What is fetuin-A?

Fetuin-A is a protein secreted by liver and fat (adipose) tissue that acts to worsen our control of blood sugar levels and promote fat accumulation.

Elevated levels of fetuin-A (also known as alpha-2 Heremans-Schmid glycoprotein (AHSG)) have been linked to obesity, Type II diabetes, non-alcoholic fatty liver disease (NAFLD), and metabolic syndrome.

What is the link between fetuin-A levels and body composition?

Several studies have found a positive association between fetuin-A levels and amount of body fat. Put in simple terms, the higher fetuin-A levels someone has, the higher amount of body fat they seem to carry.

For example, in studies comparing obese and normal-weight subjects, circulating fetuin-A levels are shown to be significantly higher in obese subjects, with fetuin-A level positvely correlated with BMI.

Source: Ismail, N. A., Ragab, S., Abd El Dayem, S. M., Abd ElBaky, A., Salah, N., Hamed, M., ... & Koura, H. (2012). Fetuin-A levels in obesity: differences in relation to metabolic syndrome and correlation with clinical and laboratory variables. Archives of Medical Science, 8(5), 826-833.

Of course, BMI is only a crude measure of body composition, but other studies using CT (computed tomography) scans have linked higher fetuin-A levels with greater amounts of visceral fat tissue - the type of fat that sits around internal organs. As we’ve described before, visceral fat is metabolically active and shown to worsen insulin sensitivity and promote inflammation.

A question worth asking here is whether higher fetuin-A levels are simply a marker or correlate of greater amounts of fat tissue, or whether fetuin-A drives fat accumulation. This question has been addressed by one study which used a technique known was bidirectional Mendelian randomisation. This tries to assess whether one factor (e.g. fetuin-A level) is a cause or consequence of another factor (e.g. BMI, body fat levels), or whether there is a bidirectional causal relationship between them. The study concluded that high circulating fetuin-A levels were a cause of high BMI, but that the reverse relationship (i.e. high BMI causing high fetuin-A levels) was not true.

When we look at how fetuin-A acts in the body, there are several plausible mechanisms by which high fetuin-A levels can promote accumulation of (visceral) fat tissue. We’ll look at this in the next section.

How does fetuin-A promote fat accumulation?

There are several related mechanisms by which fetuin-A may promote the accumulation of fat (particularly visceral fat) tissue. These include:

• fetuin-A worsens insulin sensitivity
• fetuin-A promotes chronic inflammation
• fetuin-A alters fat metabolism by fat cells
• fetuin-A reduces the production of adiponectin

Let’s take a look at these mechanisms individually.

- Poorer insulin sensitivity

Insulin is a hormone that allows tissues to take up and use glucose from our bloodstream. It also has a number of other effects on fat and carbohydrate metabolism. (You can read more about insulin and its effects in the body in the Fasting Blood Glucose trait article.)

As described in the aforementioned article, insulin exerts its effects in the body binding to a specialised receptor on the surface of cells: the insulin receptor. In particular, when insulin binds to a particular part of the insulin receptor, the alpha subunit, it triggers a signaling cascade that leads to the movement of specialised glucose transporter proteins (GLUTs) into the surface membrane of cells. These transport proteins then allow glucose to move from the bloodstream to the interior of cells.

As illustrated in the diagram below, fetuin-A released by fat cells also binds to the alpha subunit of the insulin receptor. In doing so, it prevents insulin from effectively binding to the insulin receptor and triggering a signalling cascade.

Source: Ward, K., Mulder, E., Frings-Meuthen, P., O’Gorman, D. J., & Cooper, D. (2020). Fetuin-A as a potential biomarker of metabolic variability following 60 days of bed rest. Frontiers in physiology, 11, 573581.

By disrupting insulin receptor signalling, fetuin A acts to reduce the sensitivity of tissues (such as liver, skeletal muscle, and fat cells) to insulin. As a result of this poorer insulin sensitivity, it is harder for tissues to take up glucose from the bloodstream. This leads to high blood glucose levels (hyperglycaemia), which the body tries to compensate for by releasing abnormally high levels of insulin (hyperinsulinaemia).

The combination of elevated blood glucose and insulin levels promotes the conversion of glucose into fat, which is stored in fat tissue, including visceral fat. In this way, high fetuin-A levels promote the accumulation of fat.  

- Promotion of chronic inflammation

Fetuin-A is also shown to stimulate the release of pro-inflammatory cytokines: signaling molecules that promote inflammation. Chronic, low-grade inflammation within fat tissue is widely acknowledged to worsen insulin sensitivity, which, as discussed above, can lead to fat deposition.

- Altered fat metabolism

Fetuin-A may also alter the build-up and breakdown of fat stores in fat cells (adipocytes).

