Leptin Receptor Research Articles

Phyllanthus emblica Fruit Improves Obesity by Reducing Appetite and Enhancing Mucosal Homeostasis via the Gut Microbiota-Brain-Liver Axis in HFD-Induced Leptin-Resistant Rats.

The impact of leptin resistance on intestinal mucosal barrier integrity, appetite regulation, and hepatic lipid metabolism through the microbiota-gut-brain-liver axis has yet to be determined. Water extract of Phyllanthus emblica L. fruit (WEPE) and its bioactive compound gallic acid (GA) effectively alleviated methylglyoxal (MG)-triggered leptin resistance in vitro. Therefore, this study investigated how WEPE and GA intervention relieve leptin resistance-associated dysfunction in the intestinal mucosa, appetite, and lipid accumulation through the microbiota-gut-brain-liver axis in high-fat diet (HFD)-fed rats. The results showed that WEPE and GA significantly reduced tissues (jejunum, brain, and liver) MG-evoked leptin resistance, malondialdehyde (MDA), proinflammatory cytokines, SOCS3, orexigenic neuropeptides, and lipid accumulation through increasing leptin receptor, tight junction proteins, antimicrobial peptides, anorexigenic neuropeptides, excretion of fecal triglyceride (TG), and short-chain fatty acids (SCFAs) via a positive correlation with the Allobaculum and Bifidobacterium microbiota. These novel findings suggest that WEPE holds the potential as a functional food ingredient for alleviating obesity and its complications.

Long-duration leptin transgene expression in dorsal vagal complex does not alter bone parameters in female Sprague Dawley rats

The hypothalamus and dorsal vagal complex (DVC) are both important for integration of signals that regulate energy balance. Increased leptin transgene expression in either the hypothalamus or DVC of female rats was shown to decrease white adipose tissue and circulating levels of leptin and adiponectin. However, in contrast to hypothalamus, leptin transgene expression in the DVC had no effect on food intake, circulating insulin, ghrelin and glucose, nor on thermogenic energy expenditure. These findings imply different roles for hypothalamus and DVC in leptin signaling. Leptin signaling is required for normal bone accrual and turnover. Leptin transgene expression in the hypothalamus normalized the skeletal phenotype of leptin-deficient ob/ob mice but had no long-duration (≥10 weeks) effects on the skeleton of leptin-replete rats. The goal of this investigation was to determine the long-duration effects of leptin transgene expression in the DVC on the skeleton of leptin-replete rats. To accomplish this goal, we analyzed bone from three-month-old female rats that were microinjected with recombinant adeno-associated virus encoding either rat leptin (rAAV-Leptin, n = 6) or green fluorescent protein (rAAV-GFP, control, n = 5) gene. Representative bones from the appendicular (femur) and axial (3rd lumbar vertebra) skeleton were evaluated following 10 weeks of treatment. Selectively increasing leptin transgene expression in the DVC had no effect on femur cortical or cancellous bone microarchitecture. Additionally, increasing leptin transgene expression had no effect on vertebral osteoblast-lined or osteoclast-lined bone perimeter or marrow adiposity. Taken together, the findings suggest that activation of leptin receptors in the DVC has minimal specific effects on the skeleton of leptin-replete female rats.

Leptin receptor reactivation restores brain function in early-life Lepr-deficient mice.

Obesity is a chronic disease caused by excessive fat accumulation that impacts the body and brain health. Insufficient leptin or leptin receptor (LepR) is involved in the disease pathogenesis. Leptin is involved with several neurological processes, and it has crucial developmental roles. We have previously demonstrated that leptin deficiency in early life leads to permanent developmental problems in young adult mice, including an imbalance in energy homeostasis, alterations in melanocortin and the reproductive system and a reduction in brain mass. Given that in humans, obesity has been associated with brain atrophy and cognitive impairment, it is important to determine the long-term consequences of early-life leptin deficiency on brain structure and memory function. Here, we demonstrate that leptin-deficient (LepOb) mice exhibit altered brain volume, decreased neurogenesis and memory impairment. Similar effects were observed in animals that do not express the LepR (LepRNull). Interestingly, restoring the expression of LepR in 10-week-old mice reverses brain atrophy, in addition to neurogenesis and memory impairments in older animals. Our findings indicate that leptin deficiency impairs brain development and memory, which are reversible by restoring leptin signalling in adulthood.

