Skip to content

FGF21

Also called: Fibroblast growth factor 21

Written by Reviewed Sep 2026

A hormone from the liver. In mice, it is the signal of fasting. In people, it mostly responds to how little protein you ate, not how few calories, and a two-day fast does not move it at all.

What it is

FGF21 is an odd member of a family of growth factors. Most of its relatives carry a sticky part that keeps them close to the cell that made them, so they only act nearby. FGF21 lacks that sticky part. It drifts off into the blood and acts as a hormone. It is made mainly by the liver, and also by fat, muscle and the pancreas.

It only works on tissues that carry a helper protein called beta-Klotho. FGF21 needs that helper to link up with its receptors. A tissue without beta-Klotho does not respond to FGF21 at any level. Beta-Klotho is found in fat, the liver, the pancreas and the brain. That includes the parts of the brain that shape what an animal chooses to eat.

Across species, FGF21 is credited with a long list of effects. In the liver, it drives more fat burning and ketone making. In fat, it drives more sugar uptake and more release of a fat hormone called adiponectin. It is linked to more energy burned, white fat turning "brown", and a better insulin response. It also cuts cravings for sweet things and alcohol, and raises appetite for protein.

This is the biggest gap between people and rodents anywhere in fasting science. That gap is the reason this page exists.

How it works

In rodents, FGF21 was found to be switched on in the liver by PPAR alpha. PPAR alpha is a gene switch, turned on by fat, that runs the liver's fasting program, including the key ketone-making enzyme. That puts FGF21 right inside the ketone response, and it is why rodent research treats it as the hormone of fasting.

In people, the main input is different. A two day fast did nothing to FGF21 in the blood. A ketogenic diet did nothing. Seven days of fasting raised it 74%. Meanwhile, a single-meal test showed protein shutting the FGF21 response down. A sugar drink caused a clear rise. Adding protein to the same sugar drink wiped the rise out. Adding fat did not clearly change it.

So in a person, FGF21 follows the balance of sugar to protein in what was eaten, more than it follows a calorie shortfall. The authors of the meal study read it as a signal that pushes the body toward a balanced diet with enough protein. That fits with its effect of making people want protein. It is a different job from being the hormone of running out of energy.

What switches it on

In people: eating a lot of sugar compared with protein, and long fasting at seven days, but not at two. In rodents: the liver's fasting and ketone program, through PPAR alpha. The drug fenofibrate, which switches on PPAR alpha, raises it in people too.

On the timing
In people, FGF21 rises much later than almost anyone thinks, and this was measured directly. Ketosis from a two day fast did not change FGF21 levels. Neither did a ketogenic diet. A 74% rise came only after seven days of fasting. Any claim that a 16 or 24 hour fast raises FGF21 in people is not backed by that study. It is the key fasting study on this hormone in people.

What has been measured

In people

FGF21 is in the blood, so it is easy to measure in people. There are fasting studies, and there are also studies of lab-made versions of FGF21, tested against a dummy drug in patients. The picture is consistent. The effects on blood fats and the liver show up in people. The blood-sugar-lowering effect that made FGF21 famous in rodents mostly does not.

  • The biggest study: 128 patients with a serious fatty liver disease (steatohepatitis) and moderate to advanced liver scarring. They got a dummy drug, or efruxifermin, a lab-made FGF21, at 28 mg or 50 mg a week. Liver samples were taken at the start and at week 24. Scarring improved by at least one stage, without getting worse, in 8 of 41 people on the dummy drug (20%). It improved in 15 of 38 on 28 mg (39%) and 14 of 34 on 50 mg (41%). This is a real positive result, in sick people, measured in the liver itself (The Lancet Gastroenterology and Hepatology, 2023).
  • The key fasting study in people, and its findings are often misreported. Blood FGF21 varied 250-fold across 76 healthy people. It had no link to age, sex, BMI, blood fats or blood sugar. With that much spread between people, group averages hide huge differences from person to person. FGF21 did not change with the time of day. Ketosis from a two day fast did not change FGF21 levels, and neither did a ketogenic diet. A 74% rise came only after seven days of fasting. Patients without diabetes who had high triglycerides had twice the normal FGF21. The drug fenofibrate raised it a further 28%. The authors conclude plainly that FGF21 may do a different job in people than in mice (Cell Metabolism, 2008).
  • 75 patients with a serious fatty liver disease (steatohepatitis), confirmed by liver sample, with mild to advanced scarring and at least 10% liver fat on MRI. They got a dummy drug, or pegbelfermin, a lab-made FGF21, at 10 mg daily or 20 mg weekly, for 16 weeks. The study's two main measures were safety and the change in liver fat (The Lancet, 2019).
  • 20 volunteers had their energy burn measured in a sealed room during a 24 hour fast. How much their energy burn fell varied from person to person. It went along with how their bodies responded to mild cold, and with changes in FGF21. The exact percentage drop is not in the paper's summary, so it is not quoted here (Diabetes, 2020).
  • The first test of a lab-made FGF21 (LY2405319) in people with obesity and type 2 diabetes, over 28 days, against a dummy drug, at 3, 10 or 20 mg daily. Blood fats clearly improved. LDL cholesterol and triglycerides fell, HDL rose, and the fat-carrying proteins shifted to a less artery-clogging pattern. Body weight, fasting insulin and adiponectin also moved the right way. Blood sugar only showed a trend toward lower. This is the key result, and it is often left out. In people, the effects on blood fats, weight and adiponectin carried over. The sugar-lowering effect mostly did not (Cell Metabolism, 2013).
  • Protein wipes out the response within a single meal. Healthy volunteers each tried three drinks with the same amount of sugar: sugar alone, sugar plus protein, and sugar plus fat. Sugar alone raised FGF21 clearly. Adding protein wiped out the rise completely. Adding fat did not clearly change it. Blood sugar control did not explain the effect. Protein beats sugar in controlling FGF21 (American Journal of Physiology: Endocrinology and Metabolism, 2023).