Lipolysis is the process of breaking down stored fat (in the form of triglycerides) into free fatty acids that circulate in the bloodstream. While this may intuitively seem like a good thing in terms of weight loss, increased lipolysis may actually cause weight gain. Free fatty acids circulating in the bloodstream can trigger low-grade inflammation, causing poorer insulin sensitivity (insulin resistance), which promotes the accumulation of fat.

On this note, basal lipolysis is shown to be elevated in obese people, whereas lipolysis in response to adrenaline release (such as during exercise) is reduced.

By increasing basal lipolysis and impairing hormone-induced lipolysis, fetuin-A may act to promote fat accumulation.

- Lower adiponectin production

Adiponectin is a hormone released by fat cells that acts to enhance tissues’ sensitivity to insulin. Fetuin-A is shown to inhibit the secretion of adiponectin, thereby worsening insulin sensitivity. Poorer insulin sensitivity, in turn, can promote fat accumulation.

What is the AHSG gene?

Fetuin-A, which is also known as AHSG (alpha-2 Heremans Schmidt glycoprotein), is coded for by your AHSG gene.

Variants of the AHSG gene can affect production of the fetuin-A protein, leading to changes in circulating fetuin-A levels. This, in turn, can have a small effect on how readily you accumulate fat tissue.

How do AHSG gene variants affect fetuin-A levels?

The Met (rs4917) variant of the AHSG gene has been associated with lower circulating fetuin-A levels.

This variant is created by a SNP (Single Nucleotide Polymorphism) in the AHSG gene, designated rs4917, which causes a C>T change in the DNA code, resulting in a change from the amino acid threonine (Thr) to methionine (Met) in the AHSG protein.

The rs4917 SNP therefore gives rise to two corresponding AHSG gene variants or alleles:

• Thr (C) allele
• Met (T) allele

A 2017 meta-analysis which looked at the AHSG genotypes of 9,055 subjects of European descent and 2,199 African Americans found that those who carried the Met (T) allele had significantly lower fetuin-A levels.  

Source: Jensen, M. K., Jensen, R. A., Mukamal, K. J., Guo, X., Yao, J., Sun, Q., ... & Ix, J. H. (2017). Detection of genetic loci associated with plasma fetuin-A: a meta-analysis of genome-wide association studies from the CHARGE Consortium. Human molecular genetics, 26(11), 2156-2163.

As shown in the table above (focussing on the combined beta coefficients), in European subjects, each additional copy of the Met (T) allele was associated with a 0.0657 +/- 0.0018 g/L lower fetuin-A level. For African Americans, the corresponding figure was 0.0413 +/- 0.0034 g/L lower fetuin-A levels.

To put these figures in context, the mean fetuin-A levels in the analysed studies were around 0.50 g/L. Moreover, the rs4917 AHSG SNP explained 13% and 14% of the variance in fetuin-A levels in African Americans and Europeans, respectively.

Given that fetuin-A levels are positively associated with amounts of body fat, it is possible that lower fetuin-A levels in Met (T) allele carriers would be linked to lower amounts of fat. We’ll discuss the relationship between AHSG variants and body composition in the following section.

How do AHSG gene variants affect body composition?

Some studies suggest that people with the Met (T) allele have a healthier body composition, with less body fat, although the findings are mixed.

In one study of Swedish men, researchers divided subjcts into two groups: an obese group (with a BMI >/= 25 kg/m2) and a lean group (with a BMI < 25 kg/m2). The researchers then compared the AHSG genotypes of both groups to see if one genotype was overrepresented in either group. The study found that, relative to the Thr/Thr (CC) genotype, those with the Met/Met (TT) genotype had a 1.74 higher odds of being in the lean group.

Despite this apparent association with leanness, other studies have not found a link between AHSG genotype and body composition. For example, a magnetic resonance imaging (MRI) study found that AHSG genotype did not affect regional fat distribution.

Why do AHSG gene variants affect body composition?

AHSG variants are likely to influence body composition by affecting circulating levels of fetuin-A, which in turn impacts upon insulin sensitivity and fat metabolism.

On this note, a study of 7,638 White Danish subjects found that those with the Met (T) allele had better insulin sensitivity. This improved insulin sensitivity is likely to be protective against fat accumulation.

Source: Lavebratt, C., Dungner, E., & Hoffstedt, J. (2005). Polymorphism of the AHSG gene is associated with increased adipocyte β2-adrenoceptor function. Journal of lipid research, 46(10), 2278-2281.

Another study on fat tissue biopsies found that the fat cells of those with the Met/Met (TT) genotype are more sensitive to terbutaline - a drug similar to adrenaline that stimulates B2 adrenergic receptors.

As can be shown in the graph above, the rate of lipolysis (i.e. the breakdown of stored fat into fatty acids) was much (35 times) higher in those with the Met/Met (TT) genotype compared to those with the Met/Thr and Thr/Thr genotypes.

More research is needed, but this would tentatively suggest that people with the Met/Met (TT) genotype can more readily burn fat in response to stimulation from adrenaline (such as during exercise). This would help prevent fat accumulation.

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