Do You Have The “Thin” Gene?

Happy Thanksgiving! As you dig into your Thanksgiving dinner, a time when many of us overeat, you may well ask: Will I regret it tomorrow when I check my weight? Will it be ok? New research suggests that it may depend on whether you have a single “C” or a “T” at a critical position in one of three billion inherited units in your DNA!

A new study has identified a gene that predisposes some individuals to being thin. Those that carry this gene have an easier time staying fit and a lower risk of significant weight gain. In the previous installment of this series on overeating, we reviewed the lessons from Dr. David Kessler Bestseller, The End of Overeating, which reveals why some of us cannot help but overeat. Most people logically can differentiate between foods that are “good” vs. “bad” for your body. The food industry, however, spends millions to keep consumers addicted to salt, fat and sugar. While other factors including lifestyle choices can overall affect weight, this study suggests that genetics may play a larger role in weight management than previously thought.

Recruiting over 790 healthy volunteers for this study, the Spanish team found that approximately 60% of Europeans have a variant of the so-called “thin gene” that lowers their risk for obesity. Having a C vs. the T variant of the FNIP2 gene was shown to correlate with a lower body mass index (BMI) and higher metabolism. After adjusting for age and sex, the results proved to be even more significant. Those that were homozygous for C gene variant, meaning that they inherited the same copy of this gene variant from both parents, had the more optimal fat to muscle mass ratios, compared to those that were heterozygous, or only had one copy of the “thin gene.”

What does this gene do? The FNIP2 “thin gene” is involved in regulating a key metabolic pathway called mechanistic target of rapamycin complex 1 (mTORC1). Through a cascade of enzymes and proteins, this cell signaling pathway senses incoming nutrients, energy levels, and growth factors to either promote or limit cell growth. In other words, it tells your body to grow or produce more fat cells in response to the type of foods that you eat. This gene is, therefore, involved in various processes on the cellular levels that influence appetite, energy storage, and metabolism among other functions.

Fernandez et. al found that having the T variant of this gene correlated with lower expression of FNIP2 proteins. In fact, individuals with two copies of the T allele had significantly less of these proteins in their blood compared to those that had at least one C allele copy. Together these findings suggest that increased expression of this protein may reduce the risk of obesity.

How can one gene variation have such a large effect on weight? Fernandez et. al argue that the difference between a T vs. C allele in this region of the FNIP2 gene impacts how post-transcriptional factors regulate the expression of FNIP2 proteins. When the T allele is present, miR-181b-59, a microRNA gene regulator, strongly binds to the FNIP2 gene and prevents expression of the protein as demonstrated by the figure below. miR-181b-59, however, does not bind to the C allele, which enables FNIP2 to be transcribed and expressed.

How big of a role does this one gene play in weight maintenance and metabolism? To confirm their findings in humans, Fernandez et. al developed a mouse model in which they “knocked-in,” or inserted, the C gene variant into the animal’s FNIP2 DNA sequence. Just as they observed in the healthy volunteers, mice that had two copies of this gene had lower fat content, especially the female mice. Mice with two T alleles, on the other hand, developed and sustained more fat cells. This suggests that a T vs. C allele in the FNIP2 protein gene may be a key predictor for being overweight or obese.

Obesity remains one of the most imminent threats to public health in America. People with poor fat to muscle mass ratios not only have a higher risk of metabolic complications, including insulin resistance, cardiovascular disease, and cancer, but also risk more severe complications associated with Covid-19 and other viral infections. Although lifestyle choices, such as high calorie diets and limited physical activity, can increase the risk of being overweight or obese, emerging research shows that genetics may be a key predictor of weight maintenance.

As the group from Spain’s IMDEA Food Institute argues, “Obesity is preventable, but causes and consequences must be deeply understood to design efficient preventative measures and tools.” Although genetics are not destiny, the findings from this study suggest that the amount of FNIP2 proteins in the blood may serve as a useful measure for key metabolic markers. This sets the stage for a future in which obesity can be treated through gene therapeutic interventions that can give you the “thin gene.” Next in this series, we will take a deeper look at how genetics drives cellular and metabolic processes that regulate our appetites.