How Genes Influence Appetite & Obesity (PCSK1)

The PCSK1 gene helps produce proprotein convertase 1/3 (PC1/3), an enzyme abundant in the brain and endocrine system. PC1/3 activates a range of hormones and peptides involved in [R, R]:

• Temperature control
• Nutrient absorption
• Appetite and feeding behavior
• Glucose and fat metabolism
• Energy expenditure

Given the crucial role of PCSK1 in the above processes, variants in this gene correlate with various health conditions, including diabetes, malabsorption, obesity, and thyroid disorders [R].

PCSK1 encodes an enzyme (PC1/3) with complex roles in metabolism. Variants in this gene correlate with obesity, hormonal disorders, and malabsorption.

PCSK1 in Weight Control

PCSK1 was among the first discovered genes with a role in severe hereditary obesity. It’s the third most common contributor to obesity caused by a single gene (monogenic) [R, R].

PCSK1-deficient mice quickly develop obesity due to uncontrolled food intake. Likewise, mutations in this gene cause early-onset obesity in humans, despite severe diarrhea and malabsorption [R, R, R].

Crucial Roles in Appetite

Animal and clinical research has identified overeating as the primary cause of PCSK1-associated obesity [R, R, R].

The PC1/3 enzyme is crucial in the hypothalamus, where it activates an array of peptides involved in food intake and metabolism. It turns POMC into alpha-MSH, a powerful appetite-suppressing hormone [R, R].

By activating the MC4R receptors, a-MSH reduces food intake, stimulates energy expenditure, and improves glucose metabolism [R].

Mice and humans lacking PC1/3 have impaired POMC activation and lower a-MSH levels in the hypothalamus [R, R].

_{Source: Huvenne et al. (2016), Rare Genetic Forms of Obesity: Clinical Approach and Current Treatments in 2016}

The mechanism described and illustrated above belongs to the leptin-melanocortin pathway, the master controller of appetite and energy balance [R].

PC1/3 plays a crucial role in the leptin-melanocortin pathway by turning POMC into alpha-MSH. This pathway suppresses appetite, boosts metabolism, and stimulates energy expenditure.

Other Pathways

PC1/3 activates many other hormones involved in energy balance and metabolism. It enables glucose metabolism by turning proinsulin into active insulin. Not surprisingly, common variants in the PCSK1 gene have been associated with diabetes and impaired insulin levels [R, R, R].

PCSK1-associated obesity most likely results from a combination of [R]:

• Increased appetite
• Reduced energy expenditure
• Impaired glucose metabolism

PCSK1 is one of the most studied genes when it comes to obesity. A huge meta-analysis gathered data from over 330K people and confirmed a significant link between three PCSK1 variants and obesity [R]:

• rs6232: people with the less common “C” allele had 15% higher obesity rates
• rs6234/rs6235: people with the less common “C/G” alleles had 7% higher obesity rates

The second and third SNP are always inherited together, so the authors presented them as a pair.

The SNPs had a higher impact among children, with 53% and 15% higher obesity rates for rs6232 and rs6234/rs6235, respectively. They were significant only in European (Caucasian) descendants, which made the vast majority of total subjects [R].

Another large meta-analysis of 19 trials and over 200K participants came to a similar conclusion. It observed 19% higher odds of obesity for rs6232 and 9% for rs6234/rs6235 [R].

In two studies of 4,174 subjects from China and Taiwan, rs6234/rs6235 were associated with a higher body-mass index (BMI) and waist circumference (WC) but only in men [R, R].

Rs6232 and rs6234/rs6235 are associated with obesity among European descendants, especially children. Rs6234/rs6235 may correlate with obesity in East Asian men. 

How It Works

As mentioned, mutations that reduce PCSK1 activity may contribute to increased appetite and impaired metabolism. The above variants have a much milder impact on the gene functioning, but they can still mimic these changes to a lesser extent.

The “C” allele at rs6232 changes one amino acid in the PC1/3 structure, hindering the production of this enzyme and reducing its activity by 30%. It lies right next to a mutation that causes obesity and overeating in mice [R, R].

On the other hand, rs6234 and rs6235 cause changes in the enzyme region responsible for proper folding and recognition of target hormones. Scientists haven’t yet identified the functional consequences of these SNPs, but they likely impair enzyme activity in some way [R, R].

Obesity-associated PCSK1 variants may impair enzyme activity, secretion, or recognition of hormones. Rs6232-C reduces enzyme activity by up to 30%.

SNP Summary and Table

Primary SNP:

PCSK1 rs6232

• ‘C’ = associated with higher obesity rates
• ‘T’ = not associated with obesity

Population Frequency: Only around 6,5% of European descendants carry the “C” allele. It’s a bit more common in South Asian populations (10%) and much less common in East Asian and African populations (0.5%).

Other Important SNPs:

PCSK1 rs6234

• ‘C’ = associated with obesity and higher waist circumference 
• ‘G’ = not associated with obesity

PCSK1 rs6235

• ‘G’ = associated with obesity and higher waist circumference 
• ‘C’ = not associated with obesity

Population Frequency: These two SNPs are always inherited together, which means they act as a single genetic factor. Around 38,5% of Europeans carry one copy and 7% carry both copies of the minor alleles (C and G, respectively). They are more common in East Asians (57%) and less common in Africans (33%).