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Fibroblast growth factor 21 (FGF21) is a cell signaling protein typically containing 209 amino acid residues which makes part of the FGF superfamily, being encoded by the mammalian FGF21 gene. FGF21 can be sythesized in several organs but is mainly produced in the liver in a regulated manner, typically responding to stress or dietary factors such as caloric balance and amino acid composition. Depending on the relation between production and target sites, FGF21 can operate in an autocrine, paracrine or endocrine modality. Responsive FGF receptors can be found in several tissues, serving to regulate multiple metabolic pathways through the organ system, tipically so in fat tissue, where it appears to promote glucose uptake and fatty acid metabolism. Within the liver, FGF21 is responsable for fatty acid oxidation both upon fasting and consumption of a ketogenic diet. When given systemically to obese individuals (mice, monkeys or human), FGF21 can reduce body weight, as well as abnormally high circulating insulin, triglycerides, LDL-cholesterol levels. FGF21 administration appears to cause beneficial actions on many abnormalities of the metabolic syndrome in animals. In obese mice, FGF21 treatment can also reduce circulating glucose and abnormal fat accumulation in the liver. Given its properties as a potent activator of glucose uptake by adipocytes and its capacity to normalize glucose and triglyceride levels in genetically obese mice, FGF21 was proposed as a possible therapeutic agent for diabetes in 2005. In 2022, Novartis described an FGF21 analog capable of reducing triglyceride levels in mildly hypertriglyceridemic human subjects. In addition, FGF21 has anti-inflammatory properties limiting toxicity if the liver is exposed to toxic agents, including ethanol and tylenol.

Also, FGF21 has effects on sugar and alcohol consumption. Mice overexpressing FGF21 or treated with FGF21 avoid consuming both fructose and alcohol. Thus, FGF21 inhibits simple sugar intake and preference for sweet foods. These actions appear to be mediated through FGF21 receptors in the paraventricular nucleus of the hypothalamus, correlating with reduced dopamine neurotransmission within the nucleus accumbens. A single-nucleotide polymorphism of the FGF21 gene – the FGF21 rs838133 variant (frequency 44.7%) – has been identified as a genetic mechanism responsible for the sweet tooth behavioral phenotype, a trait associated with cravings for sweets and high sugar consumption, in both humans and mice.

FGF family
FGFs act through a family of four FGF receptors. FGF family members possess broad mitogenic and cell survival activities and are involved in a variety of biological processes including embryonic development, cell growth, morphogenesis, tissue repair, tumor growth and invasion. FGF21 is a member of the fibroblast growth factor (FGF) family, more specifically a member of the endocrine subfamily which includes FGF23 and FGF15/19. Unlike other FGFs, endocrine FGFs are secreted into the circulation and may act on distant target organs.

FGF21 receptor
Located in the plasma membrane of target cells, the FGF21 receptor consists of

The binding of many FGF family members to their receptors is generally dual, requiring the interaction of the FGF molecule with the FGF receptor protein (FGFR) at a first, extracellular binding site, as well as the binding of FGF to a co-receptor (oftentimes a heparin moieity) adjacent the receptor at a second binding site. FGF21 and other endocrine FGFs -however- lack a heparin moieity, Instead, their second binding site interacts with a co-receptor termed β-Klotho (a non-enzymatic, β-glucuronidase-like moieity), whose presence in the vicinity of the FGFR is essential both for the binding of FGF and for the elaboration of the hormonal signalling action.

Absence of β-Klotho from the FGF21 receptor FGF21 and other endocrine FGFs -however- lack a heparin binding site, t

and thus can be released into the circulation. FGF21 is the primary endogenous agonist of the FGF21 receptor, which is composed of the co-receptors FGF receptor 1 and β-Klotho, a non-enzymatic, β-glucuronidase-like moieity. Loss of β-Klotho from the receptor abolishes all effects of FGF21.

Function
FGF21 is a highly potent insulin sensitizer. FGF21 stimulates glucose uptake in adipocytes but not in other cell types. This effect is additive to the activity of insulin. FGF21 induces the insulin-sensitizing hormone adiponectin.

FGF21 treatment of adipocytes is associated with phosphorylation of FRS2, a protein linking FGF receptors to the Ras/MAP kinase pathway. FGF21 injection in ob/ob mice results in an increase in Glut1 in adipose tissue. FGF21 also protects mice from diet-induced obesity when overexpressed in transgenic mice and lowers blood glucose and triglyceride levels when administered to diabetic rodents. Treatment of mice with FGF21 results in increased energy expenditure, fat utilization and lipid excretion. FGF21 has also been reported to cause the "browning" of white fat through a brain-dependent mechanism.

