Understanding the Physiology of FGF21 (Fisher and Maratos-Flier, 2015)

SNT Gatchaman

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Understanding the Physiology of FGF21
Ffolliott Martin Fisher and Eleftheria Maratos-Flier

Fibroblast growth factor 21 (FGF21) is a peptide hormone that is synthesized by several organs and regulates energy homeostasis. Excitement surrounding this relatively recently identified hormone is based on the documented metabolic beneficial effects of FGF21, which include weight loss and improved glycemia. The biology of FGF21 is intrinsically complicated owing to its diverse metabolic functions in multiple target organs and its ability to act as an autocrine, paracrine, and endocrine factor.

In the liver, FGF21 plays an important role in the regulation of fatty acid oxidation both in the fasted state and in mice consuming a high-fat, low-carbohydrate ketogenic diet. FGF21 also regulates fatty acid metabolism in mice consuming a diet that promotes hepatic lipotoxicity. In white adipose tissue (WAT), FGF21 regulates aspects of glucose metabolism, and in susceptible WAT depots, it can cause browning. This peptide is highly expressed in the pancreas, where it appears to play an anti-inflammatory role in experimental pancreatitis. It also has an anti-inflammatory role in cardiac muscle. Although typically not expressed in skeletal muscle, FGF21 is induced in situations of muscle stress, particularly mitochondrial myopathies. FGF21 has been proposed as a novel therapeutic for metabolic complications such as diabetes and fatty liver disease.

This review aims to interpret and delineate the ever-expanding complexity of FGF21 physiology.

Link (PDF pay-walled)
 

SNT Gatchaman

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Some quotes, as the article is pay-walled —

Fibroblast growth factor 21 (FGF21) is a fairly recent entry to the list of factors controlling energy homeostasis.
... the physiology of FGF21 is quite complex largely because it is synthesized in multiple organs and can act on multiple target tissues in either a paracrine or an endocrine fashion
hepatic FGF21 expression is upregulated after fasting or consumption of a ketogenic diet and by the transcription factor PPARα.
... treatment with PPARα agonists—including fenofibrate, Wy-14643, and GW7647—substantially increases hepatic FGF21 expression
Adenovirus-mediated knockdown of FGF21 in livers of mice consuming a ketogenic diet led to significant pathology, including fatty liver, and severe serum hypertriglyceridemia led to reduced hepatic fatty acid oxidation. Liver-specific FGF21 knockdown also led to impaired assembly and export of VLDL particles, a major pathway by which triglycerides are cleared from the liver. Consistent with a role of FGF21 in the adaptive response of mice to a ketogenic diet, which includes weight loss and increased energy expenditure despite normal caloric intake, FGF21−/− mice have an atypical response, gaining rather than losing weight.
FGF21 binds to FGFRs with extremely low affinity, and effective binding and signal transduction require interaction with a coreceptor, KLB. KLB binds FGF21 at the C terminus. Interaction with the FGFR occurs through the N terminus of FGF21.
... both termini of FGF21 must be intact for FGFR activation to occur. KLB expression is essential for FGF21 signaling and is the primary determinant of tissue specificity.
In mice, Klb is expressed in all adipose tissue depots, the liver, the exocrine pancreas and endocrine pancreas, and the suprachiasmatic nucleus (SCN) and the paraventricular nucleus of the hypothalamus.
As with most other FGFs, FGF21 activates signaling through the Ras/Raf MAPK signaling pathway.
Even though the actions of FGF21 lead to improved metabolic profiles, FGF21 levels are greatly increased in obese humans, leading to the suggestion that obesity may give rise to an FGF21-resistance state.
In adipocytes, TNF-α-induced inflammation reduces KLB expression and diminishes the response of the cells to FGF21. Hypoglycemia similarly reduces KLB levels in pancreatic islets in mice.
The liver emerged early on as a potential site of FGF21 action, after hepatic FGF21 was identified as a downstream target of PPARα. PPARα is activated by fatty acids during both fasting and consumption of a ketogenic diet and regulates the transcription of many enzymes mediating fatty acid oxidation and ketosis.
Extremely high levels of circulating FGF21 have been reported in mice consuming diets deficient in methionine or leucine, and increased circulating FGF21 has been found in mice with depletion of plasma alanine levels. In the case of ketogenic diets, methionine deficiency appears to be the specific contributor to the rise in FGF21.
Under dietary challenges, FGF21 expression appears to change only in the liver. The hepatocyte is believed to be the major source of circulating FGF21.
The beneficial effects on the liver may be mediated directly by FGF21 on hepatocytes or, alternatively, through secondary mediators responding to hepatic FGF21 via either adipose tissue or the CNS.
Several studies have described this process in human and rodent models and further highlight FGF21 as a key regulator of the interface between the nutritional state of an organism and the required adaptive metabolic response.
FGF21 may act as a signal to defend core body temperature. ... studies found that cold exposure rapidly induced FGF21 expression in BAT in adult mice, a response that was downstream of beta-adrenergic signaling that induced activating transcription factor 2 transcriptional activity
Although the molecular mechanisms regulating these processes are not well defined, PGC-1α has been implicated in this process, as FGF21 dramatically increases PGC-1α protein levels independently of mRNA levels in vivo and in vitro.
Mild cold exposure increased circulating FGF21 levels in humans, correlating with increased energy expenditure and lipolysis
In humans, FGF21 is found in cerebrospinal fluid (CSF), and there is a linear relationship between serum levels and CSF levels. FGFR1, FGFR2, and FGFR3 are expressed in the brain, as is KLB, although at fairly low levels.
FGF21 is also reported to affect circadian periodicity and fertility, suggesting direct action of FGF21 in the CNS.
Although the suprachiasmatic nucleus has been proposed to mediate the effects of FGF21 in the brain, its obligate coreceptor Klb is not restricted to the SCN.
Two recent reports demonstrate that the central actions of FGF21 can increase energy expenditure by increasing sympathetic activity.
... the β-blocker propranolol attenuated the response to central but not peripherally delivered FGF21. This report also suggests that the paraventricular nucleus may mediate FGF21 actions on sympathetic activity.
The data on central FGF21 action are intriguing and have led to the suggestion that many actions of FGF21 on the liver, particularly those in gluconeogenesis, may be mediated through the brain, possibly through regulation of corticotropin-releasing factor in the paraventricular nucleus, stimulating glucocorticoid (corticosterone) production in the adrenal cortex.
Furthermore, consumption of a ketogenic diet for 4 months led to a substantial reduction in circulating FGF21 levels.
Intriguingly, there was a negative association between FGF21 and the insulin-like growth factor IGF1.
In humans, very high levels of FGF21 have been reported in association with mitochondrial myopathies. The highest levels, in the thousands of pictograms, are seen in patients with mitochondrial severe neurogastrointestinal encephalomyopathy.
Unlike other hormones, FGF21 signaling is not confined to a single tissue and does not regulate a single physiological process. In fact, depending on the environmental stimulus and the site of production, FGF21 can function as a classical endocrine hormone and as an autocrine factor; this latter mode of action represents at least one method by which the physiological actions of FGF21 are compartmentalized.
Hence FGF21 appears to regulate seemingly opposable physiological states such as the nutritionally limited state of fasting and the energy-depleting processes of adipose tissue thermogenesis.