The role of soluble leptin receptor in the pathogenesis of coronary heart disease

Introduction. The participation of soluble leptin receptor (SLR) in the formation of hyperleptinemia and leptin resistance in patients with coronary artery disease (CAD) in combination with obesity is discussed. Aim. Study of the role of SLR in the pathogenesis of ischemic heart disease. Materials and methods. A cohort study of 744 patients was performed: 465 patients with CAD (56 years old, Q1=44; Q3=62), 270 patients without CAD (52 years old, Q1=44; Q3=56). Methods: EchoCG, heart computed tomography, coronary angiography. In the blood serum, the lipids, glucose, creatinine, uric acid, and c-reactive protein were assessed using a highly sensitive method (HF-CRP). Concentrations of SLR, leptin (LN), adiponectin (total and high molecular weight), fatty acid binding protein-4 (FABP-4) tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), serum insulin were determined by enzyme immunoassay. Results. The level of SLR in blood serum in men and women with CAD is lower than in men without CAD (p <0.001). In CAD patients, obesity was associated with a low SLR level in the blood serum and a high free LN index. At a serum SLR concentration of <7.5ng/ml in men with CAD, the incidence of obesity was higher simultaneously with signs of visceral obesity of the heart, the presence of atherosclerotic plaques in the common carotid arteries, high glycaemic levels, insulin, IL-6, and LN in serum, serum LN/adiponectin ratio and a high HOMA-IR index. Diabetes mellitus, visceral obesity, high levels of hs-CRP, TNF-α, FABP-4, serum insulin, and HOMA-IR index were more often detected in women with coronary artery disease with SLR <10.2 ng/ml. In men and women with CAD, there were no differences in SLR concentration depending on the extent of coronary atherosclerosis. Conclusion. An increase in the free LN index indicates the disruption of connections in the leptin-receptor system and reflects the mechanisms of compensation for overcoming the resistance of peripheral tissues to leptin, which is confirmed by a noticeable negative relationship between the levels of SLR and leptin in the serum of men with coronary artery disease. A low concentration of SLR in patients with CAD is associated with obesity, pro-atherogenic and pro-inflammatory markers of cardiovascular diseases.

Exocrine Pancreatic Function in Girls with Anorexia Nervosa

Objectives: To assess pancreatic exocrine function in patients with anorexia nervosa using a breath test with 13C-labeled mixed triglycerides (MTG-BT) and to determine the relationship between the test results and selected biochemical and hormonal parameters. Material and methods: Anthropometric measurements, biochemical and hormonal parameters (serum leptin, soluble leptin receptor (sLR), acylated and desacylated ghrelin, free leptin index (FLI)), and MTG-BT were performed in a group of 31 girls with the restrictive type of AN, as well as 38 healthy girls (C). Results: The average cumulative dose of 13C-triglycerides recovered with exhaled air (%CD) was similar in both study groups, while the average time from 13C-triglycerides administration to peak 13CO2 excretion in expired air (time to peak (TTP)) was significantly longer in patients with AN compared to C. In both groups, %CD correlated negatively with FLI. TTP correlated negatively with sLR and FLI in the AN and with serum insulin and HOMA-IR values in the C. Conclusions: In girls with AN, the pancreatic efficiency of lipase secretion was found to be normal, while the kinetics of this enzyme secretion were disturbed. These changes may result from disorders in the functioning of the adipose–insular and islet–acinar axes.

Circulating Level of Soluble Leptin Receptor and its Association with Cardiometabolic Risk Factors among Obese Subjects in Kerala, South India

