Fibroblast growth factor 21 (FGF21) is a hormone involved in regulating energy metabolism 1 and has been studied extensively in animal models where various beneficial effects have been found 2. FGF21 analogues have also been produced for human use and similar beneficial effects have been observed in humans 3. FGF21 is considered to be a hepatokine, which is secreted from the liver to the blood stream and transported to target tissues, where it acts through the FGF receptor in presence of the β-klotho coreceptor 4. The understanding of the regulation of circulating FGF21 is mainly based on animal studies, whereas the picture is less clear in humans. Both chronic conditions and acute stimuli have been reported to induce FGF21 in humans and several mechanisms have been proposed.
Several chronic conditions have been associated with increased circulating levels of FGF21, particularly conditions characterized by a dysregulated energy metabolism such as type 2 diabetes 5,6, obesity 7, nonalcoholic fatty liver disease 8, and the metabolic syndrome 9. Interestingly, plasma FGF21 also increases in response to normophysiological stimuli such as 7 days of fasting. The appreciation of the acute regulation of FGF21 in the human physiology is only just emerging. On the basis of animal studies, FGF21 was estimated to have a relatively short half-life of 30–120 min 10. This indicates that circulating FGF21 has a rapid turnover and could be acutely regulated. In humans, it was shown that FGF21 could increase in the circulation within minutes during an acute bout of exercise 11. Later, the kinetics of the exercise-induced FGF21 were established and showed that pre-exercise levels were reached within 90–120 min after exercise was ended 12. Thus, the kinetic of FGF21 in humans is dynamic and the plasma concentration can alter rapidly. In animal studies, particularly in mice, the blood volume is limited, which makes repeated measurement of hormones difficult; thus, few studies have examined the acute changes in circulating FGF21 in animal models.
During the last decade, several human studies have dealt with the regulation of FGF21, applying different interventions. Under both chronic pathological conditions and normal physiological conditions, challenges have been identified as regulators of circulating FGF21. This review summarizes the human evidence of FGF21 regulation. We propose that the ratio between circulating glucagon and insulin is a denominator in various conditions where FGF21 is elevated. This pivotal mechanism regulating circulating FGF21 in humans thereby provides a mechanistic link to conditions with insulin resistance explaining the elevated circulating levels of FGF21.
FGF21 was identified during 2000 and found to be predominantly expressed in the liver 13. When FGF21 is specifically knocked out in the liver in mice, it disappears from the circulation 14. This strongly points to the liver being the organ responsible for producing the circulating levels of FGF21. One method to elucidate whether an organ secretes or takes up hormones or metabolites is measuring the arterial-to-venous difference; in humans, however, it is difficult to assess an arterial-to-venous difference specifically in the liver. When inserting a catheter into the hepatic vein and an artery, it is possible to assess the arterial-to-venous difference over the splanchnic bed in healthy fasting humans. By applying this approach, a release of FGF21 could be found after an overnight fast, and furthermore, the splanchnic bed release of FGF21 increased during an exercise bout in healthy individuals 12. This suggests that the liver in humans is the major contributor to the circulating levels of FGF21, even though a contribution from the intestine, pancreas, or spleen cannot be excluded.
