The
enzyme DGAT (
acyl-CoA:
diacylglycerol acyltransferase) catalyses the final step of
triacylglycerol (
triglyceride) synthesis. Mice overexpressing hepatic DGAT2 fed a high-fat diet develop
fatty liver, but not
insulin resistance, suggesting that DGAT2 induces a dissociation between
fatty liver and
insulin resistance. In the present study, we investigated whether such a phenotype also exists in humans. For this purpose, we determined the relationships between genetic variability in the DGAT2 gene with changes in liver fat and
insulin sensitivity in 187 extensively phenotyped subjects during a lifestyle intervention programme with
diet modification and an increase in physical activity. Changes in body fat composition [MR (magnetic resonance) tomography], liver fat and intramyocellular fat ((1)H-MR spectroscopy) and
insulin sensitivity [OGTT (oral
glucose tolerance test) and euglycaemic-hyperinsulinaemic clamp] were determined after 9 months of intervention. A change in
insulin sensitivity correlated inversely with changes in total body fat, visceral fat, intramyocellular fat and liver fat (OGTT, all P<0.05; clamp, all P< or =0.03). Changes in total body fat, visceral fat and intramyocellular fat were not different between the genotypes of the SNPs (single nucleotide polymorphisms) rs10899116 C>T and rs1944438 C>
T (all P> or =0.39) of the DGAT2 gene. However, individuals carrying two or one copies of the minor T allele of SNP rs1944438 had a smaller decrease in liver
fat (-17+/-10 and -24+/-5%; values are means+/-S.E.M.) compared with subjects homozygous for the C allele (-39+/-7%; P=0.008). In contrast, changes in
insulin sensitivity were not different among the genotypes (OGTT, P=0.76; clamp, P=0.53). In conclusion, our findings suggest that DGAT2 mediates the dissociation between
fatty liver and
insulin resistance in humans. This finding may be important in the prevention and treatment of
insulin resistance and
Type 2 diabetes in subjects with
fatty liver.