The Discovery of FGF21

Around the year 2000, a new human hormone came to light.  It is a “fibroblast growth factor”, and the 21^st one found, so was logically named FGF21.  Its emergence is still the cause of much excitement in the health field because this hormone appears to positively influence many processes that promote long-term health.  The main effects of FGF21 are increased insulin sensitivity (FGF21 is one of the most potent insulin sensitizers ever identified); increased energy expenditure; weight loss; and improved response to stress.  FGF21 also has potent lowering effects on the amount of fat in the liver and on triglyceride levels in the blood, which come about through alterations in the metabolism that takes place in the liver and fat tissues. (1)

Through the influences of FGF21, both lifespan (the number of years a person lives from birth until death) and healthspan (the number of years a person lives in full health without chronic or debilitating disease) are lengthened.  In other words, FGF21 promotes what everyone hopes to enjoy  – a long, active, healthy life.  In fact, recent research has highlighted the ability of FGF21 to alleviate many of the chronic disorders that are presently plaguing our health including obesity, type-2 diabetes, dyslipidemia, atherosclerosis, hypertension, and other cardiovascular diseases.  It is likely that FGF21 is at least part of the power behind the remarkable health benefits that arise from eating plants. (2,3)

Of course, drug companies are feverishly working on presenting FGF21 as a patented medication that would bestow its benefits on people.  However, this has proven to be a difficult task.  FGF21 is broken down in the body very rapidly and would require multiple injections a day to be of therapeutic use.  In addition, harmful side effects have cropped up.  To start with, FDF21 administration can cause diarrhea, nausea, vomiting and dehydration.  (3)  But more worrying are possible long-term safety concerns stemming from observed changes in vital signs as well as potential systemic side effects on bone loss and the cardiac system. (4,5,6)

(NOTE: Systemic side effects are those that occur in tissues distant from the site of contact between the body and the substance in question.)

Fortunately, there really is no need to create a medication to reap the benefits of FGF21.  It is produced in the body, predominantly by the liver, but also by adipocytes (fat cells), the pancreas and skeletal muscle, in response to different stimuli.   FGF21 acts both locally at its production site but also as a hormone circulating in the bloodstream.  Research is discovering factors that lead to increases in FGF21 secretion. (7,4)  For instance, cold and starvation both augment FGF21 production, but there are many more promoting influences coming to light.

Let’s examine the factors that we know of so far that impact the production of FGF21 by our bodies.

 

Restriction of Protein and Specific Amino Acids

Lowering Protein in the Diet

FDF21 levels rise extensively when eating a lower protein diet.  This was illustrated by a study from 2014 that found rapidly increased FGF21 levels from dietary protein restriction, but not from energy restriction.  This research indicated elevations of over 150% in humans. (8)  Such increases do not require a worrying drop in dietary protein.  Most North Americans presently eating the Standard American Diet are consuming much greater amounts of protein than the official recommended daily amount. Even dropping protein intake down to the quantity recommended for health appreciably increases FGF21 levels. (9)  Eating a low amount of animal-sourced foods or avoiding them completely naturally causes a mild restriction in the protein present in the diet and results in a boost in the production of FGF21 by the liver.  (10)  Recent studies in humans have also demonstrated that lower protein intake is connected with improvements in risk factors that contribute to the risk of heart disease, type-2 diabetes and stroke as well as with increased longevity.  (11)

 

 Restriction of Specific amino acids  (11,12,13,14,15)

Proteins are made up of a variety of amino acids.  Many different proteins are required for health and the human body puts together combinations of amino acids to manufacture the specific proteins it needs.  Nine of the amino acids required by the human body are designated “essential amino acids” because they cannot be produced by our bodies and must be obtained through the diet.   Preliminary evidence suggests that restricting some of these essential amino acids, specifically methionine, tryptophan, and the BCAAs (Branched Chain Amino Acids) leucine, isoleucine and valine, has shown the same boosting effect on FGF21 as lowering protein in general.

Additionally, we now know that the source of protein from the diet influences our health.  Multiple studies have illustrated that eating plant-based protein is linked to better health than eating animal-based protein and FGF21 is likely part of the reason for this.  Methionine, tryptophan and the BCAAs are present in the highest amounts in foods sourced from animals, namely meats (including poultry and fish), dairy products and eggs.  Plants are generally lower in protein than animal-sourced foods and some of the essential amino acids are also limited in some plant-based foods. Rest assured, however, that all nine essential amino acids can be easily acquired from a plant-based diet by eating a variety of plant proteins every day.  These include vegetables, fruits, legumes, whole grains, nuts and seeds.

