Leptin plays a key role in the regulation of
body weight through the sympathetic nervous system; however, the contributions of
leptin-receptor polymorphisms to
obesity and sympathetic nerve activity have not been fully clarified. In the present study, we examined the relationships between
leptin-receptor polymorphisms, plasma
leptin and whole-body
norepinephrine (NE) spillover as an index of sympathetic nerve activity in a Caucasian male cohort. In 129 young healthy normotensive men with a wide range of body mass index (BMI) (19.4-39.5 kg/m(2)), we measured
leptin-receptor polymorphisms (Gln223Arg, Lys656Asn, and Lys109Arg), plasma
leptin levels, whole-body NE spillover, whole-body NE clearance, BMI and blood pressure (BP) levels in the supine position after overnight fasting.
Overweight-obese (BMI>or=25 kg/m(2)) subjects had significantly greater BMI, BP levels, plasma
leptin and whole-body NE spillover compared to lean (BMI<25 kg/m(2)) subjects, but the NE clearance was similar.
Overweight-obese subjects had significantly higher frequencies of the Arg223 allele and the Arg223 homozygous allele of Gln223Arg and the Asn656 allele of Lys656Asn compared to lean subjects. Subjects carrying the Arg223 homozygous or the Asn656 allele had higher levels of plasma
leptin, BMI, waist circumference, and waist-to-hip ratio, but significantly less whole-body NE spillover, especially when they were also
overweight-obese. BP levels and whole-body NE clearance were similar between subjects with and without the Arg223 homozygous or Asn656 allele. No differences were found in the distributions of the Arg109 allele of Lys109Arg polymorphism between nonobese and
overweight-obese subjects. In addition, BMI, BP, plasma
leptin levels, whole-body NE spillover and whole-body NE clearance were similar between those with and without the Arg109 allele. Together, these findings demonstrate that
leptin-receptor polymorphisms were related to the incidence of
obesity in a Caucasian male population. These polymorphisms were accompanied by high plasma
leptin levels (
leptin resistance) and lower whole-body plasma NE spillover (blunted sympathetic nerve activity). We therefore hypothesize that
leptin-receptor play a role in the development of
obesity through
leptin resistance and blunted
leptin-mediated sympathetic nerve activity.