Leptin Receptor Gene Research Articles

Association of Leptin and Leptin receptor Gene polymorphisms with Insulin resistance in pregnant women: A cross-sectional study

Introduction: Leptin is an adipokine hormone that regulates insulin sensitivity and lipid profile, which may contribute to complications like gestational diabetes.The goal of the study was to examine if there was a link between the leptin (LEP)/leptin receptor (LEPR) gene polymorphism and insulin resistance in pregnant women, and to determine the extent to which the leptin gene polymorphism could cause insulin resistance.. Methods: 208 pregnant women participated in this cross-sectional study of which 74 were insulin resistant cases and 134 were insulin sensitive controls. The study was carried out from December 2018 to December 2020 at a charitable hospital in Mangalore, Karnataka, India. Genotyping of leptin and its receptor gene were carried out using the Polymerase Chain Reaction- Restriction fragment Length Polymorphism (PCR-RFLP) method. Serum levels of leptin, insulin, and C peptide were assayed using Enzyme Linked Immuno Sorbent Assay (ELISA) and lipid profile by automated chemistry analyzer. Statistical analysis was carried out using SPSS 23. Results: Insignificant association was observed between leptin receptor gene polymorphisms and insulin resistance, and leptin gene and insulin resistant women. There was no significant difference in the serum leptin levels among the cases and control (61.62±29.23 and 59.88±22.25). However, fasting blood sugar, insulin, C peptide, Triglycerides (TG), and very low-density Lipoprotein (VLDL) levels were significantly higher in cases as compared to controls (p=0.0068, p<0.0001, p<0.0001 and 0.01 respectively). Homeostatic Model Assessment for Insulin Resistance (HOMA IR) was greater in subjects with homozygous dominant, 'GG' of LEPR (p=0.0409) and hyperinsulinemia (p=0.023) as compared to other genotypes. However, hyperglycaemia was observed in subjects with homozygous dominant, ‘AA’ of leptin gene (p=0.0173). Conclusion: No significant association was found between leptin and leptin receptor gene polymorphisms with insulin resistance in pregnancy. However, genotyping of these genes may be useful in predicting insulin resistance and gestational diabetes in pregnancy.

Association of the Human Leptin Receptor Gene (rs1137101; Gln223Arg) Polymorphism and Circulating Leptin in Patients with Metabolic Syndrome in the Indian Population.

Phenotypic expression of metabolic syndrome is precipitated by environmental variables along with the individual genetic susceptibility to the obesogenic environment and growing body of evidence suggest a paramount role of adipocytokines. Therefore, identifying the genetic influence on circulation leptin levels and clarifying genotype-phenotype correlation of rs1137101 {Leptin receptor gene (LEPR) Gln223Arg (Q223R; A668G)} in metabolic syndrome were the primary objective of this study. A total of 447 adult participants, including 214 metabolic syndrome patients and 233 healthy controls, were genotyped using polymerase chain reaction-restriction fragment length polymorphism method to unravel the effects of genetic risk loci {Leptin receptor gene; Gln223Arg (Q223R; A668G); rs1137101} on the occurrence of metabolic syndrome in consort with circulation leptin levels. Suitable descriptive statistics was used for different variables. The genotype frequencies were found to be in Hardy-Weinberg equilibrium for both cases (p > 0.2722) as well as in controls (p > 0.2331). However, genotype (x2: 11.26, 2 d.f. p = 0.0036) and allele distribution (x2: 10.51, 2 d.f. p: 0.0012) of the LEPR Gln223Arg (Q223R; A668G) differed significantly between cases and controls. Gln/Arg genotype (OR = 1.6099; 95% CI = 1.0847-2.3893; p value = 0.0181), Arg/Arg genotype (OR = 2.8121; 95% CI = 1.4103-5.6074; p value = 0.0033) and R allele (OR = 1.5875; 95% CI = 1.1996-2.1008; p value = 0.0012) were significantly associated with increased risk of metabolic syndrome in univariate analysis. Further a multivariate logistic regression adjusted for potential confounders showed that Arg/Arg genotype (OR = 1.9; 95% CI = 1.271-2.639; p-value < 0.05) and Gln/Arg (OR: 1.3; 95% CI = 0.873-2.034; p value < 0.05) have a significant risk for the occurrence of the metabolic syndrome. A progressive increase in the serum leptin levels from major homozygous alleles to minor homozygous alleles were observed indicating that rs1137101 modify the serum leptin concentrations in patients with metabolic syndrome. These findings provide enough evidence of a significant association of LEPR Gln223Arg (Q223R; A668G) polymorphism in the LepR gene in Indian patients with increased risk of metabolic syndrome for R allele and Arg/Arg homozygote. Thus, rs1137101 might be a pleiotropic locus for metabolic syndrome and its components in studied population.