LEPR isoform expression changes in local fat depots in coronary atherosclerosis and acquired heart defects

Aim. To evaluate the expression of leptin receptor isoforms in local fat depots in patients with coronary artery disease (CAD) and acquired heart defects (AHDs).Material and methods. The study included 120 patients with CAD. The comparison group consisted of 96 patients with degenerative aortic stenosis (AS). Expression of six leptin receptor isoforms (LEPR1, LEPR2, LEPR2/2, LEPR3, LEPR3/2, LEPR4) was assessed using quantitative real-time polymerase chain reaction in subcutaneous (SAT), epicardial (EAT) and perivascular (PVAT) adipose tissue. Statistical processing was carried out using the Statistica 10.0 and SPSS 17.0 for Windows software package.Results. In EAT, minimal expression of LEPR1, LEPR2, LEPR2/2, LEPR3, LEPR3/2, LEPR4 was detected relative to SAT and PVAT in the group of CAD patients. In patients with CAD, mRNA levels of six LEPR isoforms were lower than in patients with AS. In indi­viduals with AHDs, a decrease in the expression of LEPR1, LEPR2, LEPR2/2, LEPR3, LEPR3/2, LEPR4 in SAT relative to EAT and PVAT was recorded. However, only the LEPR1 and LEPR2 isoforms were significantly lower in SAT in patients with AS when com­pared with patients with CAD. In PVAT, the maximum mRNA levels of six LEPR isoforms were found in both groups. There were no significant differences in LEPR1, LEPR2, LEPR2/2, LEPR3, LEPR3/2, LEPR4 expression between patients with CAD and AHDs.Conclusion. Patients with CAD are characterized by a marked decrease in the expression of six LEPR isoforms in EAT. A decrease in the expression of studied LEPR isoforms in EAT is associated with impaired adipogenesis, adipocyte hypertrophy, insulin resistance, increased proinflammatory factors, hyperleptinemia, and progression of atherosclerosis. The identified features of EAT in patients with СФВ can probably have both local and systemic negative effects on the cardiovascular system.

Leptin receptor Gln223Arg and Lys109Arg polymorphisms may be associated with HBV-related hepatocellular carcinoma risk: A system review and meta-analysis.

Increasing evidence has suggested a strong association of hepatocellular carcinoma (HCC) susceptibility and Gln223Arg (rs1137101) and Lys109Arg (rs1137100) polymorphisms in leptin receptor (LEPR) genes. To provide a quantitative assessment for such correlation, we reviewed all related systems and conducted meta-analysis for case and control researches. A literature search of Web of Science, EMBASE, PubMed, Scopus as well as China National Knowledge Infrastructure databases was collected. 95% confidence intervals (95% CIs) together with odds ratios (ORs) were calculated. Five case-control researches consisting of 1323 cases and 1919 control cases were incorporated into meta-analysis. Researches indicated A-allelic and AA genotype of rs1137101 were substantially related to boosted susceptibility of hepatitis B virus (HBV)-related HCC (mutant model, OR = 1.81, 95% CI = 1.36-2.41, p < .001; allelic model, OR = 1.55, 95% CI = 1.32-1.83, p < .001). On the contrary, we observed GG genotype of rs1137101 substantially related to reduced risk of HBV-related HCC (wild model, OR 0.59, 95%CI = 0.46-0.75, p < .001). We observed AA genotype of rs1137100 relevant to boosted HCC risk (mutant model, OR = 1.51, 95%CI = 1.14-2.01, p = .005) as well as in those with HBV-related HCCs (homozygous model, OR = 2.12, 95%CI = 1.49-3.02, p < .001; mutant model, OR = 1.67, 95%CI = 1.23-2.26, p = .001). G-allele and AA genotype of rs1137101 might be in connection with boosted HBV-related HCC susceptibility, and wild-type GG genotype might prevent diseases. AA genotype of rs1137100 might also improve HBV-related HCC susceptibility. Such conclusions ought to be validated by larger and better-designed researches.

Canonical transient receptor potential channels and hypothalamic control of homeostatic functions.

