title: Leptin-receptor polymorphisms relate to obesity through blunted leptin-mediated sympathetic nerve activation in a Caucasian male population.
abstract: 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.
authors: Human Neurotransmitter Laboratory, Baker Heart Research Institute, Melbourne, Australia. kmasuo@baker.edu.au
authors: Kazuko
authors: K
authors: Masuo
authors: Nora E
authors: NE
authors: Straznicky
authors: Gavin W
authors: GW
authors: Lambert
authors: Tomohiro
authors: T
authors: Katsuya
authors: Ken
authors: K
authors: Sugimoto
authors: Hiromi
authors: H
authors: Rakugi
authors: Florentia
authors: F
authors: Socratous
authors: Jacqueline
authors: J
authors: Hastings
authors: Elisabeth A
authors: EA
authors: Lambert
authors: Toshio
authors: T
authors: Ogihara
authors: Murray D
authors: MD
authors: Esler
mesh_terms: D000328:Adult; D000483:Alleles; D001794:Blood Pressure; D015992:Body Mass Index; D006801:Humans; D020738:Leptin / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000235:genetics / Q000503:physiopathology*; D011110:Polymorphism, Genetic; D054411:Receptors, Leptin / Q000235:genetics*; D013564:Sympathetic Nervous System / Q000503:physiopathology*; D044465:White People
chemical_list: D020738:Leptin; D054411:Receptors, Leptin