FGF21 stimulates ketogenesis in the liver. In adipocites, FGF21 induces mitochondrial biogenesis and function by activating PGC-1α.

In late-pregnant cows, FGF21 plasma levels change from undetectable to high upon parturition and the begining of lactation, apparently reflecting a change to an energy insufficient state during early lactation, where the liver was the major source of FGF21.

Regulation
Expression of the FGF21 gene is primarily upregulated by PPAR-α in the liver, and by PPAR-γ in adipose tissue. FGF21 is specifically induced by mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) activity. The oxidized form of ketone bodies (acetoacetate) in a cultured medium also induced FGF21, possibly via a sirtuin 1 (SIRT1)-dependent mechanism. HMGCS2 activity has also been shown to be increased by deacetylation of lysines 310, 447, and 473 via SIRT3 in the mitochondria.

While FGF21 is expressed in numerous tissues, including liver, brown adipose tissue, white adipose tissue (WAT) and pancreas, circulating levels of FGF21 are derived specifically from the liver in mice. Non-liver production of FGF21 is believed to fulfill autocrine functions.33383173 In liver, FGF21 expression is regulated by PPARα and levels rise substantially with both fasting and consumption of ketogenic diets.

Liver X receptor (LXR) represses FGF21 in humans via an LXR response element located from -37 to -22 bp on the human FGF21 promoter.

At a systemic level, thyroid hormone can regulate adipose and hepatic FGF21 expression and serum levels in mice. In heathy human subjects, hypercaloric, high-fat feeding acutely increases circulating FGF21.31919514 In elderly subjects with T2D, resistance training significantly lowered circulating FGF-21.32345132

Clinical significance
Serum FGF21 levels are significantly increased in obesity and in patients with type 2 diabetes mellitus (T2DM) indicating a state of FGF21-resistance.

Elevated levels also correlate with liver fat content in non-alcoholic fatty liver disease and positively correlate with Body Mass Index in humans, again suggesting obesity as a FGF21-resistant state. Both high sugar and low protein diets can elevate FGF21 in animals and humans.

FGF21 can inhibit mTORC1 in the liver and stimulate adiponectin secretion from fatty tissues, thereby inhibiting aging-associated metabolic syndrome. FGF21 protects against diabetic cardiomyopathy primarily by PGC-1α-induction of beta oxidation. The anti-inflammatory effects if FGF21 may primarily be due to inhibition of NF-κB in macrophages. In mice, FGF21 has been shown to protect against high fat diet-induced inflammation and islet hyperplasia in the pancreas, a finding of possible clinical relevance.

A single-nucleotide polymorphism (SNP) of the FGF21 gene – the FGF21 rs838133 variant (frequency 44.7%) – has been identified as a genetic mechanism responsible for the sweet tooth behavioral phenotype, a trait associated with cravings for sweets and high sugar consumption, in both humans and mice. Finally, circulating FGF21 levels may have prognostic value for the early detection injury in patients with liver transplantation.https://pubmed.ncbi.nlm.nih.gov/26806156/

Preclinical studies
Mice lacking FGF21 fail to fully induce PGC-1α expression in response to a prolonged fast and have impaired gluconeogenesis and ketogenesis.

FGF21 stimulates phosphorylation of fibroblast growth factor receptor substrate 2 and ERK1/2 in the liver. Acute FGF21 treatment induced hepatic expression of key regulators of gluconeogenesis, lipid metabolism, and ketogenesis including glucose-6-phosphatase, phosphoenol pyruvate carboxykinase, 3-hydroxybutyrate dehydrogenase type 1, and carnitine palmitoyltransferase 1α. In addition, injection of FGF21 was associated with decreased circulating insulin and free fatty acid levels. FGF21 treatment induced mRNA and protein expression of PGC-1α, but in mice PGC-1α expression was not necessary for the effect of FGF21 on glucose metabolism.

In mice FGF21 is strongly induced in liver by prolonged fasting via PPAR-alpha and in turn induces the transcriptional coactivator PGC-1α and stimulates hepatic gluconeogenesis, fatty acid oxidation, and ketogenesis. In mice, FGF21 may be necessary for them to display the hibernation-like state of torpor, also for eliciting and coordinating the adaptive response to fasting and starvation. FGF21 expression is also induced in white adipose tissue by PPAR-gamma, which may indicate it also regulates metabolism in the fed state. FGF21 is induced in both rodents and humans consuming a low protein diet. FGF21 expression is also induced by diets with reduced levels of the essential dietary amino acids methionine, isoleucine, or threonine, or with reduced levels of branched-chain amino acids. Methionine restriction can increase circulating FGF21 between 5-fold and 10-fold in mice.

