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Background  Toll-like-receptor 4 (TLR) is discussed to provide a molecular link between obesity, inflammation and insulin resistance. Genetic studies with replications in non-diabetic individuals in regard to their fat distribution or insulin resistance according to their carrier status of a common toll-like receptor 4 (TLR4) variant (TLR4 D299G/T399I ) are still lacking.    Methodology/Principal Findings  We performed a cross-sectional analysis in individuals phenotyped for prediabetic traits as body fat composition (including magnetic resonance imaging), blood glucose levels and insulin resistance (oral glucose tolerance testing, euglycemic hyperinsulinemic clamp), according to TLR4 genotype determined by candidate SNP analyses (rs4986790). We analyzed N = 1482 non-diabetic individuals from the TÜF/TULIP cohort (South Germany, aged 39±13 y, BMI 28.5±7.9, mean±SD) and N = 5327 non-diabetic participants of the METSIM study (Finland, males aged 58±6 y, BMI 26.8±3.8) for replication purposes. German TLR4 D299G/T399I  carriers had a significantly increased body fat ( XG  in rs4986790: +6.98%,  p  = 0.03, dominant model, adjusted for age, gender) and decreased insulin sensitivity ( XG : −15.3%, Matsuda model,  p  = 0.04;  XG : −20.6%,  p  = 0.016, clamp; both dominant models adjusted for age, gender, body fat). In addition, both liver fat ( AG : +49.7%;  p  = 0.002) and visceral adipose tissue ( AG : +8.2%;  p  = 0.047, both adjusted for age, gender, body fat) were significantly increased in rs4986790 minor allele carriers, and the effect on liver fat remained significant also after additional adjustment for visceral fat ( p  = 0.014). The analysis in METSIM confirmed increased body fat content in association with the rare  G  allele in rs4986790 ( AG : +1.26%,  GG : +11.0%;  p  = 0.010, additive model, adjusted for age) and showed a non-significant trend towards decreased insulin sensitivity ( AG : −0.99%,  GG : −10.62%).    Conclusions/Significance  TLR4 D299G/T399I  associates with increased total body fat, visceral fat, liver fat and decreased insulin sensitivity in non-diabetic Caucasians and may contribute to diabetes risk. This finding supports the role of TLR4 as a molecular link between obesity and insulin resistance.

The D299G/T399I Toll-Like Receptor 4 Variant Associates with Body and Liver Fat: Results from the TULIP and METSIM Studies