A gene is a segment of DNA with instructions for building molecules, usually proteins, that perform jobs within the body. Scientists studying human metabolism are interested in the CREB3 regulatory factor (CREBRF) gene due to its role in how the body manages energy.
Understanding this gene helps explain why certain individuals and populations may have different predispositions to metabolic conditions. This research reveals complex interactions between our ancestry, our genes, and the modern environment.
The Primary Function of CREBRF
The CREBRF gene provides instructions for producing the CREB3 regulatory factor protein, which helps manage how cells respond to stress by regulating energy use and storage. As a metabolic regulator, it influences how the body handles nutrients.
Within the cell, the protein is involved in pathways that sense nutrient availability, such as the mTORC1 pathway, a signaling network that governs cell growth and metabolism in response to food. This regulatory function is important for maintaining balance, or homeostasis, within the body. The protein helps to fine-tune energy expenditure and fat storage, ensuring that cells have the resources they need without storing excess in a harmful way.
The Polynesian Variant and Its Discovery
A specific variant of the CREBRF gene, rs373863828, is a focus of genetic research. Discovered through studies of the Samoan population, it is found in approximately 26% of Samoans but is extremely rare in most other global populations, suggesting a unique evolutionary history.
This discovery supports the “thrifty gene” hypothesis, which proposes that genes advantageous for surviving famine can cause health problems when food is plentiful. For ancient Polynesians on long ocean voyages with inconsistent food supplies, a gene that promoted efficient energy storage would have been beneficial.
This is a missense variant, meaning a single change in the DNA code alters the resulting CREBRF protein. This alteration is thought to change the protein’s function, making it more effective at storing fat. The high prevalence of this variant in Polynesian populations is believed to be a legacy of this ancestral advantage.
Metabolic Effects on the Body
The rs373863828 variant of the CREBRF gene presents a paradox. Carriers have a 1.3-fold increased risk of obesity because it promotes more efficient fat storage, leading to a higher Body Mass Index (BMI). This “thrifty” characteristic likely provided a survival advantage in environments with scarce resources.
However, the same variant offers protection against type 2 diabetes, with carriers showing a 1.6-fold decreased risk. This challenges the typical link between higher body weight and diabetes risk. The protective mechanism relates to how and where fat is stored, encouraging it to be stored in subcutaneous adipose tissue (under the skin) rather than other parts of the body.
When fat accumulates in organs like the liver and pancreas, it can interfere with insulin signaling and contribute to insulin resistance, a precursor to type 2 diabetes. The CREBRF variant appears to promote a healthier pattern of fat distribution by enhancing the capacity of fat cells to store fat safely.
This leads to a situation where individuals may have a higher total body fat percentage but are metabolically healthier for their weight. The variant is associated with lower fasting glucose levels, indicating better blood sugar control and mitigating some negative consequences of obesity.
Broader Implications for Genetic Research
The study of the CREBRF gene illustrates gene-environment interaction, where a gene’s impact depends on context. A gene beneficial for survival in an environment of food scarcity is now associated with obesity in a world of caloric abundance. This shows how the health implications of our genetics can change with shifts in lifestyle.
Furthermore, the concentration of this variant in a specific population emphasizes the importance of diversity in genetic research. Studying unique populations can uncover biological mechanisms that might be missed in more heterogeneous groups. The findings from the Samoan population encourage researchers to look for other population-specific variants to learn how human biology has adapted.