Soluble Leptin Receptor Research Articles

1517-P: A Longitudinal Study of a Panel of Adipokines and Gestational Diabetes Risk

Prospective studies with measurement of a comprehensive panel of adipokines in early pregnancy and gestational diabetes (GDM) risk are sparse, and studies of adipokines for prediction of GDM are limited. We investigated a panel of adipokines in relation to GDM risk. In a nested case-control study within the NICHD Fetal Growth Studies-Singleton cohort (2009-2013), we identified 107 GDM cases and selected 214 controls matched on age, race/ethnicity, and gestational week (GW) at blood draw. Plasma Leptin, Soluble Leptin Receptor (sOB-R), Free Leptin, Chemerin, Fatty Acid Binding Protein 4 (FABP4), Retinol Binding Protein 4, Adiponectin, Omentin1, and Vaspin were measured prior to GDM at GWs 10-14, 15-26. Adjusting for maternal age, GW of blood collection, nulliparity, and family history of diabetes, conditional logistic analysis was performed to estimate adjusted odds ratios (aOR) for associations of adipokines with GDM. Receiver-operating-characteristic (ROC) curves assessed the predictive value of adipokines for GDM diagnosis. Leptin, Free Leptin, Chemerin, and FABP4 concentrations were significantly higher. Adiponectin, and sOB-R were significantly lower among cases than controls. At GW 10-14, Adiponectin, and sOB-R were significantly and inversely related to GDM risk. For example, across increasing quartiles of sOB-R the aOR were 1.00 (ref), 0.37 (0.19, 0.74), 0.28 (0.13, 0.59), and 0.24 (0.11, 0.52) (Ptrend≤.0001). In contrast, Leptin, Free Leptin, Chemerin, and FABP4 were significantly and positively associated with GDM risk. In general, associations of adipokines with GDM were stronger at GW 15-26. In addition, at GW 15-26, sOB-R significantly improved GDM prediction over conventional risk factors (age, GW, race, nulliparity, family history of diabetes, prepregnancy BMI) and glucose (P = 0.02). A panel of adipokines may be implicated in the pathogenesis of GDM with significant associations and incremental predictive value detected in early pregnancy before GDM is usually screened for. Disclosure E.C. Francis: None. M. Li: None. S. Hinkle: None. J. Chen: None. L. Chen: None. C. Zhang: None. Funding National Institutes of Health

1486-P: Longitudinal Interrelationships of Adiposity-Associated Biomarkers in Women

Background: Most prior studies on associations of adiposity-associated biomarkers are cross-sectional. Understanding their longitudinal interrelationships may provide mechanistic insights into biologic pathways that lead to cardiometabolic diseases. Methods: We included 850 healthy women in the Nurses’ Health Study II (mean age: 45y) who provided two blood samples in 1996-1999 and 2010-2011 and measured plasma concentrations of adiponectin (ADPN), leptin, soluble leptin receptor, insulin, retinol binding protein-4, high-sensitivity C-reactive protein (hsCRP), and interleukin-6 (IL-6). All biomarkers were log2-transformed. Spearman partial correlations were used to examine cross-sectional biomarker associations at baseline and follow-up. Multivariable general linear models were used to evaluate associations of each biomarker change over 13 years with (1) concurrent changes in other biomarkers (change-change) and (2) baseline levels of other biomarkers (baseline-change). Results: In cross-sectional analyses, most biomarkers were correlated after multivariable adjustment including BMI (p<0.05) both at baseline and follow-up, with the strongest associations observed between leptin/insulin and hsCRP/IL-6. There were similar associations in the change-change analysis with multivariable adjustment including weight change. However, only two associations were consistently present in the baseline-change analysis after multivariable adjustment including baseline BMI. Every doubling in baseline hsCRP was associated with 3.1% leptin change (p=0.01), whereas every doubling in baseline ADPN was associated with -9.2% insulin change (p=0.01). Notably, baseline insulin was not associated with other biomarker changes. Conclusions: While most adiposity-associated biomarkers were interrelated both cross-sectionally and longitudinally, our results suggest that baseline hsCRP and ADPN were strong predictors for long-term changes in leptin and insulin, respectively. Disclosure M. Baden: Other Relationship; Self; Manpei Suzuki Diabetes Foundation. F. Hu: None. T. Huang: None. Funding National Institutes of Health; Manpei Suzuki Diabetes Foundation

A Longitudinal Study of a Panel of Adipokines and Gestational Diabetes Risk (OR36-01-19)