 

Restricting Methionine

Plant-based diets have lower levels of the amino acid, methionine, as compared to omnivorous diets.   Significant data now suggests that the level of methionine in a diet can have a profound effect on health and longevity in humans. Specifically, a diet restricted in methionine results in greater production of FGF21. (11)

Methionine is an essential amino acid, one of two sulfur-containing amino acids along with cysteine, and plays a beneficial role in protecting liver cells and preventing the oxidation of fats with indications that it may help to stave off atherosclerosis.  Eliminating methionine completely is not a good idea but limiting it may have benefits (14).

 

Restricting Branched-Chain Amino Acids (BCAAs)

There are three branched-chain amino acids, leucine, isoleucine and valine, which are named for the branched carbon side-chains in their chemical structure.  BCAAs have been long associated with poor health.  They are correlated to multiple diseases of aging including Alzheimer’s disease and shortened lifespan.  Higher BCAA blood levels are linked with obesity and insulin resistance.  Increased consumption of BCAAs is allied with higher incidence of type-2 diabetes in humans.  Research suggests that BCAAs may also be critically important in cancer development, with some types of cancer driven to further progression in high BCAA situations.  (11)

Short-term dietary restriction of BCAAs in humans with type-2 diabetes decreases insulin secretion, induces FGF21, improves oral glucose sensitivity and enhances metabolism of fats.  All this suggests that reducing dietary BCAAs might promote longer healthspans and increased lifespans in mammals.  (11)

Specifically reducing the three branched chain amino acids (leucine, isoleucine, and valine) to the same level as that found in a low protein diet is sufficient to improve many aspects of metabolic health. (16)

  

Restricting Tryptophan (11)

The essential amino acid tryptophan has been widely studied as a key regulator of metabolic health.  Tryptophan restriction has been shown to induce FGF21 and promote metabolic health in animal models.  In humans, higher tryptophan levels are correlated with poorer cognitive function during aging.

Conversely, other studies suggest that tryptophan has a positive effect on anxiety and depression and may be beneficial during aging.  The mechanisms by which tryptophan restriction promotes health and longevity are still unclear and we must await the results of further scientific investigations to help sort this out.

 

High Carbohydrate Diets (17)

As we have seen, lower protein diets are linked to increasing levels of circulating FGF21.  Since a diet lower in protein is inevitably higher in the other macronutrients, a group of researchers speculated on the effect that carbohydrates and fats might have on FGF21 levels.  And indeed, they published the results of their study in 2017.

For this research, adult men were fed three diets for three days each in a random cross-over design, with each intervention separated by at least three weeks.

The three diets were as follows;

1  High-calorie high-carbohydrate diet containing 80% of energy from carbohydrates, 11% of energy from protein and 9% of energy from fat

2  High-calorie high-fat diet containing 10% of energy from carbohydrates, 12% of energy from protein and 78% of energy from fat

3  Eucaloric control diet containing 62% of energy from carbohydrates, 14% of energy from protein and 24% of energy from fat.

(NOTE:  A eucaloric diet means a daily diet which contains about the same number of calories that are used by the body in a day so that the eater maintains their current weight.)

Results showed that the high-calorie high-carbohydrate diet resulted in an 8-fold increase in the concentration of FGF21 in the blood compared with eating the eucaloric diet.  The high-calorie high-fat diet did not appreciably increase blood FGF21 concentration.  These results occurred without protein restriction.

The conclusion from this study was that eating a diet high in carbohydrates has a remarkable stimulating effect on the secretion of FGF21. In this study neither protein restriction nor calorie excess stimulated increased production and release of FGF21.

  

High Fiber Diets

The short-chain fatty acid, butyrate, is produced in large amounts from fermentation (digestion) of dietary fiber by the healthy gut bugs that are part of the microbiome living in our large intestine.  Studies have illustrated that butyrate increases the production of FGF21 in the liver.  A diet consisting mainly of whole-plant foods is very high in fiber.  There is no fiber at all in animal-sourced foods.  (18)

 

Exercise

A direct relationship between daily physical activity and FGF21 blood levels has also been discovered.  Nothing happens after a single bout of exercise, but two weeks of daily physical activity is associated with significantly increased FGF21.  This results in improvements in the usage of food energy by increasing the action of insulin and improving carbohydrate and lipid metabolism. (19)

