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Fibroblast growth factor 21' is a protein that in mammals is encoded by the FGF21 gene. FGF21 is a hepatokine – i.e., a hormone secreted by the liver – that regulates multiple metabolic pathways through the organ system. 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. Within the liver, FGF21 is responsable for fatty acid oxidation both upon fasting and consumption of a ketogenic diet. In addition it 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 are mediated through FGF21 receptors in the paraventricular nucleus of the hypothalamus and correlate 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
The binding of FGFs to their receptors is generally complex, requiring both interaction of the FGF molecule with the FGF receptor itself, and binding to a heparin moieity in the receptor through a heparin binding domain in FGF. Endocrine FGFs -like FGF21- lack such a binding domain 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 special type of  β-glucuronidase. Loss of β-Klotho abolishes all effects of FGF21 activity.

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. 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.

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.

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.