ObjectivesProspective studies with measurement of a comprehensive panel of adipokines in early pregnancy and gestational diabetes (GDM) risk are sparse, and studies of adipokines for prediction of GDM are limited. We aimed to prospectively investigate a comprehensive panel of adipokines in relation to GDM risk. MethodsWe investigated a panel of adipokines in relation to GDM risk. In a nested case-control study within the NICHD Fetal Growth Studies-Singleton cohort (2009–2013), we identified 107 GDM cases and selected 214 controls matched on age, race/ethnicity, and gestational week (GW) at blood draw. Plasma Leptin, Soluble Leptin Receptor (sOB-R), Free Leptin, Chemerin, Fatty Acid Binding Protein 4 (FABP4), Retinol Binding Protein 4, Adiponectin, Omentin1, and Vaspin were measured prior to GDM at GWs 10–14, 15–26. Adjusting for maternal age, GW of blood collection, nulliparity, and family history of diabetes, conditional logistic analysis was performed to estimate adjusted odds ratios (aOR) for associations of adipokines with GDM. Receiver-operating-characteristic (ROC) curves assessed the predictive value of adipokines for GDM diagnosis. ResultsBefore GDM diagnosis, Leptin, Free Leptin, Chemerin, and FABP4 concentrations were significantly higher, and Adiponectin, and sOB-R were lower among cases than controls. At GW 10–14, Adiponectin, and sOB-R were significantly and inversely related to GDM risk. For example, across increasing quartiles of sOB-R the aOR were 1.00 (ref), 0.37 (0.19, 0.74), 0.28 (0.13, 0.59), and 0.24 (0.11, 0.52) (Ptrend ≤ .0001). In contrast, Leptin, Free Leptin, Chemerin, and FABP4 were significantly and positively associated with GDM risk; Ptrend ≤ .0001, ≤.0001, 0.005, 0.004, respectively. In general, associations of adipokines with GDM were stronger at GW 15–26. In addition, at GW 15–26, sOB-R significantly improved GDM prediction over conventional risk factors (age, GW, race, nulliparity, family history of diabetes, prepregnancy BMI) and glucose (P = 0.02). ConclusionsA panel of adipokines may be implicated in the pathogenesis of GDM with significant associations and incremental predictive value detected in early pregnancy before GDM is usually screened for. Funding SourcesEllen Francis was supported by the Graduate Partnership Program in the Office of Intramural Training & Education, a component of the National Institutes of Health. Supporting Tables, Images and/or Graphs▪

The relationship of epicardial obesity and levels of cardiac fibrosis markers

Lipotoxic myocardial damage with its fibrosis and subsequent formation of heart failure may develop due to epicardial obesity (EO). The possibility of early diagnosis of lipotoxic cardiac fibrosis is not well understood.Aim.To study the relationship of EO with the level of myocardial fibrosis markers.Material and methods.The study included 80 men aged 54,3±8,2 with grades I-III obesity. The level of metabolic factors, pro-inflammatory cytokines, adipokines (adiponectin, leptin), soluble leptin receptor and free fatty acids was determined for all patients; the presence of EO was determined by echocardiography with epicardial fat thickness (EFT) ≥7 mm. Coronary artery disease, arterial hypertension, type 2 diabetes mellitus, the presence of left ventricular diastolic dysfunction were the exclusion criteria of the study.Results.The patients were divided into 2 groups: group I with EO (n=49) and group II without EO (n=31). Group I showed a statistically significant increase in the levels of interleukin-6 (IL-6), C-reactive protein, tumor necrosis factor-α (TNF-α), leptin, a decrease in adiponectin, as well as an increase in all studied myocardial fibrosis markers. In addition, in the group with EO, a positive relationship between the EFT and TNF-α (r=0,29; p=0,041), IL-6 (r=0,28; p=0,049), leptin (r=0,41; p=0,004) and a negative relationship with the level of adiponectin (r=-0,29; p=0,042). We determine a significant effect of the degree of EO on the increase in the level of cardiac fibrosis markers (r=0,28, p=0,049), collagen (r=0,33, p=0,019), transforming growth factor-β (r=0,29, p=0,045).Conclusion.The results suggest that elevated levels of profibrotic factors in patients with EO may be signs of the presence of preclinical, and therefore, earlier lipotoxic myocardial fibrosis, which was not detected during echocardiographic research in the form of diastolic dysfunction.

Platelet Serotonin Levels Are Associated with Plasma Soluble Leptin Receptor Concentrations in Normoglycemic Women.