A 2019 study compared the effects of 8 weeks of aerobic exercise versus resistance training in males with type-2 diabetes.  The aerobic group completed 30 to 45 minutes of aerobic running training at 65% to 75% of maximum heart rate at each workout.  The resistance group completed three sets of a maximum of 10 repetitions of the leg press, bench press, knee extension, seated cable row, knee flexion, military press and calf rise at each workout.  At the end of the study both groups showed increased FGF21 blood levels with a 42% boost in the resistance group and a 29% FGF21 improvement in the aerobic exercise group.  (20)

 

Starvation and Fasting

Starvation markedly increases the body’s production of FGF21.  However, though fasting can quadruple FGF21 levels, it takes at least a week before any effect is seen and ten days for a major increase.  That’s a long time to go without eating and not recommended for optimal health.   (21,22)

 

Food for thought

The human body is an extremely complicated organism which performs innumerable functions every minute of every day to ensure that we not only stay alive but thrive.  The recent discovery of FGF21 highlights the realization that we are a long way from knowing everything about how our bodies work.  It is feasible that we may never completely comprehend the relationships between our intricate body systems and the multitude of biochemicals, both from within and from outside of our bodies, that interact with them.

What we do understand is that there are simple choices we can make in our lifestyle to provide, as best we can, the elements needed for a long and fulfilling life.  What we choose to eat to provide the calories, macronutrients (carbohydrates, protein and fat), fiber, water, vitamins, minerals and bioactive compounds that our body can employ as raw materials for its biological processes is up to us.

The strongest evidence that we have at this point, with decades of study to back it up, supports the following pillars of good health (23,24);

• Eat a diet consisting of mostly or completely plant-sourced foods
• Enjoy daily moderate exercise
• Get plenty of restful sleep
• Socialize with friends
• Don’t smoke
• Limit alcohol intake
• Manage stress

 

SOURCES:

1  Flippo, K.H., Potthoff, M.J. Metabolic Messengers: FGF21. Nat Metab 3 (2021): 309–317. Doi.org/10.1038/s42255-021-00354-2.

2  Salminen, A., Kaarniranta, K., Kauppinen, A.  Regulation of longevity by FGF21: Interaction between energy metabolism and stress responses.  Ageing Res Rev. 2017 Aug; 37:79-93. Doi:10.1016/j.arr.2017.05.004.

3  Talukdar, S., Zhou, Y., Li, D., et al. A Long-Acting FGF21 Molecule, PF-05231023, Decreases Body Weight and Improves Lipid Profile in Non-human Primates and Type 2 Diabetic Subjects. Cell Metab. 2016;23(3): 427-440.

4  Pérez-Martí, A., Sandoval, V., Marrero, P.F., Haro, D., Relat, J.  Nutritional regulation of fibroblast growth factor 21: from macronutrients to bioactive dietary compounds.  Horm Mol Biol Clin Investig. 2016 Sep 1; 30(1):  Doi: 10.1515/hmbci-2016-0034.

5  Kim, A.M., Somayaji, V.R., Dong, J.Q., et al. Once-weekly administration of a long-acting fibroblast growth factor 21 analogue modulates lipids, bone turnover markers, blood pressure and body weight differently in obese people with hypertriglyceridaemia and in non-human primates. Diabetes Obes Metab. 2017;19(12):1762-72.

6 Shao, W., Jin, T. Hepatic hormone FGF21 and its analogues in clinical trials. Chronic Dis Transl Med. 2022; 8: 19- 25. Doi.org/10.1016/j.cdtm.2021.08.005.

7  Huang, Z., Xu, A., Cheung, B.M.Y.  The Potential Role of Fibroblast Growth Factor 21 in Lipid Metabolism and Hypertension.  Curr Hypertens Rep. 2017. Apr; 19(4): 28. Doi: 10.1007/s11906-017-0730-5.

8  Laeger, T., Henagan, T.M., Albarado, D.C., Redman, L.M., Bray, G.A., Noland, R.C., Münzberg, H., Hutson, S.M., Gettys, T.W., Schwartz, M.W., Morrison, C.D. FGF21 is an endocrine signal of protein restriction. J Clin Invest. 2014 Sep; 124(9): 3913-3922. Doi: 10.1172/JCI74915. Epub 2014 Aug 18. PMID: 25133427; PMCID: PMC4153701.

