What is PC1/3?

PC1/3 is short for prohormone convertase 1/3.

It is an enzyme which belongs to a class known as prohormone convertases. This class of enzymes are responsible for producing and activating various hormones from their precursor molecules.

PC1/3, in particular, plays a key role in the production of hormones and neuropeptides (signalling proteins that change the activity of neurons) in the brain.

Many of these hormones and neuropeptides linked to PC1/3 regulate our eating behaviour, largely by changing the activity of brain circuits that control appetite, food intake, and energy balance.

KEY POINTS

• PC1/3 is an enzyme that helps to make hormones and other signalling molecules.
• Many of the hormones made by PC1/3 are involved in the control of eating behaviour and energy balance.

How is PC1/3 involved in the control of eating behaviour?

When it comes to brain regions that regulate eating behaviour, one of the most important areas is the hypothalamus. It is a small structure, deep in the centre of the brain, that plays a role in homeostasis – maintaining a stable internal environment within the body.

As well as maintaining stable body temperature, blood pressure, fluid and electrolyte balance, the hypothalamus also regulates our energy balance i.e. how much energy we take in via food, and how much energy we use for metabolic processes or store (e.g. as fat).

In particular, a part of the hypothalamus called the arcuate nucleus (ARC) contains two distinct populations of neurons that either stimulate or suppress food-intake:

• POMC neurons – which suppress appetite
• AgRP/NPY neurons – which stimulate appetite

When POMC neurons in the hypothalamus are stimulated, they produce an appetite-suppressing or “anorexigenic” hormone called α-MSH (alpha-melanocyte stimulating hormone).

α-MSH then binds to specialised receptors (called MC4R) on the surface of neurons in another part of the hypothalamus, the paraventricular nucleus (PVN). When α-MSH activates these PVN neurons, they act on wider brain circuits to reduce food intake and effect metabolic changes that increase energy expenditure.

Source: Ramos-Molina, B., Martin, M. G., & Lindberg, I. (2016). PCSK1 variants and human obesity. Progress in molecular biology and translational science, 140, 47-74.

AgRP and NPY also bind to MC4R receptors on neurons in the paraventricular nucleus (PVN). However, in contrast to α-MSH, they inhibit activity in PVN neurons. This ultimately leads to the stimulation of appetite and the reduction of energy expenditure.

Aside from α-MSH, NPY and AgRP, other hormones / signalling molecules can also influence the activity of hypothalamic circuits that regulate food intake. For example, CART (cocaine- and amphetamine regulated transcript) acts to suppress food intake in a similar fashion to α-MSH.

But how does PC1/3 fit into this picture?

PC1/3 is required to make α-MSH, NPY, AgRP, and CART from their respective precursor molecules.

Both POMC and AgRP/NPY neurons in the hypothalamus express the PC1/3 enzyme, which allows them to make appetite-suppressing and appetite-stimulating hormones, respectively.

Studies in mice have highlighted the importance of PC1/3 in the control of eating behaviour. Mice that are genetically engineered to be deficient in the PC1/3 enzyme show reduced levels of α-MSH in their hypothalamus. Due to the lack of appetite-suppressing activity by α-MSH, these mice eat significantly more food and become obese.

Reduced PC1/3 enzyme activity has also been linked to obesity in humans. As we’ll describe in following sections, extremely rare mutations of the PCSK1 gene can cause total or near-total loss of PC1/3 enzyme activity. This, in turn, causes a childhood obesity syndrome characterised by extreme appetite (a phenomenon known as ‘hyperphagia’).

KEY POINTS

• The hypothalamus is a central part of the brain that contains circuits that regulate food intake and appetite.
• PC1/3 helps to make hormones and neuropeptides (nerve signalling molecules) that act on these hypothalamic circuits and thereby regulate food intake.
• Changes in the activity of PC1/3 may influence food intake and risk of obesity.

What is PCSK1?

The PC1/3 (prohormone convertase 1/3) enzyme is coded for by the PCSK1 gene.

Mutations within this gene give rise to different PCSK1 gene variants, which can affect the activity of the PC1/3 enzyme and have an impact on eating behaviour and risk of obesity.

KEY POINTS

• The PCSK1 gene codes for the PC1/3 enzyme.
• PCSK1 gene variants can influence eating behaviour and obesity risk.

How do PCSK1 gene mutations affect PC1/3 activity?

There are several different mutations within the PCSK1 gene that can alter the activity of the PC1/3 enzyme. Some of these mutations are rare, whereas others are more common.

- Rare mutations

Some extremely rare mutations can cause a condition known as ‘PCSK1 deficiency’. These mutations (e.g. c.1095 + 1G>A, illustrated in the diagram below) cause inactivation of the PCSK1 gene and, consequently, a total or near-total loss of PC1/3 enzyme activity.

Infants born with PCSK1 deficiency develop severe diarrhoea and malabsorption because they cannot produce active PC1/3 enzyme, which is used to make gut hormones that support absorption of nutrients.  

After 2 years of age, children with PCSK1 deficiency demonstrate severe overeating and appetite (known as “hyperphagia”) and develop morbid obesity.

