in both mice and humans
  • increases the urge in mice to drink water while intoxicated
  • may actively suppress the desire for alcohol
  • in 2023, researchers were able to quickly sober up drunk FGF21-null mice by boosting their levels of FGF21 and that this sobering effect comes from how it activates a specific part of the brain that controls alertness, known as the noradrenergic nervous system