9  Maida. A,, Zota, A., Sjøberg, K.A., Schumacher, J., Sijmonsma, T.P., Pfenninger, A., Christensen, M.M., Gantert, T., et al.  A liver stress-endocrine nexus promotes metabolic integrity during dietary protein dilution. J Clin Invest. 2016 Sep 1;126(9):3263-78. doi: 10.1172/JCI85946. Epub 2016 Aug 22. PMID: 27548521; PMCID: PMC5004939.

10  McCarty, M.F. The moderate essential amino acid restriction entailed by low-protein vegan diets may promote vascular health by stimulating FGF21 secretion. Horm Mol Biol Clin Investig. 2016 Feb 12; 30(1):/j/hmbci.2017.30.issue-1/hmbci-2015-0056/hmbci-2015-0056.xml. Doi: 10.1515/hmbci-2015-0056.

11  Babygirija, R., Lamming, D.W. The regulation of healthspan and lifespan by dietary amino acids. Transl Med Aging. 2021; 5:17-30. Doi:10.1016/j.tma.2021.05.001

12  https://khni.kerry.com/news/nutrition-for-plant-based-diets-managing-nutrient-intake-and-bioavailability/#_ftn18

13  https://www.healthline.com/nutrition/essential-amino-acids#how-to-take-them

14  https://www.brendadavisrd.com/methionine-restricted-diet/

15  Fontana, L., Cummings, N.E., Arriola Apelo, S.I., Neuman, J.C., Kasza, I., et al.  Decreased Consumption of Branched-Chain Amino Acids Improves Metabolic Health. Cell Rep. 2016 Jul 12; 16(2):520-530. Doi: 10.1016/j.celrep.2016.05.092. Epub 2016 Jun 23. PMID: 27346343; PMCID: PMC4947548.

16  Fontana, L., Cummings, N.E., Arriola Apelo, S.I., Neuman, J.C., Kasza, I., et al.  Decreased Consumption of Branched-Chain Amino Acids Improves Metabolic Health. Cell Rep. 2016 Jul 12; 16(2):520-530. Doi: 10.1016/j.celrep.2016.05.092. Epub 2016 Jun 23. PMID: 27346343; PMCID: PMC4947548.

17  Lundsgaard, A.-M., Fritzen, A.M., Sjøberg, K.A., et al. Circulating FGF21 in humans is potently induced by short term overfeeding of carbohydrates. Mol Metab. 2017;6(1):22-29.

18  Li, H., Gao, Z., Zhang, J., Ye, X., Xu, A., Ye, J., Jia, W. Sodium butyrate stimulates expression of fibroblast growth factor 21 in liver by inhibition of histone deacetylase 3. Diabetes. 2012 Apr; 61(4):797-806. Doi: 10.2337/db11-0846. Epub 2012 Feb 14. PMID: 22338096; PMCID: PMC3314370.

19  Cuevas-Ramos, D., Almeda-Valdés, P., Meza-Arana, C.E., Brito-Córdova, G., Gómez-Pérez, F.J., Mehta, R., Oseguera-Moguel, J., Aguilar-Salinas, C.A. Exercise increases serum fibroblast growth factor 21 (FGF21) levels. PLoS One. 2012;7(5):e38022. Doi: 10.1371/journal.pone.0038022. PMID: 22701542; PMCID: PMC3365112.

20  Keihanian, A., Arazi, H., Kargarfard, M. Effects of aerobic versus resistance training on serum fetuin-A, fetuin-B, and fibroblast growth factor-21 levels in male diabetic patients. Physiol Int. 2019 Mar 1; 106(1): 70-80. Doi: 10.1556/2060.106.2019.01. PMID: 30888221.

21  Fazeli, P.K., Lun, M., Kim, S.M., Bredella, M.A., Wright, S., Zhang, Y., Lee, H., Catana, C., Klibanski, A., Patwari, P., Steinhauser, M.L. FGF21 and the late adaptive response to starvation in humans. J Clin Invest. 2015 Nov 3; 125(12): 4601-4611. Doi: 10.1172/JCI83349. PMID: 26529252; PMCID: PMC4665770.

22  Reitman, M.L. FGF21: a missing link in the biology of fasting. Cell Metab. 2007 Jun;5(6):405-407. Doi: 10.1016/j.cmet.2007.05.010. PMID: 17550773.

23  https://healthybrains.org/pillars/

24 https://thepointretreats.com/blog/four-pillars-of-optimal-health-that-lead-to-a-blue-zone-life/