Going Back to the Biology of FGF21: New Insights (Lewis et al, 2019)

SNT Gatchaman

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Going Back to the Biology of FGF21: New Insights
Jo E. Lewis, Francis J.P. Ebling, Ricardo J. Samms, Kostas Tsintzas

Fibroblast growth factor 21 (FGF21) is a protein highly synthesized in the liver that exerts paracrine and endocrine control of many aspects of energy homeostasis in multiple tissues. In preclinical models of obesity and type 2 diabetes, treatment with FGF21 improves glucose homeostasis and promotes weight loss, and, as a result, FGF21 has attracted considerable attention as a therapeutic agent for the treatment of metabolic syndrome in humans. An improved understanding of the biological role of FGF21 may help to explain why its therapeutic potential in humans has not been fully realized. This review will cover the complexities in FGF21 biology in rodents and humans, with emphasis on its role in protection from central and peripheral facets of obesity.

Link (Paywalled)
 

SNT Gatchaman

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Some quotes, as the article is pay-walled —

Since its initial isolation from liver in 2000, FGF21 has been shown to be widely expressed in metabolic organs, including the gastrointestinal tract, adipose tissue, and pancreas. FGF21 has been demonstrated to cross the blood–brain barrier in rats, is detectable in human cerebrospinal fluid (CSF), and there is a linear relationship between serum and CSF levels.
FGF21 biology demonstrates circadian rhythmicity (serum concentrations exhibit a clear diurnal rhythm) and dysregulation correlates with obesity-induced lipid disorders.
the physiological role of FGF21 is in the adaption to altered metabolic demand, for example, in times of stress; levels of FGF21 are increased under a variety of physiological interventions and pathogenic events, including starvation (acutely in mice, chronically in humans), obesity (in mice and humans), and exercise (in mice and humans).
Caloric restriction, for example, promotes mitochondrial biogenesis and fatty acid oxidation, whereas white adipose tissue (WAT) rapidly expands in response to an obesogenic diet by increasing lipid storage and the number of adipocytes.
Initially, FGF21 was shown to stimulate glucose uptake in 3T3-L1 adipocytes via glucose transporter 1 (GLUT1). Subsequently, FGF21 was shown to increase glucose uptake in brown adipose tissue (BAT) and WAT in lean mice, suggesting a differential response to FGF21 dependent on metabolic status and/or adiposity.
FGFR activation by FGF21 is dependent on obligate co-receptor βKlotho (KLB)
In mice, KLB expression is seen in adipose tissue, the liver, gall bladder, colon, and pancreas, as well as the suprachiasmatic and paraventricular nuclei of the hypothalamus and discrete regions of the brainstem.
The CNS integrates a vast array of signals from the periphery to regulate feeding behavior and energy homeostasis; dysregulation results in obesity and T2D.
KLB is highly expressed in the suprachiasmatic nucleus in the hypothalamus and in a number of hindbrain regions ... does not exclude the possibility that KLB might be expressed at lower levels or in isolated cells in other regions of the brain. (... immunostaining of KLB in the paraventricular nucleus of the hypothalamus of mice).
Overexpression of FGF21 lowers circulating levels of insulin and activation of the HPA axis and suppresses the reproductive axis.
... in humans, neither ketogenic diets (up to 3 months) nor short-term fasting (up to 48 hours) increase serum FGF21 levels. Interestingly, elevations in FGF21 in humans are seen following prolonged fasting (7–10 days).
... recent evidence suggests that FGF21 is an insulin-dependent postprandial hormone in humans.
FGF21 secretion has been shown to respond to oral carbohydrate consumption, with fructose reported to increase plasma levels of FGF21 in humans to a greater extent than glucose.
The fibroblast activation protein (FAP) is a serine protease that cleaves and inactivates FGF21. Interestingly, patients with T2D have elevated circulating levels of FAP when compared with nondiabetic controls, and this is associated with an attenuated ratio of bioactive to total FGF21 in response to an oral glucose tolerance test, suggesting that chronic states of insulin resistance may lead to inactivation of FGF21 and limit its metabolic effects.
... obesity is generally associated with high serum FGF21 in humans, suggesting that chronic adiposity may lead to an FGF21 resistant state.
FGF21 has also been suggested to act as an exercise-induced myokine, as its serum levels are elevated in response to whole-body submaximal exercise.
... recent elegant studies using tissue arteriovenous differences have shown that exercise is a key stimulus in inducing hepatic release of FGF21 in humans.
... during submaximal exercise, most of the release of FGF21 into the systemic circulation occurs through the liver rather than skeletal muscle.
Interestingly, eccentric exercise resulted in significant elevations in arterialized and venous concentrations of its regulatory enzyme FAP
These findings raise the possibility that increased levels of FAP may play a role in the inactivation of FGF21 during this type of exercise. Collectively, the results from the literature suggest that FGF21 may be an exercise-induced hepatokine but not myokine and that strategies aiming to minimize the release of FAP may be of benefit in maximizing the metabolic effects of FGF21.
 