Background and Aims: Leptin, the peptide hormone secreted mainly by adipose tissue is reported to play the central role in the pathogenesis of obesity. Leptin exerts its biological effects through specific receptor molecules present in target tissues. Among the different isoforms of leptin receptor, the Soluble Leptin Receptor (SLR) is the major leptin binding protein seen in circulation which modulates the bioavailability of leptin. Our objectives were to analyse the level of circulating SLR among obese subjects and its association with biomarkers of obesity, serum leptin, insulin and cardiometabolic risk factors in comparison with healthy age and sex matched control subjects. Methods: About 173 study participants of both genders were selected and grouped as case (n=102) and control (n=71) with a cut off point of BMI 25kg/m2. Waist to hip ratio (WHR) and body fat percentage (BF%) were calculated from anthropometric measurements. Leptin, insulin, soluble leptin receptor were estimated in fasting blood samples by sandwich ELISA method. Fasting plasma glucose and lipid profile were measured by standard enzymatic methods in autoanalyzer. Homeostasis Model Assessment of Insulin resistance (HOMA-IR) was calculated. Comparison between groups was done by independent sample ‘t’ test. P values <.05 were considered statistically significant. Results: The SLR level was found to be increased in obese group in comparison with control group(P =.001). A significant increase in serum leptin and insulin level was observed in obese group when compared to control (P =.001). Obese group showed more than two fold increase in insulin resistance expressed as HOMA-IR when compared to control subjects (P =.001). But no significant difference in the synthesis of insulin expressed as HOMA-beta between the groups. No significant difference in serum lipoprotein levels was observed between the two groups. Conclusion: Increased level of circulating soluble leptin receptor has been observed in obese subjects in comparison with control subjects and is associated with hyperleptinemia, hypertension and insulin resistance.

Free Leptin Index is Elevated in Preeclamptic but not Healthy Women throughout Gestation. A Prospective Cohort Study

The ratio leptin/soluble leptin receptor (sOB-r), free leptin index (FLI), is used as a marker of leptin sensitivity/resistance in different pathologies. The aim of this study was to evaluate FLI in healthy non-pregnant, healthy pregnant and mild preeclamptic women during pregnancy. We conducted a nested case-control study within a longitudinal observational prospective cohort study. Serum leptin (p=0.0001) and sOB-r (p=0.0000) levels rose significantly throughout pregnancy in healthy pregnant and preeclamptic women [leptin (p=0.0000); sOB-r (p=0.0380)]. Serum leptin levels were significantly higher in preeclamptic compared to healthy pregnant women at 2nd (p=0.0245) and 3rd trimesters of pregnancy (p=0.0016). Additionally, serum sOB-r levels were significantly lower in preeclamptic women during the 2nd (p=0.0236) and 3rd trimester (p=0.0024) of pregnancy compared to healthy pregnant women. Moreover, we found that FLI did not vary significantly during any of the three periods studied in healthy pregnant women (p=0.7640), whereas, increased throughout preeclamptic pregnancy (p=0.0037). Indeed, FLI was significantly higher at 2nd (p=0.0053) and 3rd (p=0.0003) trimesters of pregnancy in preeclamptic compared to healthy pregnant women. Additionally, FLI was significantly higher during luteal phase compared to the follicular phase (p=0.0039). These results demonstrate that FLI increases significantly in preeclamptic pregnant women towards the end of pregnancy.

Quantile-specific heritability of sibling leptin concentrations and its implications for gene-environment interactions

Abstract“Quantile-dependent expressivity” occurs when the effect size of a genetic variant depends upon whether the phenotype (e.g., leptin) is high or low relative to its distribution. Leptin concentrations are strongly related to adiposity, whose heritability is quantile dependent. Whether inheritance of leptin concentrations is quantile dependent, and whether this explains the greater heritability in women than men in accordance with their greater adiposity, and explains other gene-environment interactions, remains to be determined. Therefore, leptin and leptin receptor concentrations from 3068 siblings in 1133 sibships from the Framingham Heart Study Third Generation Cohort were analyzed. Free leptin index (FLI) was calculated as the ratio of leptin to soluble leptin receptor concentrations. Full-sib (βFS) regression slopes were robustly estimated by quantile regression with nonparametric significance assigned from 1000 bootstrap samples. The analyses showed βFS increased significantly with increasing percentiles of the offspring’s age- and sex-adjusted leptin distribution (Plinear = 0.0001), which was accelerated at the higher concentrations (Pquadratic = 0.0003). βFS at the 90th percentile (0.418 ± 0.066) was 4.7-fold greater than at the 10th percentile (0.089 ± 0.032, Pdifference = 3.6 × 10−6). Consistent with quantile-dependent expressivity, the βFS was greater in female sibs, which was attributable to their higher leptin concentrations. Reported gene-environment interactions involving adiposity and LEP, LEPR, MnSOD, PPARγ, PPARγ2, and IRS-1 polymorphisms were consistent with quantile-dependent expressivity of leptin concentrations. βFS for leptin receptor concentrations and free leptin index also increased significantly with increasing percentiles of their distributions (Plinear = 0.04 and Plinear = 8.5 × 10−6, respectively). In conclusion, inherited genetic and shared environmental effects on leptin concentrations were quantile dependent, which likely explains male–female differences in heritability and some gene-environment interactions.