Most peripheral serotonin (5-hydroxytryptamine (5HT)) is synthetized in the gut with platelets being its main circulating reservoir. 5HT is acting as a hormone in key organs to regulate glucose and lipid metabolism. However, the relation between platelet 5HT levels and traits related to glucose homeostasis and lipid metabolism in humans remains poorly explored. The objectives of this study were (a) to assess the association between platelet 5HT levels and plasma concentration of nonesterified fatty acids (NEFAs) and some adipokines including leptin and its soluble leptin receptor (sOb-R), (b) to assess the association between platelet 5HT levels and anthropometric traits and indexes of insulin secretion/sensitivity derived from oral glucose tolerance test (OGTT), and (c) to evaluate changes in platelet 5HT levels in response to OGTT. In a cross-sectional study, 59 normoglycemic women underwent a standard 2-hour OGTT. Plasma leptin, sOb-R, total and high molecular weight adiponectin, TNFα, and MCP1 were determined by immunoassays. Platelet 5HT levels and NEFAs were measured before and after OGTT. The free leptin index was calculated from leptin and sOb-R measurements. Insulin sensitivity indexes derived from OGTT (HOMA-S and Matsuda ISICOMP) and plasma NEFAs (Adipose-IR, Revised QUICKI) were also calculated. Our data show that among metabolic traits, platelet 5HT levels were associated with plasma sOb-R (r = 0.39, p = 0.003, corrected p = 0.018). Platelet 5HT levels were reduced in response to OGTT (779 ± 237 vs.731 ± 217 ng/109 platelets, p = 0.005). In conclusion, platelet 5HT levels are positively associated with plasma sOb-R concentrations and reduced in response to glucose intake possibly indicating a role of peripheral 5HT in leptin-mediated appetite regulation.

Adipokines, cortisol and cytokine alterations in recent onset anorexia nervosa. A case–control study

IntroductionPsychological and neuroendocrine alterations are typical characteristics in anorexia nervosa patients. The role of adipokines and cytokines as mediators of body systems’ adaptations to the patients’ abnormal eating behavior is not well understood. The duration of disease seems to be a determinant of nutritional status and associated hormone changes. We aimed to assess whether alterations in adipokines, cytokines and cortisol do already exist in patients with a recent disease onset by means of a case–control study. MethodsForty-one adolescent female patients on their first-episode and diagnosed with anorexia nervosa, were matched by age and socioeconomic status (SES) (1:1) with healthy girls. Leptin, soluble leptin receptor (sOB-R), adiponectin, cortisol, and the cytokines IL-1β, IL-2, IL-6 and TNF-α were examined. ResultsThe results showed reduced leptin and increased sOB-R and cortisol levels in AN patients. Adiponectin was also increased but opposite to the previous biomarkers did not correlate with BMI Z-score. Serum TNF-α and IL-2 showed significantly lower and higher values, respectively, in the AN patients than in the controls. Cortisol showed the strongest correlation with sOB-R (r=0.436; P=0.005). ConclusionsOur study confirms previous findings on adipokine and cortisol alterations in AN patients, while overall cytokine results did not show a clear disruption in AN patients with short disease duration. The results highlight the need to disentangle the role of the sOB-R in the interactions between leptin and cortisol secretion.

Change in Plant-Based Diet Quality Is Associated with Changes in Plasma Adiposity-Associated Biomarker Concentrations in Women

ABSTRACTBackgroundA healthful plant-based diet is associated with lower risk of cardiometabolic diseases. However, it is still unclear whether such benefits are due to its favorable effects on adiposity-associated biomarkers.ObjectiveWe investigated the associations between biomarkers and 3 plant-based diet indices: an overall plant-based diet index (PDI); a healthful plant-based diet index (hPDI); and an unhealthful plant-based diet index (uPDI).MethodsIn the Nurses’ Health Study II, 831 women [baseline mean age: 45 y; body mass index (BMI, kg/m2): 24.6] were randomly selected from those who provided 2 blood samples in 1996–1999 and 2010–2011 to measure plasma concentrations of adiponectin, leptin, soluble leptin receptor (sOB-R), insulin, retinol-binding protein-4, high-sensitivity C-reactive protein (hsCRP), and interleukin-6 (IL-6). Plant-based diet indices were derived from semiquantitative food frequency questionnaires assessed at each blood collection. Linear mixed models were used to evaluate cross-sectional associations, and general linear models were used to evaluate longitudinal associations.ResultsIn cross-sectional analyses with multivariable adjustment including BMI, higher hPDI was associated with lower concentrations of leptin, insulin, and hsCRP, and higher adiponectin and sOB-R concentrations (biomarker differences per 10-point higher hPDI: −7.2%, −10.0%, −13.6%, 3.0%, and 1.9%, respectively; P ≤ 0.025). A higher uPDI was associated with higher concentrations of leptin and insulin (4.4% and 4.8%, respectively; P ≤ 0.048). In longitudinal analyses with multivariable adjustment including weight change, an increase in hPDI (improved plant-based diet quality) was inversely associated with changes in leptin and hsCRP (biomarker changes per 10-point hPDI increase: −7.7% and −17.8%, respectively; P ≤ 0.005), whereas an increase in uPDI (worsened plant-based diet quality) was positively associated with changes in leptin, hsCRP, and IL-6 (10.1%, 13.5%, and 12.4%, respectively; P ≤ 0.021).ConclusionsAdherence to a healthful plant-based diet is associated with favorable long-term changes in adiposity-associated biomarker concentrations in women.