Thankfully, PCSK1 deficiency is an extremely rare condition. As of 2016, only 21 children with PCSK1 deficiency had been identified.

In this respect, your PCSK1 and overeating trait does not look at extremely rare PCSK1 gene mutations that cause PCSK1 deficiency. Instead, we analyse more common mutations.

Source: Löffler, D., Behrendt, S., Creemers, J. W., Klammt, J., Aust, G., Stanik, J., ... & Körner, A. (2017). Functional and clinical relevance of novel and known PCSK1 variants for childhood obesity and glucose metabolism. Molecular metabolism, 6(3), 295-305.

- Common mutations

More common mutations within the PCSK1 gene can also impair PC1/3 activity and have been linked to a higher risk of obesity.

These mutations are all SNPs (Single Nucleotide Polymorphisms), which involve single letter changes in the DNA code of the PCSK1 gene. These, in turn, cause changes in the amino acid sequence of the PC1/3 enzyme, which can affect its structure, stability and enzymatic activity.

The PCSK1 and overeating trait looks at three common SNPs in the PCSK1 gene:

• rs6232 – also known as N221D
• rs6234 – also known as Q665E
• rs6235 – also known as S690T

The rs6234 and rs6235 mutations / SNPs tend to be coinherited. This means that if you inherit the rs6234 SNP in the PCSK1 gene, you are highly likely to also inherit the rs6235 SNP too (and vice versa).

(In technical terms, we say they are in strong linkage disequilibrium. This means the mutations are very close to one another on the same chromosome, so tend to be coinherited together).

For this reason, we tend to group the rs6234/rs6235 SNPs together. Let’s now take a further look at the rs6232 and rs6234/rs6235 SNPs.

rs6232

The rs6232 SNP causes an A-->G change in the DNA code, giving rise to two different PCSK1 gene variants or alleles: the ‘A’ allele and the ‘G’ allele.

The ‘G’ allele codes for a PC1/3 enzyme with significantly reduced activity, with one study suggesting a 30% reduction in activity. It is possible that this adversely affects the production of PC1/3-linked hormones and neuropeptides in the brain that regulate appetite and eating behaviour, resulting in overeating. Supporting this notion - as we’ll explore in the next section – the ‘G’ allele of the PCSK1 gene has been linked to a higher risk of obesity.  

The ‘G’ allele is present in roughly 2-5% of the global population, although the frequency of the allele varies between different ethnic groups. It is present in roughly 5% of Caucasian populations, but much rarer in non-Caucasian populations (for example, it is extremely rare in East Asian populations).  

rs6234 / rs6235

The rs6234 SNP causes a G--> C change in the DNA code (at a different location in the PCSK1 to the rs6232 SNP), giving rise to two different variants: the ‘G’ allele and the ‘C’ allele.

The ‘C’ allele is not thought to affect the catalytic activity of the PC1/3 enzyme but, instead, may affect the stability of the enzyme. This, in turn, may possibly alter the production of PC1/3-linked hormones and neuropeptides that regulate eating behaviour, leading to overeating.  

On this note, the ‘C’ allele has been linked to a higher risk of obesity.

As mentioned previously, the rs6235 SNP if often co-inherited with the rs6234 SNP. Therefore, people who inherit the ‘C’ allele (rs6234) also invariably carry the rs6235 SNP (which causes a C-->G change in the DNA code).

For the sake of simplicity, we will use the ‘C’ allele (rs6234 – rs6235) to refer both the rs6234 and rs6235 SNPs together. The 'C' allele is relatively common in the population, thought to be present in 26% of people globally.

KEY POINTS

• Rare mutations of the PCSK1 gene can result in little to no PC1/3 enzyme activity. This causes 'PCSK1 deficiency' characterised by severe childhood obesity.
• Common mutations / SNPs of the PCSK1 gene include: rs6232 and rs6234-rs6235.
• Rs6234 and rs6235 are linked SNPs - if you inherit one, you are highly likely to inherit the other.
• The rs6232 SNP gives rise to the 'G' risk allele, which causes reduced PC1/3 enzyme activity and is linked to a higher obesity risk.
• The rs6234-rs6235 SNP gives rise to the 'C' risk allele, which may affect PC1/3 enzyme stability and is linked to a higher obesity risk.

How do PCSK1 gene variants affect risk of obesity?

The ‘G’ allele (rs6232) and the ‘C’ allele (rs6234-rs6235) of the PCSK1 gene have both been associated with a higher risk of common obesity – defined as having a BMI ≥ 30 kg/m².  

One large meta-analysis, encompassing 331,175 individuals from different ethnicities, found that the ‘G’ allele (rs6232) was associated with a 15% higher risk of obesity. This is illustrated in the Forest plot below (overall OR = 1.15).

The effect of the ‘G’ allele on obesity varied according to age, with the ‘G’ allele being linked to a 53% higher risk of obesity in children and adolescents, compared to a 10% higher risk in adults.

