What Diet Increases FGF21 Levels? A Deep Dive into Dietary Triggers

January 11, 2026 •

4 min read

Studies have shown that fibroblast growth factor 21 (FGF21) is a hormone released by the liver in response to specific nutritional challenges. While the effects of a low-protein diet in increasing circulating FGF21 levels are widely noted in animal models and translated to humans, other macronutrient shifts and dietary patterns also play a significant role.

Quick Summary

This article explores the specific dietary interventions that can stimulate FGF21 production, focusing on low protein intake, carbohydrate levels, fasting, and methionine restriction. We examine how different macronutrient ratios influence this metabolic hormone and review supporting evidence from human and animal studies.

Key Points

Protein Restriction Is Key: A diet low in protein, and especially low in the amino acid methionine, is the most robust dietary method for increasing FGF21 levels in humans.
High Carbohydrates Amplify the Effect: The greatest increases in FGF21 are typically seen when a low-protein diet is combined with high carbohydrate intake, creating a specific macronutrient imbalance.
Fasting Requires Long Durations: In humans, significant FGF21 elevation through fasting requires a prolonged period (e.g., over a week), unlike in rodents where shorter fasts are effective.
Ketogenic Diets are Inconsistent: Unlike in animal models, ketogenic diets have shown inconsistent or no effect on increasing FGF21 in human trials.
High Fat has Limited Impact: Excess dietary fat does not act as a strong inducer of FGF21, especially when compared to protein restriction or excess carbohydrates.
FGF21 Responds to Macronutrient Imbalance: The surge in FGF21 is fundamentally a hormonal response to signal a perceived nutritional challenge, prompting metabolic adaptations.

The Dominant Effect of Protein Restriction

One of the most potent and consistently observed dietary triggers for increasing circulating FGF21 is the restriction of protein and/or specific amino acids. FGF21 acts as a signal of macronutrient imbalance, particularly when protein intake is low relative to other nutrients.

Low-Protein Diets

Research has clearly established that reducing dietary protein content significantly boosts FGF21 levels. This response is considered an evolutionary adaptation to promote survival and metabolic health under conditions of protein scarcity.

In human studies, significantly restricting protein intake has led to marked increases in plasma FGF21 concentrations over several days.
Mice fed a low-protein, high-carbohydrate diet show the most potent FGF21 induction, with protein intake being the primary driver.

Methionine and Amino Acid Restriction

Dietary methionine restriction, often a result of overall protein restriction, is a particularly strong activator of hepatic FGF21.

Studies have shown that methionine restriction produces a rapid and sustained increase in FGF21, which plays a central role in the resulting metabolic benefits.
The effect is so pronounced that even small amounts of added methionine to a methionine-restricted diet can reverse the metabolic effects and diminish the increase in FGF21.

The Role of Carbohydrates

While protein restriction is a primary driver, the interplay with carbohydrates is also important. The highest FGF21 levels are often seen with a combination of low protein and high carbohydrate intake.

Excess Carbohydrates

In humans, short-term overfeeding with a high-carbohydrate diet has been shown to potently increase FGF21, independent of protein restriction. This suggests that FGF21 can be part of the metabolic response to process a large carbohydrate load.

This effect is primarily driven by simple sugars like fructose and glucose, which are potent, albeit transient, inducers of FGF21 secretion.
Excessive carbohydrate intake activates a transcription factor called ChREBP in the liver, which drives FGF21 expression.

Low-Protein, High-Carbohydrate (LPHC) Synergy

The combination of low protein and high carbohydrate intake appears to provide the maximum stimulus for FGF21 production. This creates a unique macronutrient imbalance that the body signals via FGF21 to regulate metabolism and energy expenditure.

Fasting, Ketogenic Diets, and Fats

The impact of fasting, ketogenic diets, and fat consumption on FGF21 is more complex and shows differences between human and animal studies.

Prolonged Fasting and Intermittent Fasting

In humans, prolonged fasting (e.g., 7–10 days) is needed to induce significant increases in FGF21, unlike in mice where shorter fasting periods are effective. The effect of intermittent fasting on FGF21 is mixed and seems to depend on the specific protocol and metabolic context. Some studies show a decrease in FGF21 with intermittent fasting, particularly in relation to liver steatosis.