Prediction of Circulating Adipokine Levels Based on Body Fat Compartments and Adipose Tissue Gene Expression

Background: Adipokines are hormones secreted from adipose tissue (AT), and a number of them have been established as risk factors for chronic diseases. However, it is not clear whether and to what extent adiposity, gene expression, and other factors determine their circulating levels. Objectives: To assess to what extent adiposity, as measured by the amount of subcutaneous AT (SAT) and visceral AT (VAT) using magnetic resonance imaging, and gene expression levels in SAT determine plasma concentrations of the adipokines adiponectin, leptin, soluble leptin receptor, resistin, interleukin 6, and fatty acid-binding protein 4 (FABP4). Methods: We performed a cross-sectional analysis of 156 participants from the EPIC Potsdam cohort study and analyzed multiple regression models and partial correlation coefficients. Results: For leptin and FABP4 concentrations, 81 and 45% variance were explained by SAT mass, VAT mass, and gene expression in SAT in multivariable regression models. For the remaining adipokines, AT mass and gene expression explained <16% variance of plasma concentrations. Gene expression in SAT was a less important predictor compared to AT mass. SAT mass was a better predictor than VAT mass for leptin (partial correlation r = 0.81, 95% confidence interval 0.75–0.86, vs. r = 0.58, 95% confidence interval 0.46–0.67), while differences between AT compartments were small for the other adipokines. Conclusions: While plasma levels of leptin and FABP4 can be explained in a large and medium part by the amount of AT and SAT gene expression, surprisingly, these predictors explained only little variance for all other investigated adipokines.

Maternal adipokines longitudinally measured across pregnancy and their associations with neonatal size, length, and adiposity.

BACKGROUND/OBJECTIVES:Maternal obesity impacts fetal growth as early as 2nd trimester of pregnancy, yet little is known about the molecular mechanisms involved. We aimed to examine associations between maternal adipokines throughout pregnancy and neonatal size by pre-pregnancy obesity status.METHODS:In a prospective cohort of 2,802 U.S. pregnant women from the NICHD Fetal Growth Studies-Singleton Cohort (2009–2013) biospecimens were analyzed in a matched case-control subset of 321 women. Blood was collected at 10–14, 15–26 (fasting), 23–31, and 33–39 gestational weeks. Plasma leptin and soluble leptin receptor (sOB-R) and total and high-molecular-weight (HMW)-adiponectin were measured. Free leptin was calculated as leptin/sOB-R. Birthweight was abstracted from medical records. Neonatal length and skinfolds were measured.RESULTS:Leptin and sOB-R in late pregnancy tended to be positively and negatively associated with neonatal length, respectively, while free leptin throughout pregnancy tended to be positively associated with length. Free leptin associations with neonatal length were differential by obesity (i.e., inversely among women without obesity and positively among women with obesity). A per unit increase in free leptin at 33–39 weeks was associated with a shorter neonatal length by −0.55cm (95%CI −0.83, −0.28) in women without obesity and longer length by 0.49cm (95%CI 0.34, 0.65) in women with obesity. HMW-adiponectin at 33–39 weeks was inversely associated with neonatal length (β=−1.29cm; 95%CI, −1.74, −0.85) and skinfold thickness (β=−1.46mm; 95%CI, −1.58, −0.56) among women with obesity. Free leptin across pregnancy tended to be negatively associated with neonatal skinfold thickness among women without obesity, while free leptin in early pregnancy was positively associated with skinfold thickness.CONCLUSIONS:Maternal adipokines were associated with multiple pathways that influence neonatal size including length and adiposity, which differed in timing across pregnancy and by pre-pregnancy obesity. These findings provide new potential insights into mechanisms and timing by which maternal obesity may impact fetal growth.

A Network Analysis of Biomarkers for Type 2 Diabetes.

Numerous studies have investigated individual biomarkers in relation to risk of type 2 diabetes. However, few have considered the interconnectivity of these biomarkers in the etiology of diabetes as well as the potential changes in the biomarker correlation network during diabetes development. We conducted a secondary analysis of 27 plasma biomarkers representing glucose metabolism, inflammation, adipokines, endothelial dysfunction, IGF axis, and iron store plus age and BMI at blood collection from an existing case-control study nested in the Nurses' Health Study (NHS), including 1,303 incident diabetes case subjects and 1,627 healthy women. A correlation network was constructed based on pairwise Spearman correlations of the above factors that were statistically different between case and noncase subjects using permutation tests (P < 0.0005). We further evaluated the network structure separately among diabetes case subjects diagnosed <5, 5-10, and >10 years after blood collection versus noncase subjects. Although pairwise biomarker correlations tended to have similar directions comparing diabetes case subjects to noncase subjects, most correlations were stronger in noncase than in case subjects, with the largest differences observed for the insulin/HbA1c and leptin/adiponectin correlations. Leptin and soluble leptin receptor were two hubs of the network, with large numbers of different correlations with other biomarkers in case versus noncase subjects. When examining the correlation network by timing of diabetes onset, there were more perturbations in the network for case subjects diagnosed >10 years versus <5 years after blood collection, with consistent differential correlations of insulin and HbA1c C-peptide was the most highly connected node in the early-stage network, whereas leptin was the hub for mid- or late-stage networks. Our results suggest that perturbations of the diabetes-related biomarker network may occur decades prior to clinical recognition. In addition to the persistent dysregulation between insulin and HbA1c, our results highlight the central role of the leptin system in diabetes development.