Association study of leptin receptor polymorphisms in women with obesity and their impact on protein domains: a case-control study and in silico analyses

Leptin receptor (LEPR) is a member of the class I cytokine receptor family that receives and transmits leptin signals. It is primarily involved in the regulation of energy expenditure and food intake. This study aimed to evaluate the association of LEPR gene polymorphisms, Lys109Arg, Gln223Arg and Lys656Asn, with obesity in Moroccan women and to explore the structural and functional consequences of these SNPs. The variants were genotyped using the Sanger sequencing method. The three-dimensional structures of LEPR extracellular domains were determined using a template-based tertiary structure modeling web server and the protein variants were generated using in silico mutagenesis. The amino acids conservation analysis in the variants region was performed based on a protein’s evolutionary profile. The molecular dynamics simulations of the wild-types and variants N-terminal, cytokine receptor homology I and fibronectin type III domains of LEPR protein were performed to investigate their impact on the domain structures. We identified that only Lys656Asn polymorphism is associated with obesity in Moroccan women (P = 0.024). In silico analyses revealed that Lys109, Gln223 and Lys656 are exposed residues and their substitution leads to changes in protein structure through loss or gain of hydrogen bonds and hydrophobic interactions. Lys656Asn increases the stability and decreased flexibility of the fibronectin type III domain. Lys109Arg highly decreases the stability and increases flexibility and the overall dimension of N-terminal and cytokine receptor homology I domains. Gln223Arg increases the stability and the compaction level of these domains. These results provide insight into the involvement of LEPR variants in obesity development. Communicated by Ramaswamy H. Sarma

Correlations of Gene Variants LEP &lt;i&gt;rs2167270&lt;/i&gt;, LEPR &lt;i&gt;rs1137100&lt;/i&gt;, GHRL &lt;i&gt;rs696217&lt;/i&gt;, &lt;i&gt;rs27647&lt;/i&gt;, and NPY &lt;i&gt;rs16147&lt;/i&gt; with Obesity and Adolescent Eating Behavior: Case-Control Study

Background. Childhood obesity is topical global healthcare issue. The correlations between variable regions of genes encoding leptin and its receptor, ghrelin and neuropeptide Y, and the risk of obesity development in children have not been confirmed completely. Mechanisms for implementing such correlation via the influence of genes on children’s behavior remain unexplored.Objective. The aim of the study is to examine the correlation between leptin, leptin receptor, ghrelin and neuropeptide Y gene variants and obesity in adolescents and their eating behavior.Methods. The study included children aged from 10 to 18 years with exogenous constitutive obesity and normal body weight. Variants in genes for leptin LEP rs2167270, leptin receptor LEPR rs1137100, ghrelin GHRL rs696217 and rs27647, neuropeptide Y NPY rs16147 were determined. Adolescents’ eating behavior was evaluated via psychometric questionnaires DEBQ (Dutch Eating Behavior Questionnaire) and TFEQ (the Three Factor Eating Questionnaire).Results. Gene variant distribution analysis in 150 obese and 150 normal weight children has revealed correlation with obesity for the variant rs1137100 of the LEPR gene (p = 0.001). Variants rs2167270 of the LEP gene (p = 0.015), rs696217 of the GHRL gene (p = 0.040), and rs16147 of the NPY gene (p = 0.020) were associated with adolescent eating behavior predisposing to obesity.Conclusion. The leptin receptor gene variant rs1137100 is associated with obesity in adolescents, and the variants rs2167270 of the leptin gene, rs696217 of the ghrelin gene, and rs16147 of the neuropeptide Y gene are associated with changes in eating behavior.