It has been suggested that other tissues contribute toward circulating FGF21. Much attention has focused on the skeletal muscle tissue and FGF21 has been proposed to be a myokine 15. Genetically modified mice with chronically activated protein kinase B (Akt) release FGF21 from the muscle cells 16. This idea has also been tested in a human model, where Akt in the muscle tissue was activated by a hyperinsulinemic euglycemic clamp, which led to an increase in muscle FGF21 mRNA content as well as circulating levels 17. Akt in the skeletal muscle is also activated during recovery after an exercise bout 18; measurement of the arterial-to-venous difference over the human leg during and after an exercise bout, however, showed no release of FGF21 from the leg despite an increase in the circulation 12. Surprisingly, the leg tended to take up FGF21 rather than release it 12. It needs to be validated whether the increased mRNA content in the skeletal muscle observed with prolonged hyperinsulinemia can be interpreted as a release of FGF21 protein into the circulation from the leg (e.g. muscle tissue) in humans, but in normal physiology, FGF21 does not seem to be released from the muscle tissue in humans. Besides the muscle tissue, the adipose tissue has also been suggested to contribute toward circulating FGF21 levels in humans 19. The adipose tissue secretes several humoral factors termed adipokines 20. No studies have attempted to measure FGF21 release/uptake by an arterial-to-venous difference over the adipose tissue in humans. This approach is possible in humans and has shown that IL-6 is released from the adipose tissue 21. Taken together, there is strong evidence that the liver is the main source of circulating FGF21 in humans, which does not rule out that FGF21 could have paracrine or autocrine actions in other tissues.
The most potent hormone to increase circulating FGF21 in humans is glucagon. When glucagon is administered at a high pharmacological dose (1 mg) injected intramuscularly into healthy lean individuals, plasma FGF21 increases 2–3-fold over 30 min 22. That the regulation of FGF21 is independent of insulin has been suggested, as patients with type 1 diabetes respond similarly to healthy control participants 22. Recently, an interaction between glucagon and insulin was found on the regulation of plasma FGF21. When glucagon was elevated in a physiologically relevant range and duration with a concomitant suppression of the endogenous insulin production, circulating FGF21 was increased by 4–5-fold over 90 min. In contrast, no increase in circulating FGF21 could be found when the glucagon elevation was followed by a corresponding elevation in insulin 12. These data confirm the stimulatory effect of glucagon and suggest an inhibitory role of insulin; consequently, the glucagon-to-insulin ratio is the most potent signal for FGF21 induction in humans when studied in physiologically relevant doses. This idea is well in line with the hepatic origin of circulating FGF21 as both glucagon and insulin act in concert on the hepatocytes. One study proposes a stimulatory role of insulin in plasma FGF21. An increase in plasma FGF21 was observed during a hyperinsulinemic euglycemic clamp in healthy young individuals 17, whereas another study found no effect on FGF21 23. As circulating FGF21 is acutely regulated, it is important to have sufficient repeated measurements to ensure correct interpretation of the stimulus and response. The two reports evaluating the effect of hyperinsulinemia on circulating FGF21 17,23 do not have adequate time resolution to provide firm conclusions on this subject. Plasma FGF21 has been reported to be unaffected 24 or decreased 25 during an oral glucose tolerance test where insulin increases. When reducing insulin below the levels observed after an overnight fast, an infusion of somatostatin in healthy young men increased FGF21 rapidly 12, which suggests that insulin even at fasting levels could inhibit FGF21 release. In addition, insulin withdrawal from patients with type 1 diabetes also increases circulating FGF21 26. These data suggest that increasing insulin as observed during a hyperinsulinemic euglycemic clamp may only have a marginal additional inhibitory effect. This underlines that it is the balance between the stimulatory signal from glucagon and the inhibitory signal from insulin that determines the circulating FGF21 level in humans. In patients with sepsis, it was elegantly shown that insulin reduces the elevated circulating levels of FGF21 27. Thiessen and colleagues suggested that liver mitochondrial stress was the driving force of the increased plasma FGF21 levels during sepsis. An alternative explanation could be that glucagon, which is highly elevated during sepsis as a part of the stress response, was a contributing stimulus for FGF21 elevation. As suggested in a comment to another article 28, this could contribute toward the increase in plasma FGF21 observed during sepsis. Taken together, insulin seems to exert an inhibitory effect on the circulating levels of FGF21 in humans. Of other hormones, growth hormone acts on the liver and the possible regulation of circulating FGF21 has been anticipated; however, neither acute growth hormone administration to healthy individuals nor replacement of growth hormone in deficient patients affected the circulating levels of FGF21, and consequently, growth hormone is not a strong regulator of FGF21 in humans 29. Overall, the glucagon-to-insulin ratio seems to be the strongest humoral regulator of plasma FGF21 identified in humans.