Cutting Edge: Elevated Leptin during Diet-Induced Obesity Reduces the Efficacy of Tumor Immunotherapy.

Various malignancies are reproducibly cured in mouse models, but most cancer immunotherapies show objective responses in a fraction of treated patients. One reason for this disconnect may be the use of young, lean mice lacking immune-altering comorbidities present in cancer patients. Although many cancer patients are overweight or obese, the effect of obesity on antitumor immunity is understudied in preclinical tumor models. We examined the effect of obesity on two immunotherapeutic models: systemic anti-CTLA-4 mAb and intratumoral delivery of a TRAIL-encoding adenovirus plus CpG. Both therapies were effective in lean mice, but neither provided a survival benefit to diet-induced obese BALB/c mice. Interestingly, tumor-bearing leptin-deficient (ob/ob) obese BALB/c mice did respond to treatment. Moreover, reducing systemic leptin with soluble leptin receptor:Fc restored the antitumor response in diet-induced obese mice. These data demonstrate the potential of targeting leptin to improve tumor immunotherapy when immune-modulating comorbidities are present.

Changes in Oxidized Low-Density Lipoprotein Rather Than in Paraoxonase1 are Associated with Changes in the Leptin/Leptin Receptor Ratio in Obese Children During Weight-Loss Therapy.

Oxidative stress and impaired production of adipokines in childhood obesity contribute to the development of obesity-related disorders. We assessed whether weight loss after lifestyle intervention alters biomarkers of oxidant/antioxidant status, and whether these alterations are associated with changes in anthropometric parameters and adipokines in obese children. We determined oxidized low-density lipoprotein (ox-LDL), anti ox-LDL, paraoxonase1 (PON1), leptin, soluble leptin receptor (sOB-R), total adiponectin, high molecular weight adiponectin concentrations and body composition (by dual-energy X-ray absorptiometry) in 60 prepubertal obese children (Body Mass Index, BMI Z-score>2) before and after a 3-month intervention. The control group consisted of 44 non-obese children (BMI Z-score<-1+1>). Ox-LDL, ox-LDL/LDL, and anti ox-LDL concentrations as well as leptin to sOb-R ratio were reduced (p<0.001; p=0.018; p<0.001; p<0.001, respectively) in obese children with weight loss (BMI Z-score change≤-0.5) after a 3-month therapy. These parameters were stable in the obese group without weight loss (BMI Z-score change>-0.5). Changes in ox-LDL and PON1 levels in all obese children correlated positively with changes in the leptin to sOB-R ratio (r=0.400, p=0.002; r=0.304, p=0.028, respectively). After adjustment for changes in BMI Z-score in the multivariate regression model, the association between the changes in ox-LDL levels and changes in the leptin/sOb-R ratio remained statistically significant (β=0.184, p=0.014). We found out that a 3-month lifestyle intervention associated with weight loss improves the oxidant/antioxidant balance and promotes anti-atherogenic changes in prepubertal obese children in a way dependent on the alterations in the leptin to sOB-R ratio.

Impact to short-term high intensity intermittent training on different storages of body fat, leptin and soluble leptin receptor levels in physically active non-obese men: A pilot investigation

Studies have postulated High Intensity Intermittent Training (HIIT) as a superior strategy to reduce body fat. The purpose of this study was to compare the effects HIIT and steady-state training (SST) on body composition, leptin, soluble leptin receptor (sOB-R) levels, and hunger perception in physically active non-obese men. Twenty men performed five weeks of HIIT (5km - 1min running at 100% speed correspondent to VȩO2peak - v VȩO2peak - interspersed with 1-min passive recovery; n=10) or SST (5km at 70% of vVȩO2peak continuously; n=10) three times a week. Body composition, and hunger perception were assessed at pre- and post-training and were compared by a two-way analysis (group and training period) with repeated measures in the second factor. A fasting time-course (baseline, 24h, and 48h after an experimental session of exercise) of leptin and sOB-R levels were measured at pre- and post-five weeks of training and assessed by a three-way analysis (group, period and time of measurement) with repeated measures in the second and third factors. There was no effect on body composition and hunger perception. Leptin was reduced in both groups, while sOB-R was increased post-five weeks of training in HIIT but not in the SST. Although both training groups exerted alterations in leptin levels, only HIIT was able increased sOB-R levels, this suggest a superior impact on central responses in physically active non-obese men.

