Do Your Genes Favor Dietary Fat? (FGF21)

The FGF21 (Fibroblast growth factor 21) gene codes for a hormone with complex roles in metabolism, thermoregulation, and food preferences. The liver is the primary source of FGF21, where it regulates fat and glucose metabolism, response to fasting, and more [R, R, R].

More precisely, it increases insulin sensitivity and promotes fatty acid oxidation. Brown fat tissue is another significant source of FGF21, which stimulates energy production and helps the body adapt to cold temperatures [R, R].

Reduced activity of this hormone may play a role in obesity and other metabolic disorders. In preliminary research, FGF21 analogs have shown the potential to improve weight control, blood lipid profile, liver fat content, and glucose metabolism [R, R, R, R].

Variations in the FGF21 gene have been associated with different metabolic parameters, food preference, and response to macronutrients. In this post, we explore the impact of your variants on dietary fat preference and metabolism.

FGF21 is a hormone with complex roles in fat and glucose metabolism, energy balance, and temperature control. Variants in the FGF21 gene correlate with different metabolic traits and food preferences.

Dietary Preference: Fat vs. Carbs

A 2018 study analyzed the data from over 450,000 people and found a significant association between one FGF21 SNP and macronutrient preference.

Carriers of the minor “A” allele at rs838133 consumed less fat and more carbohydrates. Additionally, these subjects had lower body fat but higher waist-hip ratio and blood pressure [R].

Another trial of 38,000 participants confirmed the link between rs838133 and lower fat/higher carb preference [R].

One more SNP in this gene showed a similar trend in a study of 33,500 subjects. People with the minor “G” allele at rs838145 consumed less fat and more carbs [R].

FGF21 variants have shown a robust link with increased preference for sweets and alcohol consumption, and we’ll cover this topic in detail in another post [R, R].

People with the FGF21 variants, such as rs838133-A and rs838145-G, tend to eat less fat and more carbs. They may also have higher blood pressure and waist-hip ratio.

Fat Metabolism and the Keto Diet

As mentioned, FGF21 plays crucial roles in fat metabolism and fasting response. In studies on mice, it boosted fatty acid oxidation and the production of ketone bodies, helping them adapt to the ketogenic diet or starvation [R, R, R].

When placed on the keto diet, mice with removed FGF21 gained weight and suffered from fatty liver and glucose intolerance. They weren’t able to produce enough ketone bodies. The researchers suggested that FGF21 is essential for the metabolic adaptation to the keto diet and extended periods of fasting [R, R].

Since the above variants likely reduce FGF21 function and hinder fat burning, they may not go well with high-fat diets, especially the keto diet [R, R].

However, human studies have been less consistent: some of them found that FGF21 doesn’t drive the production of ketone bodies and may not be among the critical factors for the keto diet metabolic effects [R, R, R].

Additionally, lower FGF21 function may not have the same effects as a complete lack of this hormone, which caused an inadequate response to the keto diet in mice.

According to animal research, the lack of FGF21 causes a poor metabolic response to the keto diet. People with the above variants might face the same issue, but there’s no clinical evidence to support this.

FGF21 and PPAR-alpha

Peroxisome proliferator-activated receptor (PPAR)-alpha is a transcription factor that activates FGF21 and increases its production. These two work hand in hand to boost fat metabolism and insulin sensitivity [R, R].

The interaction between PPAR-a and FGF21 may be essential for metabolic adaptation to fasting and ketosis, but once again, the research in humans is limited [R, R].

Did you know? The lipids from breast milk stimulate the interaction between PPAR-a and FGF21 in infants. According to a group of Japanese researchers, this effect helps create “epigenetic memory that persists into adulthood” with lasting metabolic benefits [R].

SNP Summary and Table

FGF21 rs838133:

• “G” = doesn’t correlate with dietary fat preference and metabolism
• “A” = correlates with lower dietary fat preference and potentially with impaired metabolism

FGF21 rs838145:

• “A” = doesn’t correlate with dietary fat preference and metabolism
• “G” = correlates with lower dietary fat preference and potentially with impaired metabolism

Population Frequency

These two variants are almost always inherited together, meaning they act as a single genetic factor. Among European descendants, 47-48% of the population carry one and 17-18% carry both copies of the “problematic” minor alleles.

Interestingly, their frequencies in African populations don’t match at all: around 46% of people carry a minor allele at rs838133 and only around 3% at rs838145.