Alteration of serum leptin and LEP/LEPR promoter methylation in Prader-Willi syndrome

Prader-Willi syndrome (PWS) is a rare neurodevelopmental disorder based on a loss of paternally expressed but maternally imprinted genes in chromosome region 15q11–13. PWS individuals typically show insatiable appetite with subsequent obesity representing the major mortality factor unless food intake is inhibited. The neurobiological basis of PWS-typical hyperphagia has remained poorly understood. Many PWS-typical abnormalities are based on hypothalamic dysregulation, a region in which hunger and satiety are hormonally regulated, with the hormone leptin being a main long-term regulator of satiety. Previous studies in PWS have inconsistently shown leptin alterations solely in early childhood, without investigating the leptin system on an epigenetic level. The present study investigates serum leptin levels (S-leptin) and DNA methylation of the leptin (LEP) and leptin receptor gene (LEPR) promoter in 24 individuals with PWS compared to 13 healthy controls matched for sex, age, and body mass index (BMI) and relates the results to the extent of hyperphagia in PWS. S-Leptin levels were obtained by Enzyme-linked Immunosorbent Assay. LEP/LEPR-promoter DNA methylation was assessed by bisulfite-sequencing, hyperphagia by Hyperphagia Questionnaire for Clinical Trials (HQ-CT). PWS and control groups differed significantly in S-leptin levels with higher S-leptin in PWS. Methylation analysis showed significant differences in mean promoter methylation rate both for LEP and LEPR with a lower methylation rate in PWS. LEPR, but not LEP methylation correlated significantly with S-leptin levels. S-leptin and both LEP and LEPR methylation did not correlate with HQ-CT scores in PWS. The present study is the first to show significantly elevated S-leptin levels in an adult PWS cohort combined with an altered, downregulated LEP and LEPR promoter methylation status compared to sex-, age- and BMI-matched controls. Analogous to previous studies, no link to the behavioral dimension could be drawn. Overall, the results suggest an increased leptin dysregulation in PWS, whereby the findings partly mirror those seen in non-syndromic obesity.

Greater Body Fatness Is Associated With Higher Protein Expression of LEPR in Breast Tumor Tissues: A Cross-Sectional Analysis in the Women's Circle of Health Study.

BackgroundThe mechanisms underlying the association of overall and central body fatness with poorer breast cancer outcomes remain unclear; altered gene and/or protein expression of the adipokines and their receptors in breast tumors might play a role.MethodsIn a sample of Black and White women with primary invasive breast cancer, we investigated associations of body mass index (BMI), waist circumference, hip circumference, waist-to-hip ratio (WHR), fat mass index (FMI), and percent body fat with protein expression (log-transformed, n = 722) and gene expression (log2-transformed, n = 148) of leptin (LEP), leptin receptor (LEPR), adiponectin (ADIPOQ), and adiponectin receptors 1 and 2 (ADIPOR1, ADIPOR2). Multivariable linear models, adjusting for race, menopausal status, and estrogen receptor status, were used to assess these associations, with Bonferroni correction for multiple comparisons.ResultsIn multivariable models, we found that increasing BMI (β = 0.0529, 95% CI: 0.0151, 0.0906) and FMI (β = 0.0832, 95% CI: 0.0268, 0.1397) were associated with higher LEP gene expression, corresponding to 34.5% and 38.3% increases in LEP gene expression for a standard deviation (SD) increase in BMI and FMI, respectively. Increasing BMI (β = 0.0028, 95% CI: 0.0011, 0.0045), waist circumference (β = 0.0013, 95% CI: 0.0005, 0.0022), hip circumference (β = 0.0015, 95% CI: 0.0007, 0.0024), and FMI (β = 0.0041, 95% CI: 0.0015, 0.0067) were associated with higher LEPR protein expression. These associations equate to 16.8%, 17.6%, 17.7%, 17.2% increases in LEPR protein expression for a 1-SD increase in BMI, waist circumference, hip circumference, and FMI, respectively. Further, these associations were stronger among White and postmenopausal women and ER+ cases; formal tests of interaction yielded evidence of effect modification by race. No associations of body fatness with LEP protein expression, LEPR gene expression, or protein or gene expression of ADIPOQ, ADIPOR1, and ADIPOR2 were found.ConclusionsThese findings support an association of increased body fatness – beyond overall body size measured using BMI – with higher LEP gene expression and higher LEPR protein expression in breast tumor tissues. Clarifying the impact of adiposity-related adipokine and adipokine receptor expression in breast tumors on long-term breast cancer outcomes is a critical next step.

Cord blood leptin level and a common variant of its receptor as determinants of the BMI trajectory: The EDEN mother-child cohort.

