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Context: Risk alleles of the fat mass- and obesity-associated gene (FTO) are related not only to increased body mass index (BMI) values but also to mortality. It was speculated that cellular effects of the FTO gene affect most organs, especially their ability to maintain or regenerate proper function when afflicted by various diseases. FTO is highly expressed in the hypothalamus and also in the pituitary gland. The decrease in growth hormone (GH) secretion is known to cause a decrease in lean body mass in older subjects. Objective: We hypothesized an association of rs9926289 with insulin-like growth factor (IGF)-I. Design and Setting: Cross-sectional data from the Study of Health in Pomerania, a population-based study in the northeastern part of Germany, were used. Participants: For the final analyses, 3882 subjects aged 20-79 years were available. Main Outcome Measures: Continuous IGF-I, low IGF-I according to clinically meaningful age- and gender-specific reference values, and BMI were used as outcome measures. Results: Over all age groups, a statistically significant relationship between FTO and IGF-I was found. In subjects younger than 55 years of age, homozygous carriers of the FTO risk allele exhibited lower serum IGF-I levels adjusted for 5-year age groups, gender and IGF-I binding protein 3 levels (linear regression, coefficient±s.e. for FTO AA genotype:-8.6±2.8; P=0.002). Further adjustments for obesity and diabetes did not suspend this association (coefficient:-7.8; P=0.005). As expected, the FTO AA genotype effect on BMI was reduced from 0.76 to 0.62  kg  m(-2) by including IGF-I. No relationship between FTO and IGF-I levels was found in subjects aged 55 years or older (-2.7±2.4; P=0.260 for FTO AA genotype adjusted for age, gender and IGF-I binding protein 3 levels). Conclusion: We propose that the GH-IGF-I axis is a mediator for the relationship between FTO and BMI. [ABSTRACT FROM AUTHOR]