A common hormone-sensitive lipase i6 gene polymorphism is associated with decreased human adipocyte lipolytic function

Hereditary factors may be involved in the pathogenesis of type 2 diabetes. A polymorphism in the hormone-sensitive lipase (HSL) gene (HSLi6) is associ ated with obesity and diabetes, although it is unknown whether the polymorp hism is functional and thereby influences lipolysis. We genotyped 355 appar ently healthy nonobese male and female subjects for the HSLi6 polymorphism. Allele 5 was found to be the most common allele (allele frequency 0.57). I n 117 of the subjects, we measured abdominal subcutaneous fat cell lipolysi s induced by drugs acting at various steps in the lipolytic cascade. The li polysis rate induced by norepinephrine isoprenaline (acting on beta -adreno ceptors), forskolin (acting on adenylyl cyclase), and dibutyryl cyclic AMP (acting on HSL) were all decreased by similar to 50% in allele 5 homozygote s, as compared with noncarriers. Heterozygotes showed an intermediate lipol ytic rate. The difference in lipolysis rate between genotypes was more pron ounced in men than in women. We conclude that allele 5 of the HSLi6 polymor phism is associated with a marked decrease in the lipolytic rate of abdomin al fat cells. This may in turn contribute to the development of obesity.