Association of Lipin 1 Gene Polymorphisms with Measures of Energy and Glucose Metabolism**

Objective: To examine the importance of lipin 1 ( LPIN1 ) gene variation in energy and glucose metabolism. Transgenic animal models have shown that lipin, a protein encoded by the LPIN1 gene, promotes fat synthesis and storage in adipose tissue while decreasing energy expenditure and lipid oxidation in skeletal muscle. Lpin1 was identified as the mutated gene in the fatty liver dystrophy mouse, which exhibits lipin deficiency and features of human lipodystrophy. Research Methods and Procedures: We genotyped five LPIN1 polymorphisms and tested for association with resting metabolic rate (RMR), fat oxidation, fasting plasma insulin and glucose concentration, and obesity‐related phenotypes, including BMI, body fat percentage, sum of six skinfolds, and waist circumference in 712 subjects of the Quebec Family Study. Results: The strongest results were generation‐specific. In parents, RMR of the G/G IVS13 + 3333A>G homozygotes was 107 kcal/d higher than in A/A homozygotes and 39 kcal/d higher than in A/G heterozygotes ( p = 0.0003). In offspring, carriers of the C allele of the IVS18 + 181C>T variant had significantly higher ( p < 0.0003) insulin levels than T/T homozygotes. These associations remained significant after adjusting for multiple testing. Several other associations between body composition measures and the IVS18 + 181C>T variant were significant ( p = 0.05 to 0.003), suggesting a strong pattern of relationships. Discussion: These findings support the hypothesis that sequence variation in the LPIN1 gene contributes to variation in RMR and obesity‐related phenotypes potentially in an age‐dependent manner.