Cord blood leptin is an indicator of neonatal fat mass and could shape postnatal adiposity trajectories. Investigating genetic polymorphisms of the leptin receptor gene (LEPR) could help understand the mechanisms involved. We aimed to investigate the association of cord blood leptin level and the LEPR rs9436303 polymorphism, with body mass index (BMI) at adiposity peak (AP) and age at adiposity rebound (AR). In the EDEN cohort, BMI at AP and age at AR were estimated with polynomial mixed models, for 1713 and 1415 children, respectively. Multivariable linear regression models allowed for examining the associations of cord blood leptin level and LEPR rs9436303 genotype with BMI at AP and age at AR adjusted for potential confounders including birth size groups. We also tested interactions between cord blood leptin level and rs9436303 genotype. Increased leptin level was associated with reduced BMI at AP and early age at AR (comparing the highest quintile of leptin level to the others). Rs9436303 G-allele carriage was associated with increased BMI at AP and later age at AR but did not modulate the association with leptin level. These results illustrate the role of early life body composition and the intrauterine environment in the programming of adiposity in childhood.

Association of Leptin and Leptin receptor Gene polymorphisms with Insulin resistance in pregnant women: A cross-sectional study.

Introduction: Leptin, along with its receptor, are linked with mechanisms affecting a diverse array of pregnancy-specific pathologies that include gestational diabetes and intrauterine growth restriction. The goal of the study was to examine if there was a link between the leptin (LEP)/leptin receptor (LEPR) gene polymorphism and insulin resistance in pregnant women, and to determine the extent to which the leptin gene polymorphism could cause insulin resistance.. Methods: 208 pregnant women participated in this cross-sectional study of which 74 were insulin resistant cases and 134 were insulin sensitive controls. The study was carried out from December 2018 to December 2020 at a charitable hospital in Mangalore, Karnataka, India. Genotyping of leptin and its receptor gene were carried out using the Polymerase Chain Reaction- Restriction fragment Length Polymorphism (PCR-RFLP) method. Serum levels of leptin, insulin, and C peptide were assayed using Enzyme Linked Immuno Sorbent Assay (ELISA). Statistical analysis was carried out using SPSS 23. Results: Insignificant association was observed between leptin receptor gene polymorphisms and insulin resistance, and leptin gene and insulin resistant women. There was no significant difference in the serum leptin levels among the cases and control (61.62±29.23 and 59.88±22.25). However, fasting blood sugar, insulin, C peptide, Triglycerides (TG), and very low-density Lipoprotein (VLDL) levels were significantly higher in cases as compared to controls (p=0.0068, p<0.0001, p<0.0001 and 0.01 respectively). Homeostatic Model Assessment for Insulin Resistance (HOMA IR) was greater in subjects with homozygous dominant, 'GG' of LEPR (p=0.0409) and hyperinsulinemia (p=0.023) as compared to other genotypes. However, hyperglycaemia was observed in subjects with homozygous dominant, 'AA' of leptin gene (p=0.0173). Conclusion: No significant association was found between leptin and leptin receptor gene polymorphisms with insulin resistance in pregnancy. However, genotyping of these genes may be useful in predicting insulin resistance and gestational diabetes in pregnancy.

IMPACT OF BODY FAT DISTRIBUTION, ADIPOCYTOKINES AND VARIABILITY IN ASSOCIATED GENES ON KIDNEY TRANSPLANT OUTCOMES

Objective: Adiposity distribution contributes to a number of pathologies. We aimed to assess whether this distribution was associated with clinical outcomes and to identify its relationship with leptin and adiponectin gene variants and plasma concentrations in renal transplant recipients (RTR). Design and method: Anthropometric parameters were measured in 236 RTR by bioelectrical impedance analysis, allograft function and post-transplant complications were retrieved from records. Blood samples were drawn to measure plasma leptin/adiponectin levels and to seek for polymorphisms in the leptin receptor (LEPR) and adiponectin (ADIPOQ) genes. Logistic regression models were applied to identify associations. Results: The waist-to-height ratio (WHr) displayed a significant association with delayed graft function (DGF), acute rejection (AR) and post-transplant diabetes mellitus, with OR values of 2.04 (1.02–4.08) p = 0.045; 3.08 (1.22–7.79) p = 0.017 and 2.79 (1.16–6.74) p = 0.022, respectively. Waist circumference was linked to DGF [OR = 1.03 (1.01 – 1.053), p = 0.025] and AR [OR = 1.041 (1.01 – 1.073), p = 0.009]. Leptin levels were significantly higher in patients who experienced AR [19.91 ± 23.72 vs. 11.22 ± 16.42 ng/ml; OR = 1.021 (1.01–1.04), p = 0.017]. The ADIPOQ rs1501299TT genotype showed a significant association with higher WHr (0.63 ± 0.11 vs. 0.59 ± 0.87 for GG/GT genotypes; p = 0.015) and WC values (102.3 ± 14.12 vs. 96.38 ± 14.65 for GG/GT genotypes; p = 0.021). Conclusions: We have shown that WC, and especially WHr, are associated with adverse outcomes in renal transplant and hence may be useful parameters in RTR monitoring. In turn, these anthropometric parameters were affected by variability in the ADIPOQ gene, suggesting this polymorphism could be a useful marker of transplanted patients at risk.