Ketogenic Diets

Despite increasing FGF21 in rodents, ketogenic diets do not reliably increase FGF21 levels in humans. The induction seen in animal studies is often attributed to the diet's low protein content, not the high fat or low carbohydrate content directly.

High Fat Diets

Research indicates that excess fat intake alone does not induce a significant increase in FGF21 in humans, especially when compared to excess carbohydrate intake. While pharmacological activation of fat-sensing receptors can increase FGF21, dietary fat itself is not a potent trigger in humans.

Dietary Strategies to Increase FGF21

Based on current research, here are practical dietary approaches for those seeking to elevate their FGF21 levels:

Prioritize Low Protein Intake: A diet with a low protein-to-carbohydrate ratio is the most potent and reliable method to boost FGF21.
Incorporate Complex Carbohydrates: Use whole grains, starches, and other complex carbohydrates as the primary energy source to drive the low-protein, high-carbohydrate effect.
Consider Methionine Restriction: For those able to manage it, consciously restricting methionine-rich foods (e.g., meat, eggs, fish) is a highly effective way to increase FGF21.

Comparison of FGF21-Influencing Diets


Dietary Intervention	Effect on FGF21 (Humans)	Key Mechanism	Supporting Evidence
Low-Protein Diet	Potent, sustained increase	Amino acid sensing pathway (ATF4 activation)	Consistent across multiple studies
High-Carbohydrate Overfeeding	Significant, though sometimes transient, increase	Carbohydrate-sensing pathway (ChREBP activation)	Short-term overfeeding studies in humans
Ketogenic Diet	Inconsistent or no significant increase	Indirectly via protein restriction in animals; unclear in humans	Conflicting human clinical trial data
High-Fat Overfeeding	Minor or no significant increase	Less potent signal compared to carbohydrates or protein restriction	Short-term overfeeding studies show minimal effect
Prolonged Fasting	Increase after 7+ days	Activates PPARα in the liver during starvation	Requires a lengthy fasting period in humans
Intermittent Fasting	Variable, potential decrease in some contexts	Context-dependent; can decrease FGF21 in relation to liver steatosis	Depends on protocol and individual response

Conclusion

To increase FGF21 levels through diet, the most effective strategy involves reducing protein intake, particularly by restricting methionine and other essential amino acids. This effect is maximized when combined with a higher carbohydrate intake. While prolonged fasting can also trigger a rise in FGF21, the duration required in humans makes it a less practical method for chronic modulation. The impact of ketogenic or high-fat diets on human FGF21 levels is less reliable. Ultimately, focusing on a low-protein, high-carbohydrate dietary pattern appears to be the most dependable nutritional approach for upregulating FGF21, mimicking a state of macronutrient imbalance that prompts the body's protective metabolic response.

For more in-depth information on the physiological roles of FGF21 and its effects on longevity and metabolism, consult resources like the detailed review on the Frontiers in Endocrinology website.(https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2021.773975/full)

Frequently Asked Questions

A normal, balanced diet is less likely to significantly raise FGF21. The most potent increases occur under conditions of macronutrient stress, particularly with a low protein and/or high carbohydrate dietary pattern.

The effects of intermittent fasting on FGF21 are variable and complex. While prolonged fasting can increase FGF21 after about a week in humans, standard intermittent fasting protocols have shown less consistent effects and can even decrease FGF21 in some contexts, such as with liver disease.

Nutritionally triggered increases in FGF21 are a normal physiological response. However, adopting extreme diets like severe protein restriction requires medical guidance, as it could lead to nutritional deficiencies if not managed properly.

FGF21 is a metabolic hormone involved in glucose and lipid metabolism, energy expenditure, and insulin sensitivity. Some researchers believe increasing it could offer therapeutic benefits, but the effects of dietary increases vs. pharmacological administration differ and require further study.

Excess fat consumption alone is a relatively weak trigger for FGF21 elevation in humans compared to protein restriction or high carbohydrate intake. While ketogenic diets can increase FGF21 in mice, this is not consistently observed in humans.

In studies involving human FGF21, simple sugars like fructose and glucose have been shown to induce FGF21 acutely. However, high carbohydrate diets are also effective, especially when protein intake is low.

Yes. A diet focused on lower protein foods, such as starches, vegetables, and complex carbohydrates, while limiting methionine-rich foods like meat and eggs, would be a targeted approach. This should always be done under the supervision of a healthcare provider.