Metabolites have also been identified as regulators of circulating levels of FGF21. One of the first identified stimulatory signals for increasing circulating FGF21 was lipids through peroxisome proliferator-activated receptor α (PPARα) activation 30,31. These findings were based on mice studies. In humans, prolonged fasting increases circulating FGF21 32 and the proposed mechanism is through free fatty acids (FFAs)-activated PPARα. On increasing FFA by an infusion of intralipid in healthy human participants, circulating FGF21 also increases; however, the increase in plasma FGF21 occurs after 4 h of elevated FFA and only a modest 1.3-fold increase is observed 33. Increasing triglycerides by an infusion of intralipid does not increase FGF21 in humans 34. Christodoulides et al.35 administered PPAR agonist to healthy individuals and studied the effect on plasma FGF21. After 2 weeks of treatment, a 1.3-fold increase could be detected. Thus, FFA and PPAR activation in humans exerts only a modest effect of ∼1.3-fold increase in circulating FGF21, which occurs after several hours to days. In a physiological setting – as during an oral lipid tolerance test – a suppression of plasma FGF21 was observed 2 and 4 h after ingestion in 100 healthy volunteers 24. Collectively, it could be speculated that FFA-induced and PPAR-induced FGF21 is more relevant under chronic conditions than during acute regulation and that intestinal hormones may have an inhibiting effect on FGF21 secretion.
Other metabolites such as carbohydrates also regulate plasma FGF21. A combination of glucose and fructose has been suggested to induce FGF21 secretion through activation of the carbohydrate response element-binding proteins 25. Glucose alone does not increase plasma FGF21 in humans as an oral glucose tolerance test reduced 25 or did not alter plasma FGF21 levels 24. Surprisingly, an oral fructose tolerance test increases FGF21 3.4-fold acutely in healthy individuals 25. The mechanism for fructose-induced FGF21 is not clear and needs to be elucidated.
In humans, protein restriction increased FGF21 1.7-fold after 28 days on a low-protein diet 36. The increase in FGF21 could be not be explained by the effect of fasting or caloric restriction per se as the two diets were matched for caloric content. Unfortunately, no measurement on glucagon to insulin was reported. Human studies are not purely mechanistic models and it is, therefore, important to assess as many variables as possible to understand the complex interplay between metabolites and hormones.
An emerging mechanism for the stimulation of FGF21 production is mitochondrial stress 37 and FGF21 has therefore been suggested as a mitokine 38. There has been particular focus on the skeletal muscle tissue, where mitochondrial impairment in mice regulates FGF21 expression in the muscle tissue 39,40. This idea is supported by studying muscle cells in vitro41. Even though the human leg does not release FGF21 after an overnight fast or during an exercise bout 12, there could be a possible release of FGF21 from the leg in patients with myopathies; however, no data are available as yet. Alternatively, muscle-derived FGF21 may act in a paracrine or an autocrine manner, which explains why no release into the circulation would be present.
Fibroblast growth factor 21 in the physiological setting
The highest and acute increase in plasma FGF21 observed in humans is during an acute bout of exercise, which increases FGF21 up to 4–8-fold 11,12,42. FGF21 rapidly returns to baseline levels during the hours after the exercise bout. FFA increases with an exercise bout; however, as FFA administration does not increase FGF21 with a similar kinetics or magnitude 33, other stimulatory signals must drive the exercise-induced FGF21 response. When manipulating the glucagon-to-insulin ratio in resting healthy individuals, mimicking the change that occurs during exercise elicits an FGF21 response similar to exercise in both magnitude and kinetics 12. Thus, the glucagon-to-insulin ratio appears to be a pivotal signal for exercise-induced FGF21 in humans. Indeed, preventing an increase in the glucagon-to-insulin ratio during exercise blunts the exercise-induced increase in FGF21 in young healthy men 42. This observation is in line with a reduced exercise-induced FGF21 response in obese insulin-resistant patients 43 and patients with type 2 diabetes 42. Thus, exercise-induced FGF21 is driven by changes in the glucagon-to-insulin ratio in humans.