Recent molecular biological and electrophysiological studies have identified multiple transient receptor potential (TRP) channels in hypothalamic neurons as critical modulators of homeostatic functions. In particular, the canonical transient receptor potential channels (TRPCs) are expressed in hypothalamic neurons that are vital for the control of fertility and energy homeostasis. Classical neurotransmitters such as serotonin and glutamate and peptide neurotransmitters such as kisspeptin, neurokinin B and pituitary adenylyl cyclase-activating polypeptide signal through their cognate G protein-coupled receptors to activate TPRC 4, 5 channels, which are essentially ligand-gated calcium channels. In addition to neurotransmitters, circulating hormones like insulin and leptin signal through insulin receptor (InsR) and leptin receptor (LRb), respectively, to activate TRPC 5 channels in hypothalamic arcuate nucleus pro-opiomelanocortin (POMC) and kisspeptin (arcuate Kiss1 [Kiss1ARH]) neurons to have profound physiological (excitatory) effects. Besides its overt depolarizing effects, TRPC channels conduct calcium ions into the cytoplasm, which has a plethora of downstream effects. Moreover, not only the expression of Trpc5 mRNA but also the coupling of receptors to TRPC 5 channel opening are regulated in different physiological states. In particular, the mRNA expression of Trpc5 is highly regulated in kisspeptin neurons by circulating estrogens, which ultimately dictates the firing pattern of kisspeptin neurons. In obesity states, InsRs are "uncoupled" from opening TRPC 5 channels in POMC neurons, rendering them less excitable. Therefore, in this review, we will focus on the critical role of TRPC 5 channels in regulating the excitability of Kiss1ARH and POMC neurons in different physiological and pathological states.

Radiation-influenced magnetohydrodynamic third-grade nanofluid flow around non-linearly stretched cylinder

Abstract This analysis considers the magnetized third-grade fluid stream and microorganisms over a non-linear stretchy cylinder. The radiation impacts are taken into consideration. The effects of the governing flow at the cylinder are represented in the form of PDEs employing boundary layer approximations. The system of the PDEs is further reduced in dimensionless form after applying the similarity transformations. The dimensionless system of non-linear ODEs is solved through the numerical technique bvp4c. The effects of radiation and magnetism on the third-grade liquid over a non-linear extending cylinder are highlighted in graphs and numerically in tabular form. The influence of fluid variables on the velocity curve, such as third-grade parameters, second-grade coefficients, and Reynolds number, is illustrated and explored. Suitable ranges for the parameters $( {1 \le \eta \le 10,\ 0.2 \le {{\alpha }_1} \le 0.5,\ 0 \le {{\alpha }_1} \le 1.5,\ 0.1 \le \beta \le 0.3,\ 0.1 \le \gamma \le 1.6,\ 0.05 \le M \le 0.15,\ 0.5 \le \delta \le 2.0,\ 0.7 \le Pr \le 1.3,\ 0.1 \le Rd \le 0.4,0.1 \le}$ ${e \le 0.4} )$ are chosen depending upon the convergence of the numerical method. The widths of the velocity and momentum boundary layers are revealed to be increasing functions of the curvature parameter. The temperature curve declines when boosting third-grade parameters, thermal stratification, and Hartmann number while boosting up for curvature and radiation parameters.

Anorexia-Induced Hypoleptinemia Drives Adaptations in the JAK2/STAT3 Pathway in the Ventral and Dorsal Hippocampus of Female Rats.

Leptin is an appetite-regulating adipokine that is reduced in patients with anorexia nervosa (AN), a psychiatric disorder characterized by self-imposed starvation, and has been linked to hyperactivity, a hallmark of AN. However, it remains unknown how leptin receptor (LepR) and its JAK2-STAT3 downstream pathway in extrahypothalamic brain areas, such as the dorsal (dHip) and ventral (vHip) hippocampus, crucial for spatial memory and emotion regulation, may contribute to the maintenance of AN behaviors. Taking advantage of the activity-based anorexia (ABA) model (i.e., the combination of food restriction and physical activity), we observed reduced leptin plasma levels in adolescent female ABA rats at the acute phase of the disorder [post-natal day (PND) 42], while the levels increased over control levels following a 7-day recovery period (PND49). The analysis of the intracellular leptin pathway revealed that ABA rats showed an overall decrease of the LepR/JAK2/STAT3 signaling in dHip at both time points, while in vHip we observed a transition from hypo- (PND42) to hyperactivation (PND49) of the pathway. These changes might add knowledge on starvation-induced fluctuations in leptin levels and in hippocampal leptin signaling as initial drivers of the transition from adaptative mechanisms to starvation toward the maintenance of aberrant behaviors typical of AN patients, such as perpetuating restraint over eating.