In animals and in cells in a dish

The idea of FGF21 as the hormone of the fasting, ketone-making liver was set up in mice. So was its role in muscle. Those findings are solid in mice. They are also where the claims about people came from that did not hold up.

  • In mouse liver: FGF21 was found to be switched on by PPAR alpha, and to be a key driver of how the liver handles fat during ketosis. That held in fasting mice and in mice on a ketogenic diet (Cell Metabolism, 2007).
  • In mouse muscle: mice bred without FGF21 in their muscle were studied fed and fasted. FGF21 controlled mitophagy and muscle mass. FGF21 is very low in normal, healthy mouse muscle. But fasting, cell stress, mitochondrial muscle diseases and metabolic disorders switch it on. The same study made mouse muscle produce extra FGF21, to test whether FGF21 alone makes muscle waste away (Journal of Cachexia, Sarcopenia and Muscle, 2019).
  • In diabetic monkeys, work on FGF21 and blood sugar is often cited as the bridge that led to the diabetes studies in people. The paper ID found in the research behind this page did not pass the two-source check, so it is not cited here.

Why it matters

FGF21 is the clearest case on this site of something truly well proven in one species and truly different in another. The difference was measured, not assumed. In a mouse, FGF21 is the hormone of fasting. It is driven by the liver's ketone program, and it lowers blood sugar strongly. In a person, a two day fast does not move it, and a ketogenic diet does not move it. Seven days moves it 74%. A single meal with protein shuts down the rise that sugar alone causes.

The studies of lab-made FGF21 finish the picture from the other side. Giving people lab-made FGF21 reliably improves blood fats and liver fat. In the strongest study, it also improved liver scarring seen under the microscope. It does not reliably lower blood sugar in people the way it does in rodents. Drug development has followed the evidence in people into fatty liver disease, which is where that evidence actually points.

Hold both halves. FGF21 does something real in people. What it does is not what the fasting research in rodents predicted.

A claim you will see repeated

The claim that intermittent fasting raises FGF21, or that a 16 to 24 hour fast does, is not backed by the study in people that tested it. Two days of fasting caused no change. Neither did a ketogenic diet. Seven days caused a 74% rise, in a study where the hormone already varied 250-fold between people. The deeper mistake is the label. Calling FGF21 a fasting hormone brings in the whole rodent story. In people, the main thing that moves it is protein compared with sugar, not a calorie shortfall. That makes it a signal about what was eaten, not about not eating.

Sources

  1. Study in people2008
    The circulating metabolic regulator FGF21 is induced by prolonged fasting and PPARalpha activation in man

    Cell Metabolism

    Among 76 healthy people, FGF21 levels in the blood varied 250-fold and did not follow age, sex, BMI, blood fats or blood sugar. A 2 day fast did not change FGF21, and neither did a keto diet. Levels rose 74% only after 7 days of fasting. People with high blood fats had twice the normal level, and the drug fenofibrate raised it 28% more. The authors say FGF21 may work differently in people than in mice.

    Serum FGF21 varied 250-fold among 76 healthy individuals and did not relate to age, sex, BMI, serum lipids or plasma glucose, and showed no diurnal variation. Ketosis induced by a 2 day fast did not influence FGF21 levels, and neither did a ketogenic diet. A 74% increase occurred only after 7 days of fasting. Hypertriglyceridaemic non-diabetic patients had 2-fold elevated FGF21, further increased 28% by fenofibrate. The authors conclude the physiological role of FGF21 in humans may differ from that in mice.

  2. Study in people2023
    Meal sugar-protein balance determines postprandial FGF21 response in humans

    American Journal of Physiology: Endocrinology and Metabolism

    Healthy volunteers ate test meals with the same amount of table sugar. Sugar alone raised FGF21 after the meal. Adding protein wiped out that rise. Adding fat did not clearly change it. Blood sugar control did not explain this. Protein matters more than sugar for FGF21.

    Randomised double-blinded crossover meal study in healthy volunteers with sucrose content matched across arms. Sucrose alone gave an incremental area under the curve of 484 plus or minus 127 pg/mL times hour; adding protein gave minus 35 plus or minus 49, P < 0.001; adding fat gave 319 plus or minus 102, not significant versus sucrose. No evidence that glycaemic regulators explained the effect. Protein outweighs sugar in FGF21 regulation.