Genome-wide analyses reveal a strong association between LEPR gene variants and body fat reserves in ewes

BackgroundAmong the adaptive capacities of animals, the management of energetic body reserves (BR) through the BR mobilization and accretion processes (BR dynamics, BRD) has become an increasingly valuable attribute for livestock sustainability, allowing animals to cope with more variable environments. BRD has previously been reported to be heritable in ruminants. In the present work, we conducted genome-wide studies (GWAS) in sheep to determine genetic variants associated with BRD. BR (i.e. levels) and BRD (i.e. changes over time) were obtained through body condition score measurements at eight physiological stages throughout each productive cycle in Romane ewes (n = 1034) and were used as phenotypes for GWAS. After quality controls and imputation, 48,593 single nucleotide polymorphisms (SNP) were included in the GWAS.ResultsAmong the 23 QTL regions identified, a major QTL associated with BR during pregnancy and lactation was identified on chromosome 1. In this region, several significant SNPs mapped to the leptin receptor gene (LEPR), among which one SNP mapped to the coding sequence. The point mutation induces the p.P1019S substitution in the cytoplasmic domain, close to tyrosine phosphorylation sites. The frequency of the SNP associated with increased BR levels was 32%, and the LEPR genotype explained up to 5% of the variance of the trait. Higher fatness levels in ewes carrying the LEPR p.P1019S mutation were observed all along the productive cycle.ConclusionsThese results provide strong evidences for involvement of LEPR in the regulation of BR in sheep and highlight it as a major candidate gene for improving adaptive capacities by genetic selection.

Association between SNPs in Leptin Pathway Genes and Anthropometric, Biochemical, and Dietary Markers Related to Obesity.

Obesity is one of the main public health problems in Mexico and the world and one from which a large number of pathologies derive. Single nucleotide polymorphisms (SNPs) of various genes have been studied and proven to contribute to the development of multiple diseases. SNPs of the leptin pathway have been associated with the control of hunger and energy expenditure as well as with obesity and type 2 diabetes mellitus. Therefore, the present work focused on determining the association between anthropometric markers and biochemical and dietary factors related to obesity and SNPs of leptin pathway genes, such as the leptin gene (LEP), the leptin receptor (LEPR), proopiomelanocortin (POMC), prohormone convertase 1 (PCSK1), and the melanocortin 4 receptor (MC4R). A population of 574 young Mexican adults of both sexes, aged 19 years old on average and without metabolic disorders previously diagnosed, underwent a complete medical and nutritional evaluation, biochemical determination, and DNA extraction from the blood; DNA samples were subsequently genotyped. Association analyses between anthropometric, biochemical, and dietary variables with SNPs were performed using binary logistic regressions (p-value = 0.05). Although the sampled population did not have previously diagnosed diseases, the evaluation results showed that 33% were overweight or obese according to BMI and 64% had non-clinically elevated levels of body fat. From the 74 SNP markers analyzed from the five previously mentioned genes, 62 showed polymorphisms within the sampled population, and only 35 of these had significant associations with clinical variables. The risk associations (OR > 1) occurred between clinical markers with elevated values for waist circumference, waist–height index, BMI, body fat percentage, glucose levels, insulin levels, HOMA-IR, triglyceride levels, cholesterol levels, LDL-c, low HDL-c, carbohydrate intake, and protein intake and SNPs of the LEP, LEPR, PCSK1, and MC4R genes. On the other hand, the protective associations (OR < 1) were associated with markers including elevated values for insulin, HOMA-IR, cholesterol, c-LDL, energy intake > 2440 Kcal/day, and lipid intake and SNPs of the LEP and LEPR genes and POMC. The present study describes associations between SNPs in leptin pathway genes, revealing positive and negative interactions between reported SNPs and the clinical markers related to obesity in a sampled Mexican population. Hence, our results open the door for the further study of new genetic variants and their influence on obesity.

Early onset obesity due to a mutation in the human leptin receptor gene.