In mice with acute ablation of thermogenic adipose tissues, FGF21-induced weight loss appears to be at least partially mediated by increased physical activity as well as by a centrally mediated increase in energy expenditure.

Fructose ingestión also induced FGF21 in humans, where it causes a rise in FGF21 levels in serum; likewise in mice, where serum FGF21 increases and induction of FGF21 in the liver can be confirmed. A dramatic increase in circulating FGF21 in humans is induced by the consumption of alcohol. Acutely, the rise in FGF21 in response to alcohol consumption inhibits further drinking. Chronically, the rise in FGF21 expression in the liver may protect against liver damage.

Activation of AMPK and SIRT1 by FGF21 in adipocytes enhanced mitochondrial oxidative capacity as demonstrated by increases in oxygen consumption, citrate synthase activity, and induction of key metabolic genes. The effects of FGF21 on mitochondrial function require serine/threonine kinase 11 (STK11/LKB1), which activates AMPK. Inhibition of AMPK, SIRT1, and PGC-1α activities attenuated the effects of FGF21 on oxygen consumption and gene expression, indicating that FGF21 regulates mitochondrial activity and enhances oxidative capacity through an LKB1-AMPK-SIRT1-PGC-1α-dependent mechanism in adipocytes, resulting in increased phosphorylation of AMPK, increased cellular NAD+ levels and activation of SIRT1 and deacetylation of SIRT1 targets PGC-1α and histone 3.

FGF21 analogs
LY2405319 "While initial attempts to develop such medicines were primarily focused on improving hyperglycemia in type 2 diabetes patients, the robust, consistent, and durable effects on lipid metabolism in human trials gradually transformed clinical emphasis for these factors toward their use for non-alcoholic steatohepatitis (NASH) and severe hypertriglyceridemia (SHTG)."33383173

FGF21 antagonists
Peptide Inhibitors of β-Klotho (Novo-Nordisk). 33073195

LY2405319 (Lilly)
In a randomized, placebo-controlled, double-blind proof-of-concept trial, 4 weeks of daily subcutaneous treatment of obese diabetic patients with LY2405319 significantly lowered plasma triglycerides and low-density lipoprotein cholesterol (LDLc), and increased high-density lipoprotein cholesterol (HDLc). 24011069

LLF580 (Novartis)
LLF580 lowered serum triglycerides by 54%, lowered serum triglycerides by 54%, reduced liver fat by 52% over placebo (in obese, mildly hypertriglyceridemic adults, LLF580 treatment beneficial effects on serum lipids, liver fat, and biomarkers of liver injury;  mild to moderate gastrointestinal adverse effects). 34431493

AKR-001 (Amgen/ Akiro)
Favorable trends in lipoprotein profile, including triglycerides, non-high-density lipoprotein (non-HDL) cholesterol, HDL-C, and apolipoproteins B and C3 are consistent with other FGF21 analogs. 33205064

BMS-986036 (Bristol-Myers Squibb)
Subcutaneous treatment with BMS-986036 (Pegbelfermin), a recombinant PEGylated FGF21 analog, improved serum lipid profile and adiponectin levels in obese, diabetic patients, with no effect on HbA1c. 30520566

PF-05231023 (Pfizer)
Treatment (i.v.) of obese, T2D patients with PF-05231023 during 4 weeks produced a significant decreased in body weight, improved plasma lipoprotein profile, and increased adiponectin levels with no significant effects on glycemic control. 26959184

FGF21 research news

 * FGF21 release from the liver is enhanced during exercise 2015 (accompanying glycogen degradation/glucose output?)10.1016/j.molmet.2015.06.001 Glucagon also increases FGF21 2013 10.1007/s00125-012-2803-y (High hepatocyte cAMP?)
 * In rats, cafeteria diet steatosis is accompanied by high FGF21, taurine protects 2017 10.1159/000480649
 * Endocrine FGFs cause suppression of bile acid synthesis in hepatocytes, promotion of lipolysis in adipocytes, and inhibition of phosphate reabsorption and vitamin D biosynthesis in renal tubular cells 21008 10.1016/j.tem.2008.06.002
 * Synthesized by several organs..
 * In humans, neither a ketogenic diet nor fasting affects FGF21, whereas fructose ingestion leads to a rapid and robust increase in circulating FGF21
 * modified FGF21 as well as agonistic antibodies against the receptor for FGF21, namely the complex of FGF receptor 1 (FGFR1) and the obligatory coreceptor βKlotho (KLB). In addition, a novel approach to increase endogenous FGF21 activity by inhibiting the FGF21-degrading protease REVIEW 2017 10.1515/hmbci-2017-0002 Genentech 33139537
 * under most physiological manipulations, circulating Fgf21 is from the liver (55)