Acupuncture Treatment Reduces Body Weight Possibly by Down-regulating Insulin and Leptin Resistance, and Up-regulating Soluble Leptin Receptor Level in Prediabetic Patients

To observe the effect of acupuncture of Feishu (BL 13), Pishu (BL 20), etc. on body weight, blood lipid, leptin (LP) and soluble leptin receptor (sOB-R) levels in prediabetic patients, so as to explore its mechanisms underlying treatment and prevention of prediabetes. A total of 100 prediabetic patients were randomly assigned to medication (Metformin) group (n＝35), acupuncture group (n＝35) and simple lifestyle intervention group (n＝30) with random number table method. All the patients of the 3 groups were treated with lifestyle intervention (reasonable diet and moderate physical exercise) and ordered to stop administration of any hypoglycemic drugs during the treatment period. Bilateral Feishu (BL 13), Pishu (BL 20), Weishu (BL 21), Shenshu (BL 23), Zusanli (ST 36) and Sanyinjiao (SP 6) were punctured with filiform needles which were manipulated by lifting, thrusting and twirling repeatedly for about 2 min every 5 min during 30 minutes' needle retaining. The acupuncture treatment was conducted once every other day for 12 weeks. Patients of the medication group were ordered to orally take Metformin tablets (0.5 g/time, twice a day) for continuous 12 weeks. Body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), 2 h-postprandial blood glucose (2 h-PBG), fasting blood glucose (FBG), glycosyla-ted hemoglobin (HbA1c), total cholesterol (TC), triglyceride (TG), fasting insulin (FINS), serum LP and sOB-R levels were measured before and after the treatment. After the treatment, the BMI in the acupuncture group, and BMI, WC and WHR in the medication group were significantly decreased relevant to their own pre-treatment in each group (P<0.05, P<0.01). Following the treatment, the levels of FBG, 2 h-PBG, HbA1C, TC, TG, FINS, HOMA-IR and LP in both acupuncture and medication groups, and FBG in the simple lifestyle intervention group were significantly decreased in comparison with their own pre-treatment in each group (P<0.01, P<0.05), and the levels of FBG, 2 h-PBG, HbA1C, TC and TG, HOMA-IR and LP in both acupuncture and medication groups were all considerably lower than those of the simple lifestyle intervention group (P<0.01，P<0.05). The level of FINS in the medication group was significantly lower than that of the simple lifestyle intervention group (P<0.05). Additionally, following the treatment, serum sOB-R contents in both acupuncture and medication groups were obviously increased compared with their own pre-treatment in each group and also relevant to the simple lifestyle intervention group (P<0.01). No significant changes were found in the simple lifestyle intervention group in all the above-mentioned blood indexes except FBG (P>0.05). Acupuncture can induce body weight loss, down-regulate FINS, insulin resistance and LP resistance, and up-regulate sOB-R content in prediabetic patients, displaying a positive role in the treatment of prediabetes.

Physical Fitness and Its Relationship to Plasma Leptin, Leptin Soluble Receptor, and Free Leptin Index in a Saudi Population: A Comparison Between Diabetic and Non-Diabetic Individuals.

BackgroundLow physical activity is considered to be a risk factor for type 2 diabetes mellitus (T2DM). One theory suggest that leptin resistance is involved in the pathophysiology of impaired glucose metabolism. In this study we aimed to assess the correlation of physical fitness scores (PFS) with serum total leptin (TL), serum leptin soluble receptor (LSR), and free leptin index (FLI) in a group of Saudi patients with T2DM.Material/MethodsThis cross-sectional study involved 115 subjects: 52 healthy control subjects and 63 patients with T2DM. All subjects underwent body composition analysis. Blood samples were analyzed for fasting blood glucose (FBG), glycosylated hemoglobin (HbA1c), serum total leptin (TL), and serum leptin soluble receptor (LSR). Based on ideal body composition and our previous studies, physical fitness scores (PFS) were recorded for each subject.ResultsIn patients with T2DM, levels of LSR were positively correlated with PFS (r=0.281, p=0.025), while the levels of TL (r=−0.425, p=0.001) and FLI (r=−0.439, p=0.001) were negatively correlated with PFS. In control subjects, TL and FLI levels were negatively correlated (r=−0.612, p=0.001and r=−0.543, p=0.001 respectively) with PFS. In linear regression analysis, after adjustment for age and BMI, TL and FLI were independent predictors of PFS.ConclusionsSerum TL and FLI were negatively correlated while LSR was positively correlated with PFS in patients with T2DM. Therefore, they may be important biomarkers for predicting the outcomes of physical fitness and exercise programs.