Chemerin Stimulates the Secretory Activity of BME-UV1 Bovine Mammary Epithelial Cells.

Adipose tissue is an active endocrine gland, synthesizing and secreting multiple signaling molecules termed adipokines. Following the detection of adipokines and their receptors in the mammary tissue of various species, it is indicated that adipokines play a role in the development of the mammary gland. The aim of the present study was to determine the concentration-dependent influence of three adipokines, leptin, adiponectin, and chemerin, on the viability, apoptosis, and secretory activity of BME-UV1 bovine mammary epithelial cells. The study confirmed that BME-UV1 cells contain the leptin receptor (Ob-R) protein, and express transcripts of adiponectin (ADIPOR1 and ADIPOR2) and chemerin (CMLKR1 and GPR1) receptors. Regardless of the administered dose, none of the three tested adipokines had an effect on the viability of BME-UV1 cells, and the number of apoptotic cells remained unchanged. However, chemerin (100 ng/mL) stimulated BME-UV1 cells to synthesize and secrete αS1-casein, the major protein component of milk. These results indicate that chemerin may be a potent regulator of the bovine mammary epithelial cells' functional differentiation, contributing, along with the major systemic hormones and local growth factors, to the development of the bovine mammary gland.

Leptin signalling regulates transcriptional differences in granulosa cells from genetically obese mice but not the activation of NLRP3 inflammasome

Obesity is associated with increased ovarian inflammation and the establishment of leptin resistance. We presently investigated the role of impaired leptin signalling on transcriptional regulation in granulosa cells (GCs) collected from genetically obese mice. Furthermore, we characterised the association between ovarian leptin signalling, the activation of the NOD-like receptor protein 3 (NLRP3) inflammasome and macrophage infiltration in obese mice. After phenotype characterisation, ovaries were collected from distinct group of animals for protein and mRNA expression analysis: (i) mice subjected to a diet-induced obesity (DIO) protocol, where one group was fed a high-fat diet (HFD) and another a standard chow diet (CD) for durations of 4 or 16 weeks; (ii) mice genetically deficient in the long isoform of the leptin receptor (ObRb; db/db); (iii) mice genetically deficient in leptin (ob/ob); and (iv) mice rendered pharmacologically hyperleptinemic (LEPT). Next, GCs from antral follicles isolated from db/db and ob/ob mice were subjected to transcriptome analysis. Transcriptional analysis revealed opposing profiles in genes associated with steroidogenesis and prostaglandin action between the genetic models, despite the similarities in body weight. Furthermore, we observed no changes in the mRNA and protein levels of NLRP3 inflammasome components in the ovaries of db/db mice or in markers of M1 and M2 macrophage infiltration. This contrasted with the downregulation of NLRP3 inflammasome components and M1 markers in ob/ob and 16-wk HFD-fed mice. We concluded that leptin signalling regulates NLRP3 inflammasome activation and the expression of M1 markers in the ovaries of obese mice in an ObRb-dependent and ObRb-independent manner. Furthermore, we found no changes in the expression of leptin signalling and NLRP3 inflammasome genes in GCs from db/db and ob/ob mice, which was associated with no effects on macrophage infiltration genes, despite the dysregulation of genes associated with steroidogenesis in homozygous obese db/db. Our results suggest that: (i) the crosstalk between leptin signalling, NLRP3 inflammasome and macrophage infiltration takes place in ovarian components other than the GC compartment; and (ii) transcriptional changes in GCs from homozygous obese ob/ob mice suggest structural rearrangement and organisation, whereas in db/db mice the impairment in steroidogenesis and secretory activity.

Food Cravings and Obesity in Women with Polycystic Ovary Syndrome: Pathophysiological and Therapeutic Considerations.

