Can This Gene Protect You From Obesity (NEGR1)?

The NEGR1 gene encodes the NEGR1 protein (short for ‘neuronal growth regulator 1’), also known as kilon and neurotractin. NEGR1 is found in many brain areas such as the hippocampus, olfactory bulb, and cortex, and most abundantly in the hypothalamus [R, R, R, R].

As can be guessed from its name, NEGR1 is involved in the growth of brain cells. Concretely, it stimulates the outgrowth of neuron ramifications (neurites) in the developing brain and the establishment of connections between these cells [R, R, R]. 

Moreover, its wide distribution in other tissues such as the muscles and fatty tissues suggests additional function unrelated to brain development [R, R, R].

The NEGR1 gene encodes a protein mainly found in the brain and involved in the development and connection of brain cells.

NEGR1 Contribution to Weight Gain

Animal studies suggest that NEGR1 plays a complex role in regulating energy balance [R, R].

The lack of NEGR1 has been associated with altered fat transport. It increased cholesterol and triglyceride levels in isolated cells, and fat buildup in the liver and fatty tissues of mice [R, R].

In human fat tissue, NEGR1 expression was increased during the formation of fat cells and was required for their proper development [R].

Alternatively, NEGR1 may influence weight through its effects on brain structure, possibly affecting regions involved in feeding behavior. Studies in humans associated a variant commonly found in obese people with reduced white matter integrity and a tendency to eat more carbohydrates but fewer saturated and unsaturated fats [R, R, R].

Although balance is key and the relationship is complex, it seems like increased NEGR1 would be helpful for losing weight.

NEGR1 may influence body weight through its effects on energy balance, fat production and transport, and the structure of brain regions involved in feeding behavior.

The most widely-investigated NEGR1 polymorphism is rs2815752. Its major allele ‘A’ has been associated with increased obesity rates, BMI, and total body fat in multiple studies on different European, American, and Pakistaini populations. However, a German and a Japanese study failed to associate this variant with obesity traits [R, R, R, R, R, R, R, R].

The variant was also associated with obesity in Greek, Mexican, Dutch, Australian, and Brazilian children and adolescents, but not in Chinese children at puberty [R, R, R, R, R, R].

Interestingly, this variant also predicted increased weight regain after finishing different weight-loss interventions in a multi-ethnic American study [R].

The major ‘C’ variant of rs3101336 has been associated with obesity, BMI, and total body fat in Chinese, Spanish, British, and African American adults, as well as in children from the US and UK [R, R, R, R, R, R]. 

The major ‘A’ variant of another SNP (rs2568958) was linked to obesity, BMI, and total body fat in Spanish, African American, and Icelandic adults, as well as in American children. However, Chinese and Danish studies found it unrelated to BMI [R, R, R, R, R, R].

Finally, a study on British adults and children associated the major ‘G’ variant of rs1993709 with severe and early-onset obesity [R].

How It Works

All four SNPs are located near the NEGR1 gene, in a region that may help control the expression of this gene, and are often inherited together.

In cells, the minor rs1993709 variant causes higher NEGR1 levels [R, R].

rs2815752 and rs3101336 may contribute to obesity through the same mechanism [R, R, R].

The minor variant of rs2568958 has been shown to increase blood NEGR1 levels by 12% per copy [R].

Four NEGR1 variants presumably increasing its expression have been associated with lower obesity rates.

SNP Summary and Table

Primary SNP:

NEGR1 rs2815752

• ‘A’ = increased rates of obesity
• ‘G’ = lower rates of obesity
• Approximately 48% of the world population has ‘AA’
• ‘G’ is extremely rare in people of East Asian ancestry

Other Important SNPs:

NEGR1 rs3101336 

• ‘C’ =  increased rates of obesity
• ‘T’ = lower rates of obesity
• The genotype distribution is very similar to that of rs2815752 and rs2568958 for all ethnicities
• The minor ‘T’ variant is most common in African descendants

NEGR1 rs2568958 

• ‘A’ = increased rates of obesity
• ‘G’ = lower rates of obesity 
• The genotype distribution is very similar to that of rs2815752 and rs3101336 for all ethnicities
• Almost 50% of people with a European background carry one copy of each allele

NEGR1 rs1993709 

• ‘G’ = increased rates of obesity
• ‘A’ = lower rates of obesity
• The ‘A’ variant is extremely rare and less than 2% of the world population carries two copies
• The minor ‘A’ variant is slightly more common in people with European and African ancestry