Prediction of circulating adipokine levels by body fat compartments and adipose tissue gene expression

Introduction Over the past years, adipose tissue (AT) has been recognized as a metabolically active tissue and a number of AT-derived circulating biomarkers called adipokines have been proposed as mediators for the association of obesity with chronic disease risk. However, the mechanisms are not yet understood and it is even unclear to what extent the amount of subcutaneous (SAT) and visceral adipose tissue (VAT) and gene expression levels in AT predict adipokine concentrations. Methods In the present study, we aimed to assess to what extent adiposity as objectively measured by the amount of SAT and VAT using magnetic resonance imaging, and gene expression levels in SAT, collected by biopsy, determine plasma adipokine concentrations. We investigated the adipokines adiponectin, leptin, soluble leptin receptor, resistin, interleukin 6 and fatty acid binding protein 4 (FABP4) in a cross-sectional analysis of 200 participants from the population-based EPIC Potsdam cohort study. Our hypothesis was that direct quantification of SAT and VAT as well as gene expression in AT can explain a substantial amount of the variance in adipokine levels, and we calculated the explained variance of plasma adipokines from multivariable regression models. In secondary analyses, we investigated additional predictors (other anthropometric measures, personal characteristics, other gene expression and plasma concentration measures) and also obtained partial correlation coefficients adjusted for age, sex, physical activity and occupational training for a more detailed assessment and comparison of the associations. Results For leptin, 81%, and for FABP4, 45% of the variance in plasma concentrations was explained by SAT and VAT mass, and gene expression in SAT. For the remaining adipokines, AT mass and gene expression explained less than 16% of their variance. Gene expression in SAT explained a smaller proportion of the variance in comparison to AT mass. Regarding the AT compartments, leptin was more strongly correlated with SAT mass (partial correlation r = 0.81, 95% CI [0.75; 0.86]) than with VAT mass (r = 0.58, 95% CI [0.46; 0.67]). For the remaining adipokines, no substantial differences in their correlation with SAT versus VAT mass were observed. The additionally investigated predictors added only little explained variance for some adipokines. Conclusions Our data suggest that except for leptin and FABP4, adiposity as objectively measured by SAT and VAT mass, and gene expression in SAT predict plasma adipokine concentrations only to a small extent. While our findings do not contradict a potential role of adipokines in disease development, the circulating concentrations of all investigated adipokines except leptin and FABP4 are unlikely to mediate the association between adiposity and disease risk observed in epidemiological studies to a large extent.

Study of rs1137101 polymorphism of leptin receptor gene with serum levels of selenium and copper in the patients of non-ST-segment elevation myocardial infarction (NSTEMI) in an Iranian population

ObjectiveNSTEMI is a type of myocardial infarction (MI) causing partial but progressive occlusion of cardiac coronary vessels. The aim of this study was to investigate rs1137101 polymorphism of soluble leptin receptor (sLEPR) as well as circulatory selenium and copper levels in NSTEMI patients and their usefulness in analyzing susceptibility to NSTEMI. MethodsWe collected sera and whole blood of 80 NSTEMI patients and 80 healthy individuals using cTnI levels plus electrocardiography as the “gold standard”. Polymorphism analysis was done after DNA extraction by high-resolution melt PCR, selenium and copper levels by atomic absorption spectrophotometry, and sLEPR by ELISA. Results and discutionThere was Hardy-Weinberg (HWE) equilibrium for both patient and control loci (χ2 = 0.368434509 and 0.341447368, respectively). The frequencies of A/A, A/G, and G/G genotypes were 18 (22%), 37 (46%), and 25 (31%) for patients, and 30 (38%), 36 (45%), and 14 (18%) for healthy controls, respectively. The frequencies of A and G alleles were 73 (46%) and 87 (54%) for patients and 96 (60%) and 64 (40%) for control groups. There was correlation between allele G and sLEPR level and Body Mass Index (BMI). Selenium levels were lower in patient group than control group (66.307 ± 11.013 against 87.488 ± 11.839 μg/L; p < 0.001) but copper concentrations were higher (1.8105 ± 0.358 against 1.366 ± 0.454 mg/L; p < 0.001). sLEPR levels were also higher in patient than control group (30.568 ± 3.290 against 23.740 ± 5.457 ng/dL; p < .001). Low selenium and high copper concentration had positive diagnostic value for disease. ConclusionWe find for the first time that there is a significant association between rs1137101 polymorphism and susceptibility to NSTEMI. There is also statistically meaningful association between decrease in serum selenium and increase in serum copper levels with susceptibility to NSTEMI.

Association of Circulating Adipokines With Echocardiographic Measures of Cardiac Structure and Function in a Community-Based Cohort.