CB1R regulates soluble leptin receptor levels via CHOP, contributing to hepatic leptin resistance

The soluble isoform of leptin receptor (sOb-R), secreted by the liver, regulates leptin bioavailability and bioactivity. Its reduced levels in diet-induced obesity (DIO) contribute to hyperleptinemia and leptin resistance, effects that are regulated by the endocannabinoid (eCB)/CB1R system. Here we show that pharmacological activation/blockade and genetic overexpression/deletion of hepatic CB1R modulates sOb-R levels and hepatic leptin resistance. Interestingly, peripheral CB1R blockade failed to reverse DIO-induced reduction of sOb-R levels, increased fat mass and dyslipidemia, and hepatic steatosis in mice lacking C/EBP homologous protein (CHOP), whereas direct activation of CB1R in wild-type hepatocytes reduced sOb-R levels in a CHOP-dependent manner. Moreover, CHOP stimulation increased sOb-R expression and release via a direct regulation of its promoter, while CHOP deletion reduced leptin sensitivity. Our findings highlight a novel molecular aspect by which the hepatic eCB/CB1R system is involved in the development of hepatic leptin resistance and in the regulation of sOb-R levels via CHOP.

Disordered leptin and ghrelin bioactivity in adolescent idiopathic scoliosis (AIS): a systematic review and meta-analysis

Background Adolescents with scoliosis consistently demonstrate lower body weight, lean muscle mass, and bone mineral density than healthy adolescent counterparts. Recent studies have focused on understanding how leptin and ghrelin signaling may play a role in adolescent idiopathic scoliosis (AIS). In our current study, we aim to evaluate the serum levels of leptin, soluble leptin receptor (sOB-R), and ghrelin in AIS patients through systematic review and meta-analysis. Methods We conducted our systematic review by searching the keywords in online databases including PubMed, Embase, Cochrane, Elsevier, Springer, and Web of Science from the time of database inception to January 2020. Inclusion criteria were studies that measure leptin, soluble leptin receptor (sOB-R), and ghrelin levels in AIS patients. Selection of studies, assessment of study quality, and data extraction were performed by two reviewers independently. Then, data was analyzed to calculate the mean difference and 95% confidence interval (CI). Results Seven studies concerning leptin/sOB-R and three studies concerning ghrelin were qualified for meta-analysis (one study concerning both leptin and ghrelin). Serum leptin of patients with AIS were significantly lower when compared with healthy controls, with the weighted mean difference (WMD) of − 0.95 (95% CI − 1.43 to − 0.48, p < 0.0001) after reducing the heterogeneity using six studies for meta-analysis, while sOB-R and ghrelin level was significantly higher in AIS group when compared with control group, with the WMD of 2.64 (95% CI 1.60 to 3.67, p < 0.001) and 1.42 (95% CI 0.48 to 2.35, p = 0.003), respectively. Conclusion Our current meta-analysis showed that serum level of leptin in AIS patients was significantly lower when compared with control subjects, while serum sOB-R and ghrelin levels were significantly higher in AIS patients. More clinical studies are still required to further validate the predictive value of leptin or ghrelin for the curve progression for AIS patients.