Polycystic ovary syndrome (PCOS), the most common endocrine disorder in women of reproductive age, constitutes a metabolic disorder frequently associated with obesity and insulin resistance (IR). Furthermore, women with PCOS often suffer from excessive anxiety and depression, elicited by low self-esteem due to obesity, acne, and hirsutism. These mood disorders are commonly associated with food cravings and binge eating. Hypothalamic signaling regulates appetite and satiety, deteriorating excessive food consumption. However, the hypothalamic function is incapable of compensating for surplus food in women with PCOS, leading to the aggravation of obesity and a vicious circle. Hyperandrogenism, IR, the reduced secretion of cholecystokinin postprandially, and leptin resistance defined by leptin receptors' knockout in the hypothalamus have been implicated in the pathogenesis of hypothalamic dysfunction and appetite dysregulation. Diet modifications, exercise, and psychological and medical interventions have been applied to alleviate food disorders, interrupting the vicious circle. Cognitive-behavioral intervention seems to be the mainstay of treatment, while the role of medical agents, such as GLP-1 analogs and naltrexone/bupropion, has emerged.

Hydrogen sulfide regulates macrophage polarization and necroptosis to accelerate diabetic skin wound healing

Hydrogen sulfide (H2S), recognized as the third gasotransmitter, plays a pivotal role in the pathophysiological processes of various diseases. Cystathionine γ-lyase (CSE) is the main enzyme for H2S production in the skin. However, effects and mechanisms of H2S in diabetic skin wound healing remain unclear. Our findings revealed a decrease in plasma H2S content in diabetic patients with skin wounds. CSE knockout (KO) diabetic mice resulted in delayed wound healing, reduced blood perfusion, and CD31 expression around the wounds. It also led to increased infiltration of inflammatory cells and M1-type macrophages, decreased collagen levels, α-smooth muscle actin (α-SMA), and proliferating cell nuclear antigen (PCNA) expression. Additionally, there were enhanced expressions of necroptosis related proteins, including receptor interacting protein kinase 1 (RIPK1), RIPK3 and mixed lineage kinase domain like protein (MLKL). In comparison, sodium hydrosulfide (NaHS), H2S donor, accelerated skin wound healing in leptin receptor deficiency (db/db) mice. This acceleration was accompanied by increased blood perfusion and CD31 expression, reduced infiltration of inflammatory cells and M1-type macrophages, elevated collagen levels, α-SMA, and PCNA expressions, and decreased necroptosis-related protein expressions together with nuclear factor-κB (NF-κB) p65 phosphorylation. In conclusion, H2S regulates macrophage polarization and necroptosis, contributing to the acceleration of diabetic skin wound healing. These findings offer a novel strategy for the treatment of diabetic skin wounds.

Whole-body deletion of Endospanin 1 protects from obesity-associated deleterious metabolic alterations.

The importance of the proper localization of most receptors at the cell surface is often underestimated, although this feature is essential for optimal receptor response. Endospanin 1 (Endo1) (also known as OBRGRP or LEPROT) is a protein generated from the same gene as the human leptin receptor and regulates the trafficking of proteins to the surface, including the leptin receptor. The systemic role of Endo1 on whole-body metabolism has not been studied so far. Here, we report that general Endo1-KO mice fed a high-fat diet develop metabolically healthy obesity with lipid repartitioning in organs and preferential accumulation of fat in adipose tissue, limited systematic inflammation, and better controlled glucose homeostasis. Mechanistically, Endo1 interacts with the lipid translocase CD36, thus regulating its surface abundance and lipid uptake in adipocytes. In humans, the level of Endo1 transcripts is increased in the adipose tissue of patients with obesity, but low levels rather correlate with a profile of metabolically healthy obesity. We suggest here that Endo1, most likely by controlling CD36 cell surface abundance and lipid uptake in adipocytes, dissociates obesity from diabetes and that its absence participates in metabolically healthy obesity.

The causal impact of gut microbiota on circulating adipokine concentrations: a two-sample Mendelian randomization study.