SummaryLeptin is secreted by adipocytes in response to fat storage and binds to its receptor (LEPR), which is ubiquitously expressed throughout the body. Leptin regulates energy expenditure and is anorexigenic. In this study, we describe the clinical and hormonal findings of three siblings with a personal history of rapid weight gain during the first months of life. They had delayed puberty, high levels of FSH (15.6 ± 3.7 mUI/mL; reference: 1.5–12.4) and LH (12.3 ± 2.2 mUI/mL; reference: 1.7–8.6), normal oestradiol and total testosterone and successful fertility. None of the patients had dyslipidemia, diabetes or thyroid disease. Next-generation sequencing identified a pathogenic homozygous variant c.2357T>C, p.(Leu786Pro) in LEPR. Their parents and children were heterozygous for this mutation. We compared clinical and biochemical findings of homozygous carriers with first-degree heterozygous family members and ten randomly selected patients with adult-onset morbid obesity. Homozygous carriers of the mutation had significantly higher BMI (32.2 ± 1.7 kg/m2 vs 44.5 ± 7.1 kg/m2, P = 0.023) and increased serum levels of leptin (26.3 ± 9.3 ng/mL vs 80 ± 36.4 ng/mL, P = 0.028) than their heterozygous relatives. Compared with the ten patients with adult-onset morbid obesity, serum levels of leptin were not significantly higher in homozygous carriers (53.8 ± 24.1 ng/mL vs 80 ± 36.4 ng/mL, P = 0.149), and thus serum levels of leptin were not a useful discriminative marker of LEPR mutations. We described a rare three-generation family with monogenic obesity due to a mutation in LEPR. Patients with early onset obesity should be considered for genetic screening, as the identification of mutations may allow personalized treatment options (e.g. MC4R-agonists) and targeted successful weight loss.Learning pointsThe early diagnosis of monogenic forms of obesity can be of great interest since new treatments for these conditions are becoming available.Since BMI and leptin levels in patients with leptin receptor mutations are not significantly different from those found in randomly selected morbid obese patients, a careful medical history is mandatory to suspect this condition.Loss of leptin receptor function has been associated with infertility. However, our patients were able to conceive, emphasizing the need for genetic counselling in affected patients with this condition.

The association of LEPR Q223R polymorphism with type 2 diabetes mellitus in Malaysia

BackgroundType 2 diabetes mellitus (T2DM) is a major global public health problem that leads to increased risk of morbidity and mortality due to its complications. Leptin receptor plays a crucial role in regulating glucose metabolism and insulin sensitivity. Thus, mutation in the leptin receptor gene might play a role in the pathogenesis of T2DM. ObjectiveOur study aimed to evaluate the association of the Q223R polymorphism in the LEPR gene with Malaysian T2DM patients. MethodsA case-control study was focused on the three major ethnic groups of Malaysian population (100 Malays, 100 Chinese, and 100 Indians). Genotyping analysis of LEPR Q223R polymorphism was carried out by PCR-RFLP in 150 T2DM patients and 150 non-diabetic subjects as control. Serum insulin and leptin levels were determined using ELISA. A homeostasis model assessment-insulin resistance (HOMA-IR) and BMI were also calculated. ResultsT2DM patients had significantly (P > 0.001) higher serum leptin levels as compared to the non- diabetic volunteers (166.78 pg/ml, 101.94 pg/ml, respectively). The frequency of AG genotype of LEPR Q223R variant was significantly higher in T2DM patients as compared to the control group (58.66% vs. 42%, χ2 = 8.75, p = 0.013). The A allele frequency was significantly higher in T2DM patients than the non-diabetic individuals (36.66% and 29%, respectively, P = 0.046). Furthermore, there were markedly elevated serum leptin, insulin, HOMA-IR, and BMI in diabetic patients with GG genotype of this variant as compared to AA, and AG genotypes (P < 0.05). ConclusionOur findings demonstrated a significant association between LEPR Q223R polymorphism and T2DM in Malaysian subjects, particularly in Malay and Chinese ethnics, but not for Indian ethnic. This study suggested the A allele frequency of Q223R variant significantly increases the risk of T2DM in Malaysian population. Likewise, the polymorphism of Q223R in the LEPR gene is also associated with markedly increased serum insulin, leptin, HOMA-IR, and elevated BMI in T2DM patients.

