The FTO gene contains multiple variants strongly associated with obesity and body mass index. While rs9939609 is the most famous, rs1558902 is another significant variant in the FTO gene that contributes to obesity risk through effects on appetite regulation and energy expenditure. This variant, like others in the FTO region, can be significantly modified by lifestyle factors, particularly physical activity.
Understanding the FTO Gene
FTO (Fat Mass and Obesity-Associated) was the first gene conclusively linked to common obesity:
- Discovery: First obesity gene identified through GWAS in 2007
- Function: RNA demethylase that modifies RNA molecules
- Expression: Highest in hypothalamus (brain's appetite center)
- Effects: Influences hunger, satiety, and possibly energy expenditure
The rs1558902 Variant
- T allele: Lower risk allele
- A allele: Risk allele - associated with higher BMI
Understanding Your Genotype
- T/T: Lower genetic obesity risk from this variant
- T/A: Intermediate risk - modest BMI increase
- A/A: Higher risk - ~1-3 kg higher body weight on average
Relationship with Other FTO Variants
- FTO contains a cluster of obesity-associated variants
- rs1558902 is in linkage disequilibrium with rs9939609
- Effects are not fully additive - having risk alleles at multiple FTO SNPs doesn't multiply risk
- Testing one FTO variant provides similar predictive information to testing multiple
How FTO Affects Weight
Appetite Effects
- Risk allele carriers report increased hunger
- Reduced feelings of fullness after meals
- Higher ghrelin (hunger hormone) levels
- Altered brain response to food cues
Food Preferences
- Preference for energy-dense, high-fat foods
- May consume more calories at meals
- Increased snacking behavior
- Higher attraction to palatable foods
Energy Balance
- Primary effect appears to be on food intake rather than metabolism
- Some evidence for effects on adipocyte (fat cell) biology
- May influence whether fat is stored as white or beige fat
- Possible effects on resting energy expenditure
The IRX3/IRX5 Connection
Mechanism Update
- Recent research suggests FTO variants may actually affect nearby IRX3 and IRX5 genes
- IRX3/IRX5 influence fat cell type (thermogenic vs. storage)
- Risk alleles associated with more white (storage) fat
- May be the actual molecular mechanism underlying obesity association
Implications
- Obesity effect may be more about fat cell biology than appetite alone
- Potential for future targeted therapies
- Understanding mechanism helps guide interventions
Exercise: The Key Modifier
Remarkable Gene-Lifestyle Interaction
- FTO's effect on obesity is dramatically reduced by physical activity
- Active A/A carriers can achieve similar BMI to inactive T/T carriers
- ~30% reduction in FTO effect among physically active individuals
- This is one of the most well-documented gene-exercise interactions
Exercise Recommendations
- Minimum target: 150 minutes moderate activity weekly
- Optimal: 300+ minutes for weight management
- Include both: Cardio and resistance training
- NEAT matters: Non-exercise activity (walking, stairs, standing) counts
Why Exercise Works
- May normalize appetite signaling
- Improves insulin sensitivity
- Promotes healthier fat distribution
- Counters sedentary effects that amplify FTO
Dietary Strategies
Protein Emphasis
- High-protein diets associated with better outcomes in FTO risk carriers
- Protein is the most satiating macronutrient
- Helps compensate for reduced satiety signaling
- Aim for protein at each meal
Volume and Fiber
- High-fiber, low-energy-density foods increase fullness
- Vegetables, fruits, whole grains
- More food volume for fewer calories
- Helps manage intake despite increased appetite
Fat Quality
- Some evidence that saturated fat effects are stronger in FTO risk carriers
- Mediterranean-style diet may be particularly beneficial
- Emphasize olive oil, nuts, fatty fish
- Limit saturated fat intake
Meal Patterns
- Regular meals prevent excessive hunger
- Avoid skipping meals (leads to overeating)
- Plan snacks to avoid impulsive eating
- Front-load calories earlier in the day
Behavioral Strategies
Environment Design
- Keep high-calorie foods out of sight and reach
- Use smaller plates and serving sizes
- Pre-portion snacks into single servings
- Make healthy choices the default
Mindful Eating
- Eat without distractions (TV, phone)
- Pay attention to hunger and fullness cues
- Slow down - satiety signals take time
- Recognize emotional vs. physical hunger
Self-Monitoring
- Food tracking can help - FTO carriers may underestimate intake
- Regular weighing catches trends early
- Plan meals and snacks in advance
- Record exercise to ensure consistency
Weight Maintenance Challenges
Regain Risk
- FTO risk allele associated with weight regain after loss
- Appetite effects persist after weight loss
- Long-term vigilance is necessary
- Not a character flaw - it's biology
Successful Maintenance
- Continued physical activity is crucial
- Self-monitoring (weighing, food tracking) helps
- Support systems (groups, apps, providers) beneficial
- Recognize that maintenance requires ongoing effort
Pediatric Considerations
Early Effects
- FTO effects visible from childhood
- Risk allele children tend to have higher BMI
- Eating behavior differences present early
- Early healthy habits especially important
Family Approach
- Model healthy eating patterns
- Encourage active family lifestyle
- Limit screen time
- Avoid restrictive dieting (can backfire)
- Focus on health behaviors, not weight
Prevalence
- A allele frequency: ~40-45% in Europeans
- A/A genotype: ~16-20%
- Population variation: Lower in East Asians (~15% A allele)
- Very common: Most people carry at least one FTO risk allele
Testing with NutraHacker
NutraHacker's Fitness Report analyzes FTO variants along with MC4R and other weight-related genes, providing a comprehensive view of your genetic influences on weight and metabolism.
Frequently Asked Questions
What's the difference between rs1558902 and rs9939609?
Both are variants in the FTO gene region associated with obesity risk. They are in linkage disequilibrium, meaning they're often inherited together. Their effects are largely overlapping rather than additive. Testing either variant provides similar predictive information about your FTO-related obesity risk.
Can I really overcome FTO genetics with exercise?
Yes! This is one of the most well-documented gene-lifestyle interactions. Studies consistently show that physical activity substantially reduces FTO's effect on BMI. Active individuals with the risk genotype can achieve weights similar to inactive people without the risk genotype. Exercise is particularly important if you carry FTO risk variants.
Why is weight loss harder for some people?
FTO affects hunger and satiety signals, so risk allele carriers may genuinely feel more hungry and less satisfied than others eating the same food. You're not imagining it, and it's not about willpower. Understanding this helps you adopt specific strategies (more protein, more fiber, mindful eating, regular activity) rather than expecting to eat exactly like someone with different genetics.
References
- Frayling TM, et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science. 2007;316(5826):889-894.
- Claussnitzer M, et al. FTO Obesity Variant Circuitry and Adipocyte Browning in Humans. N Engl J Med. 2015;373(10):895-907.
- Kilpeläinen TO, et al. Physical activity attenuates the influence of FTO variants on obesity risk. Am J Clin Nutr. 2011;93(3):596-604.