Prolonged fasting is also characterized by increased glucagon levels and reduced insulin levels, thereby increasing the glucagon-to-insulin ratio. Thus, this interpretation may provide an explanation for fasting-induced FGF21 during a prolonged fast. This is well in line with the notion that stimulation of FGF21 requires several days of fasting 44. Even though prolonged fasting (7 days) led to elevated FGF21 levels in humans 32, controversy exists as fasting has been suggested only to increase FGF21 in mice 45. Fasting for 48 h 35 or 72 h 8 does not induce an increase in plasma FGF21. The discrepancy between the human findings may be because of differences in the duration of the fasting period between the studies. Recently, a comprehensive study addressed these conflicting results and showed a robust increase in both FGF21 and glucagon after 9 days of fasting 44. Thus, prolonged fasting increases the glucagon-to-insulin ratio, which could be stimulating plasma FGF21 in humans.
The proposal of the glucagon-to-insulin ratio as a key signal to regulate circulating levels of FGF21 in humans represents an interesting aspect of insulin resistance. Several pathological conditions associated with increased plasma FGF21 levels also feature insulin resistance as a characteristic. Indeed, elevated plasma levels of FGF21 have been observed in patients with type 2 diabetes 6, NAFLD/NASH 8, and obesity 9. In a chronic setting, patients with type 2 diabetes have moderately elevated levels of FGF21 compared with healthy individuals 6. This is in line with a positive association to hepatic insulin resistance, which has been found 46. Obesity, particularly in combination with insulin resistance, increases the circulation of FGF21 9. Thus, resistance to insulin and thereby reduced inhibitory signal of FGF21 release would lead to a chronic increase of FGF21. In addition, increased glucagon levels (hyperglucagonemia) would also lead to elevated levels of FGF21 in various metabolic conditions. However, in these chronic conditions, FFA and PPAR activation may act synergistically with glucagon stimulation, leading to further elevated FGF21 levels, as observed in mice 47. It is noteworthy that acute insulin resistance in patients with critical illness or sepsis 48 in addition to hyperglucagonemia 49 – thus insulin resistance in combination with hyperglucagonemia – could be a stimulator of FGF21 in patients with sepsis/critical illness. Taken together, the observation that insulin resistance increases circulating FGF21 is well in line with the proposal that the glucagon-to-insulin ratio is a key regulatory mechanism and the liver is the source of circulating FGF21.
Over the last decade, several human studies have emerged evaluating the regulation of FGF21 as summarized in Fig. 1. Of the several stimulatory signals proposed, the glucagon-to-insulin ratio appears to be a central driver in the regulation of FGF21 in humans. In a chronic setting, FFA and PPAR activation could act in synergy with insulin resistance and/or hyperglucagonemia to drive the increase in circulating levels of FGF21 in diseases such as type 2 diabetes, NAFLD, and obesity.
The Centre for Physical Activity Research (CFAS) is supported by a grant from the Danish foundation TrygFonden. During the study period, the Centre of Inflammation and Metabolism (CIM) was supported by a grant from the Danish National Research Foundation (DNRF55). CIM/CFAS is a member of DD2 – the Danish Center for Strategic Research in Type 2 Diabetes (the Danish Council for Strategic Research, grant nos 09-067009 and 09-075724). CIM is a member of DD2 – the Danish Centre for Strategic Research in Type 2 Diabetes (the Danish Council for Strategic Research, grant nos 09-067009 and 09-075724). This study was further supported by grants from the Danish foundations Augustinus Fonden and Aase og Ejnar Danielsens Fond.
Conflicts of interest
There are no conflicts of interest.
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