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≥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 overweightobese 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. (Hypertens Res 2008; 31: 1093-1100)

Genetic Determination of Serum Levels of Diabetes-Associated Adipokines

“…In a Caucasian male population, carriers of the Asn656-allele had significantly higher levels of plasma leptin ( Table 2) [148]. Another study revealed that in 132 men with obesity undergoing a polyunsaturated fatty acid-enriched hypocaloric diet, leptin levels were significantly decreased in the group homozygote for the Lys656-allele after 2 months of intervention [152].…”

“…The p.Q223R (rs1137101 A/G) polymorphism in LEPR is the most investigated. While some studies reported an association of the variant coding for the glutamine ("Q") allele with higher plasma leptin serum levels [142,143], others found that the arginine ("R") allele was associated with increased leptin levels ( Table 2) [144][145][146][147][148]. At the amino acid level, this polymorphism leads to a change in electric charge from neutral to positive in this position, and may thereby affect the functionality of the receptor and alter its signaling capacity.…”

Genetic Determination of Serum Levels of Diabetes-Associated Adipokines

“…The p.Q223R (rs1137101 A/G) polymorphism in LEPR is the most investigated. While some studies reported an association of the variant coding for the glutamine ("Q") allele with higher plasma leptin serum levels [142,143], others found that the arginine ("R") allele was associated with increased leptin levels ( Table 2) [144][145][146][147][148]. At the amino acid level, this polymorphism leads to a change in electric charge from neutral to positive in this position, and may thereby affect the functionality of the receptor and alter its signaling capacity.…”

Funkcjonalne polimorfizmy genów leptyny i receptora leptyny korelują z długowiecznością oraz z ryzykiem zawału mięśnia serca i cukrzycy 2 typu

“…The presence of the Q223R LEPR G allele was previously associated with obesity [46][47][48]. However, the findings regarding its association with altered glucose and lipid metabolism are conflicting [48][49][50][51].…”