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

[SNT Gatchaman]

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]

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.