BackgroundAdipokines mediate cardiometabolic risk associated with obesity but their role in the pathogenesis of obesity‐associated heart failure remains uncertain. We investigated the associations between circulating adipokine concentrations and echocardiographic measures in a community‐based sample.Methods and ResultsWe evaluated 3514 Framingham Heart Study participants (mean age 40 years, 53.8% women) who underwent routine echocardiography and had select circulating adipokines measured, ie, leptin, soluble leptin receptor, fatty acid–binding protein 4, retinol‐binding protein 4, fetuin‐A, and adiponectin. We used multivariable linear regression, adjusting for known correlates (including weight), to relate adipokine concentrations (independent variables) to the following echocardiographic measures (dependent variables): left ventricular mass index, left atrial diameter in end systole, fractional shortening, and E/e′. In multivariable‐adjusted analysis, left ventricular mass index was inversely related to circulating leptin and fatty acid–binding protein 4 concentrations but positively related to retinol‐binding protein 4 and leptin receptor levels (P≤0.002 for all). Left atrial end‐systolic dimension was inversely related to leptin but positively related to retinol‐binding protein 4 concentrations (P≤0.0001). E/e′ was inversely related to leptin receptor levels (P=0.0002). We observed effect modification by body weight for select associations (leptin receptor and fatty acid–binding protein 4 with left ventricular mass index, and leptin with left atrial diameter in end systole; P<0.05 for interactions). Fractional shortening was not associated with any of the adipokines. No echocardiographic trait was associated with fetuin‐A or adiponectin concentrations.ConclusionsIn our cross‐sectional study of a large, young to middle‐aged, relatively healthy community‐based sample, key indices of subclinical cardiac remodeling were associated with higher or lower circulating concentrations of prohypertrophic and antihypertrophic adipokines in a context‐specific manner. These observations may offer insights into the pathogenesis of the cardiomyopathy of obesity.

C-Reactive Protein (CRP) and Leptin Receptor in Obesity: Binding of Monomeric CRP to Leptin Receptor.

While leptin deficiency or dysfunction leads to morbid obesity, obese subjects are characterized paradoxically by hyperleptinemia indicating lack of response to leptin. C-reactive protein (CRP) has been suggested to be a key plasma protein that could bind to leptin. To examine whether CRP interferes with leptin action, mediated through its cell surface receptor, docking studies of CRP with the extracellular domain of the leptin receptor were done employing bioinformatics tools. Monomeric CRP docked with better Z-rank score and more non-bond interactions than pentameric CRP at the CRH2–FNIII domain proximal to the cell membrane, distinct from the leptin-docking site. Interaction of CRP with leptin receptor was validated by solid phase binding assay and co-immunoprecipitation of CRP and soluble leptin receptor (sOb R) from human plasma. Analysis of the serum levels of leptin, CRP, and sOb R by ELISA showed that CRP levels were significantly elevated (p < 0.0001) in non-morbid obese subjects (n = 42) compared to lean subjects (n = 32) and correlated positively with body mass index (BMI) (r = 0.74, p < 0.0001) and leptin (r = 0.8, p < 0.0001); levels of sOb R were significantly low in obese subjects (p < 0.001) and showed a negative correlation with BMI (r = −0.26, p < 0.05) and leptin (r = −0.23, p < 0.05) indicating a minimal role for sOb R in sequestering leptin.

Low Plasma Leptin and High Soluble Leptin Receptor Levels Are Associated With Mild Cognitive Impairment in Type 2 Diabetic Patients.

Background: Metabolic disturbances, such as hyperglycemia, hyperlipidemia, and obesity, are thought to be risk factors for Alzheimer's disease.Objective: This study aimed to investigate whether adipokine leptin and soluble leptin receptor (sOBR) levels are correlated with mild cognitive impairment (MCI) and metabolic status of the patients of type 2 diabetes mellitus (T2DM).Methods: Total of 169 T2DM patients were recruited and divided according to the Montreal Cognitive Assessment (MoCA) score. Their cognition and metabolic parameters were extensively assessed. Plasma leptin and sOBR levels were determined by RIA and ELISA, respectively. Free leptin index (FLI) was calculated.Results: Of 124 enrolled T2DM patients, 61 were diagnosed with MCI (MoCA < 26). In MCI group and female subgroup, leptin levels and FLI were significantly lower and sOBR concentrations were higher when compared with their respective health cognition controls (all p < 0.05). Leptin levels and FLI were positively associated with the most cognitive domains and their Waist-to-Hip Ratio (WHR), a traditional index of central obesity. Leptin, sOBR, and WHR were independent variables of MCI in all individuals (all p < 0.05). For the females, MoCA was also positively correlated with leptin (β = 0.893, p < 0.001) and negatively correlated with WHR (β = −0.363, p = 0.014). Leptin was positively correlated only with WHR (β = 0.441, p = 0.025).Conclusions: This study showed that a high level of leptin and low level of sOBR are associated with the improved cognitive function in T2DM patients and more significantly in female individuals, while WHR, as an indicator of the visceral obesity, contributes to cognitive deficits.Trial registration: Advanced Glycation End Products Induced Cognitive Impairment in Diabetes: BDNF Signal Meditated Hippocampal Neurogenesis ChiCTR-OCC-15006060; http://www.chictr.org.cn/showproj.aspx?proj=10536.