Design and fabrication of a dual-drug loaded nano-platform for synergistic anticancer and cytotoxicity effects on the expression of leptin in lung cancer treatment

Lung cancer is progressive and fatal malignancy and is one of the main causes of cancer-related death worldwide. Leptin (LEP) is a cytokine derived from adipocyte that is known to be a key mitogenic agent in lung carcinogenesis. Excessive amounts of systemic and pulmonary LEP are contributed with an enhanced risk of lung cancer. Currently, combinatorial treatments in cancer therapy are of intense interest. Metformin (Met) and Curcumin (Cur) are bioactive compounds that have several anti-cancer properties in pre-clinical and clinical studies. Herein, a dual-drug loaded nano-platform was designed for targeted drug delivery to A549 lung carcinoma cells. Met/Cur-loaded poly (D, L lactide-co-glycolide)-b-poly (ethylene glycol) (PLGA-PEG) nanoparticles (NPs) were synthesized. The inhibitory property of dual drug-loaded PLGA/PEG NPs on LEP and LEP receptor genes expression was determined compared to Met and Cur. DLS, FTIR, XRD, SEM and TEM techniques were employed for the characterization of synthesized NPs as well as nano-formulated drugs. The pattern of in-vitro drugs released from PLGA-PEG NPs was investigated through dialysis method. Cytotoxicity effects of free, nanocapsulated, and dual-loaded drugs on A549 cells were assessed by MTT assay. In addition, the expression of LEP and LEP receptor genes in A549 cells after treatments were evaluated through real-time PCR assay. According to the results, free and nanocapsulated forms of Cur and Met exhibited a cytotoxic effect on A549 cells in a dose-dependent pattern. In particular, Met-Cur-PLGA/PEG NPs posse synergistic anti-cancer properties than free and nanocapsulated forms of the drugs. Likewise, expression of LEP and LEP receptor genes in Met-Cur-PLGA/PEG NPs treated cells was much more suppressed compared to cells, which were incubated with free and nanocapsulated forms of the drugs. Our findings suggested that the co-capsulation of Met and Cur in PLGA/PEG NPs could significantly increase the efficiency of targeted drug delivery for cancer treatment proposes.

Cytokine-inducible SH2 domain containing protein contributes to regulation of adiposity, food intake, and glucose metabolism.

The cytokine-inducible SH2 domain containing protein (CISH) is the founding member of the suppressor of cytokine signaling (SOCS) family of negative feedback regulators and has been shown to be a physiological regulator of signaling in immune cells. This study sought to investigate novel functions for CISH outside of the immune system. Mice deficient in CISH were generated and analyzed using a range of metabolic and other parameters, including in response to a high fat diet and leptin administration. CISH knockout mice possessed decreased body fat and showed resistance to diet-induced obesity. This was associated with reduced food intake, but unaltered energy expenditure and microbiota composition. CISH ablation resulted in reduced basal expression of the orexigenic Agrp gene in the arcuate nucleus (ARC) region of the brain. Cish was basally expressed in the ARC, with evidence of co-expression with the leptin receptor (Lepr) gene in Agrp-positive neurons. CISH-deficient mice also showed enhanced leptin responsiveness, although Cish expression was not itself modulated by leptin. CISH-deficient mice additionally exhibited improved insulin sensitivity on a high-fat diet, but not glucose tolerance despite reduced body weight. These data identify CISH as an important regulator of homeostasis through impacts on appetite control, mediated at least in part by negative regulation of the anorexigenic effects of leptin, and impacts on glucose metabolism.

The role of circulating miRNAs in leptin resistance in obese children.

Leptin resistance is one of the important causes of obesity in children. Besides known causes of leptin resistance like mutations in leptin and leptin receptor genes, overexpression of SOCS3 in arcuate nucleus is a potential cause of leptin resistance. We aimed to determine the effects of circulating miRNAs on leptin resistance in obese children by targeting SOCS3 pathway. miRNAs potentially targeting SOCS3 were determined by using online target prediction databases. Polymorphisms in miRNA target sequences were determined by using online genome browsers. miRNA expression levels of obese (n=35) and non-obese (n=30) children were determined by qPCR method, genotyping were performed by real-time PCR method and serum leptin, leptin receptor and SOCS3 levels were measured by ELISA method. miRNA profiling have shown that serum miR-218-5p levels are significantly (p<0.05) increased in accordance with serum leptin levels in obese children. In this study we used target prediction methods for evaluating potential miRNAs which may involve in development of leptin resistance. We have shown that miR-218-5p might be taking part in leptin resistance in obese children.

Cardiovascular Characteristics of Zucker Fatty Diabetes Mellitus Rats, an Animal Model for Obesity and Type 2 Diabetes.