  3. Study in people2020
    Metabolic Responses to 24-Hour Fasting and Mild Cold Exposure in Overweight Individuals Are Correlated and Accompanied by Changes in FGF21 Concentration

    Diabetes

    20 overweight volunteers fasted 24 hours in a sealed room that measures energy use. Energy burned went down, by different amounts in different people. People whose energy use changed more also responded more to mild cold, and this tracked with changes in FGF21. The summary does not give the exact drop.

    24 hour energy expenditure measured by whole-room calorimetry during 24 hour fasting in 20 volunteers, with a decrease whose magnitude varied between individuals and correlated with the thermogenic response to mild cold and with changes in FGF21. The exact percentage decrease is not stated in the abstract.

  4. Study in people2013
    The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes

    Cell Metabolism

    Obese people with type 2 diabetes took a dummy dose or 3, 10 or 20 mg a day of LY2405319, a man-made FGF21, for 28 days. Blood fats improved: LDL and triglycerides fell and HDL rose. Weight, fasting insulin and adiponectin moved in a good direction. Blood sugar only leaned toward going down, without a clear drop.

    Randomised, placebo controlled, double blind trial of placebo or 3, 10 or 20 mg LY2405319 daily for 28 days in obese subjects with type 2 diabetes. Significant improvements in dyslipidaemia with decreased LDL cholesterol and triglycerides, increased HDL, and a less atherogenic apolipoprotein profile, plus favourable effects on body weight, fasting insulin and adiponectin. Only a trend toward glucose lowering.

  5. Study in people2019
    Pegbelfermin (BMS-986036), a PEGylated fibroblast growth factor 21 analogue, in patients with non-alcoholic steatohepatitis: a randomised, double-blind, placebo-controlled, phase 2a trial

    The Lancet

    75 people with fatty liver disease with inflammation (NASH), confirmed by liver sample, with stage 1 to 3 scarring and at least 10% liver fat, got a dummy dose, pegbelfermin 10 mg daily, or 20 mg weekly for 16 weeks. The main questions were safety and how much liver fat changed. This entry does not give the results.

    75 patients with biopsy confirmed non-alcoholic steatohepatitis, fibrosis stage 1 to 3 and at least 10% hepatic fat fraction by MRI-PDFF, randomised to placebo, 10 mg daily or 20 mg weekly for 16 weeks. Co-primary outcomes were safety and absolute change in hepatic fat fraction.

  6. Study in people2023
    Safety and efficacy of once-weekly efruxifermin versus placebo in non-alcoholic steatohepatitis (HARMONY): a multicentre, randomised, double-blind, placebo-controlled, phase 2b trial

    The Lancet Gastroenterology and Hepatology

    128 people with fatty liver disease with inflammation and stage 2 or 3 scarring got a dummy dose or efruxifermin 28 mg or 50 mg weekly. Liver samples were taken at the start and at week 24. Scarring improved by at least one stage, without the disease getting worse, in 20% on the dummy dose, 39% on 28 mg and 41% on 50 mg.

    128 patients with biopsy confirmed steatohepatitis and stage F2 or F3 fibrosis, randomised to placebo or efruxifermin 28 mg or 50 mg weekly, paired biopsies at baseline and week 24. Fibrosis improved by at least one stage with no worsening of steatohepatitis in 8 of 41 on placebo (20%), 15 of 38 on 28 mg (39%, risk ratio 2.3, 95% CI 1.1 to 4.8, P = 0.025), and 14 of 34 on 50 mg (41%).

  7. Animal study2007
    Hepatic fibroblast growth factor 21 is regulated by PPARalpha and is a key mediator of hepatic lipid metabolism in ketotic states

    Cell Metabolism

    In mice. In the liver, FGF21 is switched on by PPAR alpha. It is a key driver of how the liver handles fat during ketosis, such as when fasting or on a keto diet. This is where FGF21 got its name as the fasting hormone.

    Mouse liver. FGF21 identified as a PPAR alpha regulated gene and a key mediator of hepatic lipid metabolism in ketotic states, including the fasted and ketogenic-diet-fed states. This is the origin of the description of FGF21 as the hormone of fasting.

  8. Animal study2019
    Fibroblast growth factor 21 controls mitophagy and muscle mass

    Journal of Cachexia, Sarcopenia and Muscle

    In mice. Normal healthy mouse muscle makes very little FGF21. Fasting, cell stress, power-plant muscle diseases and metabolic problems switch it on and release it. Mice missing muscle FGF21, and mice making extra, showed that it controls power-plant cleanup and muscle size.

    Muscle-specific FGF21 knockout mice studied fed and fasted, plus in vivo overexpression of FGF21 in mouse skeletal muscle. FGF21 expression is very low in normal healthy mouse muscle but is induced and released by fasting, endoplasmic reticulum stress, mitochondrial myopathies and metabolic disorders, and it controls mitophagy and muscle mass.