Source: Nead, K. T., Li, A., Wehner, M. R., Neupane, B., Gustafsson, S., Butterworth, A., ... & Meyre, D. (2015). Contribution of common non-synonymous variants in PCSK1 to body mass index variation and risk of obesity: a systematic review and meta-analysis with evidence from up to 331 175 individuals. Human molecular genetics, 24(12), 3582-3594.

The same meta-analysis found that the ‘C’ allele (rs6234-rs6235) was linked to an increased risk of obesity, but to a lesser extent than that of the ‘G’ allele (rs6232). As shown in the Forest plot below, the ‘C’ (rs6234-rs6235) allele was associated with a 7% higher risk of obesity (overall OR = 1.07).

Interestingly, however, this association varied according to ethnicity. The increased risk of obesity conferred by the ‘C’ allele was broadly similar for white Caucasian, Hispanic and African populations, but not present in East Asian populations.

Source: Nead, K. T., Li, A., Wehner, M. R., Neupane, B., Gustafsson, S., Butterworth, A., ... & Meyre, D. (2015). Contribution of common non-synonymous variants in PCSK1 to body mass index variation and risk of obesity: a systematic review and meta-analysis with evidence from up to 331 175 individuals. Human molecular genetics, 24(12), 3582-3594.

The underlying reasons for this difference in risk between ethnicities are unclear. The authors of the study suggest, however, that ethnicity-specific lifestyle factors (e.g. diet) are unlikely to be the culprit. It may, instead, be due to a modifying effect of other genes on the PCSK1 gene.

In terms of why the ‘G’ allele (rs6232) and ‘C’ allele (rs6234-6235) of the PCSK1 gene are linked to a greater obesity risk, again it isn’t clear. As alluded to in the previous section, these PCSK1 variants can alter the activity of the PC1/3 enzyme, which may have wider effects on the production of hormones/neuropeptides (e.g. α-MSH, NPY, AgRP, and CART) that regulate eating behaviour and energy balance.

KEY POINTS

• The 'G' allele (rs6232) of the PCSK1 gene has been linked to a higher risk of obesity.
• The 'C' allele (rs6234-rs6235) of the PCSK1 gene has been linked to a slightly higher risk of obesity.
• The effect of PCSK1 gene variants on risk of obesity may vary according to age and ethnicity.

What is leptin resistance and how does it affect my overeating risk?

Leptin is a hormone secreted by our fat cells that acts to reduce food intake and increase energy expenditure.

Part of leptin’s appetite-suppressing effects rely upon its activity in hypothalamic brain circuits that control eating behaviour. These are exactly the same circuits influenced by PCSK1 gene variants.

As mentioned in a previous section, the arcuate nucleus of the hypothalamus has two major populations of neurons that, respectively, suppress or stimulate appetite: POMC neurons and AgRP/NPY neurons.

When leptin binds to receptors in the hypothalamus, it stimulates POMC neurons and promotes the production of α-MSH, which ultimately leads to the suppression of appetite. Complementing this, leptin also inhibits AgRP/NPY neurons, reducing the production of AgRP and NPY (both of which are appetite-stimulating neuropeptides).

Source: Wisse, B. E., & Schwartz, M. W. (2001). Role of melanocortins in control of obesity. The Lancet, 358(9285), 857-859.

As explained in the Leptin Resistance trait article, poor sensitivity or ‘resistance’ of the brain / hypothalamus to the appetite-suppressing effects of leptin can increase the risk of overeating.

For example, carrying excess body fat, which leads to higher circulating levels of leptin, can cause the brain to become desensitised to leptin over time. This means leptin less strongly activates POMC neurons in the hypothalamus, and therefore exerts less of an appetite-suppressing effect.

As well as carrying excess body fat, genetic factors (e.g. variants of the leptin-receptor gene [LEPR]) can also contribute to leptin resistance and increase the risk of overeating.

Given the above effects of leptin resistance on eating behaviour, your Leptin Resistance trait result is also factored in to your PCSK1 and overeating trait result.

KEY POINTS

• Leptin is a hormone that acts to suppress appetite.
• Leptin acts on hypothalamic circuits that regulate food intake and energy balance.
• Poor sensitivity to the effects of leptin (leptin resistance) can increase risk of overeating and weight gain.
• Your PCSK1 and overeating trait also factors in results from your Leptin Resistance trait.

Your PCSK1 and overeating trait

Your PCSK1 and overeating trait analyses common SNPs within the PCSK1 gene (rs6232 and rs6234-rs6235) and also factors in your Leptin Resistance trait result to assess your risk of overeating.

Depending on your genetic and lifestyle data, you will be classified into one of 4 bands:

• Increased risk of overeating – you carry the risk ‘G’ allele (rs6322) of the PCSK1 gene associated with reduced PC1/3 enzyme activity and higher obesity risk.

• Moderately increased risk of overeating – you carry the risk ‘C’ allele (rs6234-rs6235) associated with moderately increased obesity risk.

• Increased risk of overeating due to lifestyle – you do not carry risk alleles of the PCSK1 gene, but have data suggestive of leptin resistance, which elevates your overeating risk.

• Average risk of overeating – you do not carry risk alleles of the PCSK1 gene and do not have data suggestive of leptin resistance.

To find out your result, please login to truefeed.

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