Zucker fatty diabetes mellitus (ZFDM) rats harboring the missense mutation (fa) in a leptin receptor gene have been recently established as a novel animal model of obesity and type 2 diabetes (T2D). Here, we explored changes in cardiovascular dynamics including blood pressure and heart rate (HR) associated with the progression of obesity and T2D, as well as pathological changes in adipose tissue and kidney. There was no significant difference in systolic blood pressure (SBP) in ZFDM-Leprfa/fa (Homo) compared with ZFDM-Leprfa/+ (Hetero) rats, while HR and plasma adrenaline in Homo were significantly lower than Hetero. The mRNA expression of monocyte chemotactic protein-1 in perirenal white adipose tissue (WAT) from Homo was significantly higher than Hetero. Interscapular brown adipose tissue (BAT) in Homo was degenerated and whitened. The plasma blood urea nitrogen in Homo was significantly higher than Hetero. In summary, we demonstrated for the first time that HR and plasma adrenaline concentration but not SBP in Homo decrease with obesity and T2D. In addition, inflammation occurs in WAT from Homo, while whitening occurs in BAT. Further, renal function is impaired in Homo. In the future, ZFDM rats will be useful for investigating metabolic changes associated with the progression of obesity and T2D.

187P Development of a magnetic nanostructure for co-delivery of metformin and silibinin on growth of lung cancer cells: Possible action through leptin gene and its receptor regulation

Chemotherapeutic combinational approaches would be more efficient in decreasing toxicity of drug, preventing tumor progression in relation to either drug alone. Hence, the aim of this study was to construct magnetic PLGA/PEG nanoparticles (NPs) co-loaded with metformin (Met) and silibinin (Sil) to investigate their cytotoxicity as well as their impact on mRNA expression levels of leptin and leptin receptor genes in A549 lung cancer cells.

Selection for increasing milk production of cattle: the value of genetic predictor markers

Russian dairy cattle breeding, developing in line with global trends, is based on the breeding of highly productive livestock, including the use of biotechnology for the transfer of embryos obtained from genetically valuable heifers and donor cows. From 2014 to 2020, Russian agricultural enterprises produced more than 90 thousand in vivo and in vitro cattle embryos with variations of the growth of their annual number in the range from 195 to 26762 pcs. (embryos in vitro), from 2746 to 14098 pcs. (embryos in vivo). Since keeping animals that do not have high productivity is economically unprofitable, it is necessary to exclude unproductive individuals from production. As a result, it is important to predict the highest milk production (proteins, fat, milk yield) of pre-implantation embryos obtained in veterinary practice for the purposes of embryo transfer, as well as in calves in the first weeks of their life after birth in high-yielding cows. There is a growing interest in the use of genetic markers to predict heritable traits of milk production. Against the backdrop of the rapid development of molecular genetic technologies, aimed at a deeper study of mammalian genes, new types of data are being discovered, in particular, data on functional gene mutations mediated by the mechanism of alternative splicing. Currently, a new direction of research of cattle has been outlined to study functional mutations (alternative splicing defects) that favorably or adversely affect phenotypes, including the milk production of cattle. The purpose of this study was to expand knowledge about the predictive value of molecular markers developed based on information about functional mutations in the milk production predictor genes GHR (growth receptor gene), LEPR (leptin receptor gene) and PRLR (prolactin receptor gene). These potentially important markers are shown to be promising for use in breeding aimed at increasing the productivity of dairy cattle.

Obez ve sağlıklı çocuklarda leptin ve leptin reseptör gen polimorfizmleri

Purpose: The of this study is to explore the differences between leptin (LEPG2548A), which is considered efficacious in respect of adiposity and leptin receptor gene variants (LEPRQ223R, K109R, K656N). Furthermore, the relationship between these differences and the serum leptin level shall be scrutinized. Materials and Methods: A total of 300 volunteers (12-17 years of age) joined our study (150controls–150obese). Blood samples obtained from these individuals were used for DNA isolation. An examination was carried out in order to show polymorphisms of the leptin receptor gene increased by RealTime PCR previously. The variations of the leptin gene were ascertained by implementation of restriction fragment length polymorphism method. Results: Genotype dispersion calculations led to the understanding that the AA-genotype was lower in the K109R polymorphism control group than in the patient group, whereas AG-genotype was higher. The control group of Q223R polymorphism had higher AA-genotype values than the patient group, whereas it showed lower AG-genotype values. Moreover, anthropometric and metabolic results were found to be significantly higher (p in the patient group than in the control group.Conclusion: The patient group of LEPRQ223R polymorphism showed lower AA-genotype values, a higher AG-genotype dispersion and a higher allele-G value. Therefore, a relationship to adiposity has been assumed.