Val1483Ile in FASN Gene Is Linked to Central Obesity and Insulin Sensitivity in Adult White Men

Abstract

The Val1483Ile polymorphism in the human fatty acid synthase (FASN) gene is located within the interdomain region of the FASN close to the two dynamic active centers of the FASN enzyme and putatively affects FASN action. We aimed to evaluate the association of this polymorphism with obesity phenotypes, insulin sensitivity, and adipose tissue FASN activity in adult white subjects. The polymorphism was evaluated in association with metabolic variables in two independent studies: in a case–control study of 457 men (229 with normal glucose tolerance (NGT) and 228 with altered glucose tolerance (AGT)); and in 600 population‐based NGT subjects (274 men and 326 women). Adipose tissue FASN activity was analyzed using the method of Nepokroeff. The Ile variant was associated with a lower waist‐to‐hip ratio (WHR) and a lower increase in weight over a 7‐year period in NGT men. In a subset of 147 men, carriers of the Ile variant showed significantly increased insulin sensitivity. BMI (P < 0.001), WHR (P = 0.03), and Val1483Ile (P = 0.03), contributed independently to 37% of insulin sensitivity variance. In men from the population‐based study, the Ile variant was associated with a lower BMI, WHR, fasting glucose, and systolic blood pressure compared with carriers of the Val variant. In agreement with these results, the adipose tissue FASN activity was significantly lower in subjects with the Ile variant (P = 0.01). In summary, adult white men with the Ile 1483 variant of the FASN gene seem protected from developing central obesity through decreased adipose tissue FASN activity.

Effect of Genetic Variation in the Human Fatty Acid Synthase Gene (FASN) on Obesity and Fat Depot‐Specific mRNA Expression

“…Findings in children cohorts suggested sex-specific effects of the polymorphism which was confirmed recently by independent studies in Spanish whites (25). Spanish men with the Ile-allele had lower BMI, WHR, fasting glucose, and blood pressure, and they showed increased insulin sensitivity (25). However, no association was found in women (25).…”

“…Spanish men with the Ile-allele had lower BMI, WHR, fasting glucose, and blood pressure, and they showed increased insulin sensitivity (25). However, no association was found in women (25). Also in our study, in contrast to women, German adult men carrying the Ile-allele seem to be protected against obesity as suggested by the case-control study as well as by the association with lower BMI.…”

“…Further support for the protective effect of this variant against obesity came from studies in German children showing reduced BMI-SDS and improved lipid profile of boys carrying the Ile-variant (12). Findings in children cohorts suggested sex-specific effects of the polymorphism which was confirmed recently by independent studies in Spanish whites (25). Spanish men with the Ile-allele had lower BMI, WHR, fasting glucose, and blood pressure, and they showed increased insulin sensitivity (25).…”

“…Also in our study, in contrast to women, German adult men carrying the Ile-allele seem to be protected against obesity as suggested by the case-control study as well as by the association with lower BMI. Because Ile-carriers also have decreased adipose tissue FASN activity (25), it might be postulated that Val1483Ile is a functional variant in FASN. Sexual dimorphism in genetic associations in obesity, glucose, and lipid metabolism is not uncommon and has been reported for genes such as leptin (26), resistin (27), winged helix/forkhead transcription factor (28), peptide tyrosine tyrosine (29), Y2 receptor (29) and others.…”

PCB-associated steatohepatitis and the role of nuclear receptors.

“…These changes included down-regulation of fatty acid synthetase and beta 2-adrenergic receptor, polymorphisms of which have been associated with metabolic disease 123,124 . Down-regulation of GLUT4 reduces insulin-sensitive glucose uptake in nonhepatocyte liver cells and other insulin-sensitive tissues …”