Plasma Soluble Leptin Receptor Levels Research Articles

LEPR Gene Polymorphism and Plasma Soluble Leptin Receptor Levels are Associated with Polycystic Ovary Syndrome in Han Chinese Women

To investigate the association of LEPR polymorphisms and plasma leptin and soluble leptin receptor (sOB-R) levels with polycystic ovary syndrome (PCOS) in Chinese women. LEPR Lys109Arg (rs1137100) and Gln223Arg (rs1137101) polymorphisms of PCOS patients and the controls were genotyped. Plasma leptin and sOB-R levels of two groups were measured. The genotypic distributions of Lys109Arg (rs1137100) differed between the PCOS and control groups. Plasma sOB-R levels increased significantly in PCOS patients and were associated with PCOS independent of BMI. Furthermore, luteinizing hormone, triglyceride and fasting blood glucose correlated significantly to PCOS patients' sOB-R levels. LEPR Lys109Arg (rs1137100) was associated with PCOS susceptibility and genotype AA was deduced to be a protective factor for PCOS; sOB-R levels might be recognized as a new indicator for the severity of PCOS.

Plasma soluble leptin receptor levels are associated with pancreatic β-cell dysfunction in patients with type 2 diabetes.

Aims/IntroductionA soluble form of the leptin receptor (soluble Ob‐R) in the circulation regulates leptin's bioactivity, and is inversely associated with body adiposity and circulating leptin levels. However, no study has examined the clinical impact of soluble Ob‐R on glucose metabolism in diabetes. The present study aimed to investigate the association of plasma soluble Ob‐R levels with insulin resistance and pancreatic β‐cell function in patients with type 2 diabetes.Materials and MethodsA total of 289 Japanese patients with type 2 diabetes were included in the present study. Fasting plasma soluble Ob‐R levels and plasma leptin levels were measured by enzyme‐linked immunosorbent assay. Insulin resistance and pancreatic β‐cell function were estimated by homeostasis model assessment of insulin resistance, homeostasis model assessment of β‐cell function and fasting C‐peptide index.ResultsThe median plasma soluble Ob‐R level and plasma leptin level were 3.4 ng/mL and 23.6 ng/mL, respectively. Plasma soluble Ob‐R levels were negatively correlated with homeostasis model assessment of insulin resistance, homeostasis model assessment of β‐cell function and the C‐peptide index, whereas plasma leptin levels were positively correlated with each index in univariate analyses. Multivariate analyses including plasma soluble Ob‐R levels, plasma leptin levels and use of sulfonylureas, along with age, sex, body mass index and other covariates, showed that soluble Ob‐R levels were independently and negatively associated with homeostasis model assessment of β‐cell function and the C‐peptide index, but not significantly associated with homeostasis model assessment of insulin resistance.ConclusionsPlasma soluble Ob‐R levels are independently associated with pancreatic β‐cell function, but not with insulin resistance, in patients with type 2 diabetes. The present study implicates the role of soluble Ob‐R in pancreatic β‐cell dysfunction in type 2 diabetes.

Genome-wide association study identifies polymorphisms in LEPR as determinants of plasma soluble leptin receptor levels

Genome-wide association study identifies polymorphisms in LEPR as determinants of plasma soluble leptin receptor levels

Genome-wide association study identifies polymorphisms in LEPR as determinants of plasma soluble leptin receptor levels

Plasma soluble leptin receptor (sOB-R) levels were inversely associated with diabetes risk factors, including adiposity and insulin resistance, and highly correlated with the expression levels of leptin receptor, which is ubiquitously expressed in most tissues. We conducted a genome-wide association study of sOB-R in 1504 women of European ancestry from the Nurses' Health Study. The initial scan yielded 26 single nucleotide polymorphisms (SNPs) significantly associated with sOB-R levels (P < 5 x 10(-8)); all mapping to the leptin receptor gene (LEPR). Analysis of imputed genotypes on autosomal chromosomes revealed an additional 106 SNPs in and adjacent to this gene that reached genome-wide significance level. Of these 132 SNPs (including two non-synonymous SNPs, rs1137100 and rs1137101), rs2767485, rs1751492 and rs4655555 remained associated with sOB-R levels at the 0.05 level (P = 9.1 x 10(-9), 0.0105 and 0.0267, respectively) after adjustment for other univariately associated SNPs in a forward selection procedure. Significant associations with these SNPs were replicated in an independent sample of young males (n = 875) residing in Cyprus (P < 1 x 10(-4)). These data provide novel evidence revealing the role of polymorphisms in LEPR in modulating plasma levels of sOB-R and may further our understanding of the complex relationships among leptin, leptin receptor and diabetes-related traits.