mariovitali

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@SNT Gatchaman

Here is a ranked list of MECFS-related topics (total number is 952) with FGF21. i find it interesting that some highly-ranked keywords are related to liver pathology (nafld, steatohepatitis)

pparalpha.csv=0.92778516
thermogenin.csv=0.9277296
fatty_acid_oxidation.csv=0.92761904
thermogenesis.csv=0.92726797
nafld.csv=0.9263943
lipolysis.csv=0.9263244
adiponectin.csv=0.9262514
lipotoxicity.csv=0.9261797
peroxisome.csv=0.92617315
steatohepatitis.csv=0.92611456
ampk.csv=0.9257394
gluconeogenesis.csv=0.9253724
atf4.csv=0.92518157
ppargamma.csv=0.9249449
oxidation.csv=0.9245442
carnitine_palm.csv=0.92426986
free_fatty_acids.csv=0.9234381
sirt1.csv=0.9233145
leptin.csv=0.9217039
hepatocytes.csv=0.9215976
nrf2.csv=0.92113096
insulin_resistance.csv=0.9209983
vascular_calcification.csv=0.9209498
er_stress.csv=0.9209494
srebp.csv=0.92037517
caloric_restriction.csv=0.9202395
liver_disease.csv=0.9200437
beta_oxidation.csv=0.91835016
ahr.csv=0.91816944
bile_acid.csv=0.91753745
fas.csv=0.91706926
fxr.csv=0.9166556
lxr.csv=0.9159427
beta_glucuronidase.csv=0.9159404
upr.csv=0.91505146
acetyl_coa_carboxylase.csv=0.9139542
protein_kinase_r.csv=0.9135509
perk.csv=0.9129639
glucose_6_phosphatase.csv=0.91296315
mitochondrial_fusion.csv=0.91258824
rankl.csv=0.9114911
liver_injury.csv=0.91147804
cyp7a1.csv=0.91120964
glucokinase.csv=0.9112074
palmitic_acid.csv=0.91110206
osteoprotegerin.csv=0.9106395
histone_methyltransferase.csv=0.90902275
foxo1.csv=0.9086655
chop.csv=0.9083498
liver_fibrosis.csv=0.9083062
coa.csv=0.90787584
igf_1.csv=0.9078189
proteolysis.csv=0.9077896
mitochondrial_fission.csv=0.90771675
mfn2.csv=0.90755457
pi3k.csv=0.9075373
er.csv=0.90710765
abca1.csv=0.9055241
phosphorylation.csv=0.9049095
acyl_coa.csv=0.90428305
cholesterol_efflux.csv=0.9042505
acetyl_coa.csv=0.9038157
triacylglycerol.csv=0.90355974
stat3.csv=0.9028921
redox_homeostasis.csv=0.902345
autophagy.csv=0.9018193
ceramides.csv=0.90170056
sumoylation.csv=0.90166813
heparan_sulfate.csv=0.9000406
rapamycin.csv=0.899516
hgh.csv=0.8960047
mapk.csv=0.89521164
gapdh.csv=0.89498657
histone_deacetylase.csv=0.89485073
butyrate.csv=0.8939309
sod2.csv=0.8928344
opa1.csv=0.89233106
post_translational_modification.csv=0.89112294
isoprostane.csv=0.89039123
retinoic_acid.csv=0.89026624
protein_kinase_a.csv=0.8898058
rar.csv=0.88856083
abcg1.csv=0.8884095
mtdna.csv=0.8878854
tyrosine_hydroxylase.csv=0.88680786
one_carbon.csv=0.8860721
xbp1.csv=0.8860721
mitochondria_human.csv=0.88535684
cannabinoid_receptor.csv=0.8823548
pepck.csv=0.8823548
ghrelin.csv=0.88235086
hnf4a.csv=0.88130426
cd36.csv=0.88071525
proline_human.csv=0.88044196
hba1c.csv=0.8797132
ubiquitination.csv=0.8797132
drp1.csv=0.87920076
heparin.csv=0.8791511
oxysterol.csv=0.8790805
niacin.csv=0.8779385
 

Pyrrhus

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Here is a ranked list of MECFS-related topics (total number is 952) with FGF21. i find it interesting that some highly-ranked keywords are related to liver pathology (nafld, steatohepatitis)
Most of those terms are, as expected, involved in energy metabolism. Some others stick out:

protein_kinase_r.csv=0.9135509
Protein kinase R (PKR) is a key antiviral protein.


mitochondrial_fusion.csv=0.91258824
mitochondrial_fission.csv=0.90771675
:monocle:?
 

SNT Gatchaman

Senior Member
Messages
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Location
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Here is a ranked list of MECFS-related topics (total number is 952) with FGF21. i find it interesting that some highly-ranked keywords are related to liver pathology (nafld, steatohepatitis)
pparalpha.csv=0.92778516
For your top listed hit of PPAR-alpha, I've posted a paper here with the following quote:

FGF21 signals through cell-surface receptors composed of classic FGF receptors complexed with β-klotho, a membrane-spanning protein. Induction of FGF21 during fasting occurs through a mechanism that requires peroxisome proliferator-activated receptor-⍺ (PPAR⍺).