Modulation of Direct Leptin Signaling by Soluble Leptin Receptor

Soluble leptin receptor (SLR) represents the major leptin binding activity in plasma. It is generated by alternative splicing of OB-R mRNA (OB-Re) and/or ectodomain shedding of membrane-spanning receptors. To determine the role of SLR in leptin activation of its long-form receptor, OB-Rb, we established in vitro assays using a cell line stably expressing OB-Rb. Human embryonic kidney 293 cell lines stably overexpressing OB-Rb show a dose-dependent leptin-induced signal transducer and activator of transcription 3 (STAT3) tyrosine phosphorylation and STAT3-responsive luciferase (STAT3-luc) activity. We demonstrate that when SLR is incubated with free leptin, binding of leptin to OB-Rb is reduced, with corresponding decrease of leptin-induced STAT3 tyrosine phosphorylation and STAT3-luc activity. However, by preparing leptin/SLR mixtures containing the same amount of free leptin but increasing amounts of leptin-SLR complex, we show that leptin-SLR complex does not inhibit OB-Rb activation by free leptin. These results suggest that in settings in which leptin and SLR coexist, SLR may sequester leptin from productive interactions with OB-Rb. Because plasma SLR levels are independently regulated by many different physiological and pathophysiological conditions, SLR may modulate the actions of leptin in tissues in which direct action of leptin has been demonstrated.

No Influence of Surgical Stress on Postoperative Leptin Gene Expression in Different Adipose Tissues and Soluble Leptin Receptor Plasma Levels

As part of the postsurgical stress response, plasma leptin levels increase in-between 12 h postoperatively. Objective: To study the kinetics of leptin gene expression in different adipose tissues before and after severe surgical trauma in children and adults. Methods: In 22 adults and 23 children with cardiac and 19 adult patients with abdominal surgery, we measured plasma leptin concentrations preoperatively, 4 and 10–17 h postoperatively and quantified leptin mRNA expression by TaqMan real-time PCR in adipose tissue taken at the beginning and the end of surgery from subcutaneous, intrathoracic, omental and mesenteric fat. Plasma-soluble leptin receptor levels were measured in 23 children after cardiosurgery. Results: Plasma leptin levels doubled between 4 and 10–17 h postoperatively in adults (p < 0.001) as well as in children (p = 0.0002) with cardiac surgery. After abdominal surgery, 10–17 h postoperatively, plasma leptin concentrations increased significantly (p < 0.05). During the operation, leptin gene expression did not change in neither of the patient groups. Plasma-soluble leptin receptor levels decreased immediately after the onset of surgery and remained unchanged thereafter. Conclusions: Leptin gene expression is not up-regulated during surgery. The measured increase in plasma leptin after surgery does not result from elevated levels of soluble leptin receptor but may follow an up-regulation of leptin gene expression later after the operation due to postsurgical metabolic changes.

Obesity is associated with decreasing levels of the circulating soluble leptin receptor in humans.

Leptin plays a major role in the regulation of body weight. It circulates in both free and bound form. One of the leptin receptor isoforms exists in a circulating soluble form that can bind leptin. In the present study, we measured the soluble leptin receptor (SLR) levels in lean and obese humans. We investigated the relationship between plasma SLR levels, plasma leptin levels and the degree of obesity. We also examined whether SLR concentrations could be modulated by fat mass loss induced by a 3 month weight-reducing diet. A total of 112 obese (age 18-50 y; body mass index (BMI) 30-44 kg/m2; 23 men and 89 women), 38 overweight (age 19-48 y; BMI 25-29 kg/m2; 10 men and 28 women) and 63 lean (age 18-50 y; BMI 17-24 kg/m2; 16 men and 47 women) humans. A direct double monoclonal sandwich enzyme-linked immunosorbent assay (ELISA) was used for the quantitative measurement of the soluble human leptin receptor. Leptin was measured by radioimmunoassay (RIA). Body composition was assessed by biphotonic absorptiometry DEXA (dual energy X-ray absorptiometry). We observed that the SLR is present in human plasma (range 10-100 ng/ml). SLR levels were lower in obese and overweight than lean subjects (28.7+/-8.8, 40.2+/-14.9, 51.2+/-12.5 ng/ml, respectively) and were inversely correlated to leptin and percentage of body fat (r=-0.74 and r=-0.76; respectively; P<0.0001). The ratio of circulating leptin to SLR was strongly related to the percentage of body fat (r=0.91; P<0.0001). Interestingly a gender difference was observed in SLR levels, which were higher in obese and overweight men than in obese and overweight women. In obese subjects after a 3 month low-calorie diet, SLR levels increased in proportion to the decrease in fat mass. In the gel filtration profile, SLR coeluted exactly with the bound leptin fractions. Obesity, in humans is associated with decreasing levels of the circulating soluble leptin receptor (SLR). The relationship of SLR with the degree of adiposity suggests that high SLR levels may enhance leptin action in lean subjects more than in obese subjects.