Evidence from previous experimental and observational research demonstrates that the gut microbiota is related to circulating adipokine concentrations. Nevertheless, the debate as to whether gut microbiome composition causally influences circulating adipokine concentrations remains unresolved. This study aimed to take an essential step in elucidating this issue. We used two-sample Mendelian randomization (MR) to causally analyze genetic variation statistics for gut microbiota and four adipokines (including adiponectin, leptin, soluble leptin receptor [sOB-R], and plasminogen activator inhibitor-1 [PAI-1]) from large-scale genome-wide association studies (GWAS) datasets. A range of sensitivity analyses was also conducted to assess the stability and reliability of the results. The composite results of the MR and sensitivity analyses revealed 22 significant causal associations. In particular, there is a suggestive causality between the family Clostridiaceae1 (IVW: β = 0.063, P = 0.034), the genus Butyrivibrio (IVW: β = 0.029, P = 0.031), and the family Alcaligenaceae (IVW: β=-0.070, P = 0.014) and adiponectin. Stronger causal effects with leptin were found for the genus Enterorhabdus (IVW: β=-0.073, P = 0.038) and the genus Lachnospiraceae (NK4A136 group) (IVW: β=-0.076, P = 0.01). Eight candidate bacterial groups were found to be associated with sOB-R, with the phylum Firmicutes (IVW: β = 0.235, P = 0.03) and the order Clostridiales (IVW: β = 0.267, P = 0.028) being of more interest. In addition, the genus Roseburia (IVW: β = 0.953, P = 0.022) and the order Lactobacillales (IVW: β=-0.806, P = 0.042) were suggestive of an association with PAI-1. This study reveals a causal relationship between the gut microbiota and circulating adipokines and may help to offer novel insights into the prevention of abnormal concentrations of circulating adipokines and obesity-related diseases.

Significance of single-nucleotide variants of anorexigenic hormone genes in childhood obesity

Obesity-induced dysregulation of hypothalamic neurons is not completely eliminated by restoring body weight, therefore the most urgent task of modern precision medicine is to predict the trajectory of development of metabolic disorders associated with obesity in children. The aim of the study was to determine the level of association of single-nucleotide variants of genes that determine eating behavior – Neuronal growth regulator 1, Fat mass and obesity associated gene, Glucagon-like peptide-1 receptor, ghrelin, leptin receptor, cholecystokinin, in the development of metabolically unhealthy obesity. 252 obese children aged 6-18 years were examined. The main group (n=152) consisted of children with metabolically unhealthy obesity (MUO) according to Identification and prevention of Dietary- and Lifestyle-induced Health Effects in Children and Infants 2014 criteria. The control group (n=100) consisted of children with metabolically healthy obesity (MHO). All children underwent a general clinical, immunobiochemical examination at the Synevo laboratory (Ukraine). Whole-genome sequencing (CeGat, Germany) was performed in 31 children of the primary and 21 children of the control group. Static analysis: variance analysis ANOVA, method of estimating data dispersion, ROC-analysis, method of testing statistical hypotheses. The level of single nucleotide variants association of anorexigenic hormone genes with MUO that exceeded the threshold accepted by 75% of the available data was, respectively, in ascending order: leptin receptor (LEPR) rs1137101 (40.38%), Glucagon-like peptide-1 receptor (GLP1R) rs1126476 (40.38%), GLP1R rs2235868 (42.31%), GLP1R rs1042044 (42.31%), LEPR rs3790435 (48.08%), cholecystokinin (CCK) rs754635 (50%), LEPR rs2186248 (55.76%), GLP1R rs6918287 (55.76%). Genotypes of the GLP1R gene, such as CC rs10305421 determine insulin resistance (F=5.6); GA/AA rs3765468 – meta-inflammation (F=5.8); AA rs6918287 – basal hyperglycemia (F=6.3) and triglyceridemia (F=51.3), p&lt;0.05. Single-nucleotide variants of the gene GLP1R rs6918287, LEPR rs2186248, CCK rs754635 of the anorexic hormones that control eating behavior are highly associated with the presence of metabolically unhealthy obesity in children.

Expression Patterns of Leptin, Leptin Receptor, Kiss1, and HOTAIR Genes in Blood and Semen of Infertile Males with Oligospermia

Expression Patterns of Leptin, Leptin Receptor, Kiss1, and HOTAIR Genes in Blood and Semen of Infertile Males with Oligospermia

Association of leptin receptor polymorphisms with susceptibility of non-small cell lung cancer: Evidence from 2249 subjects.

Non-small cell lung cancer (NSCLC) is increasing dramatically. It is believed that energy metabolism-related genes could play an important role in etiology of NSCLC. In this study, we sought to assess the correlation between three LEPR single nucleotide polymorphisms (rs1137101, rs1137100 and rs6588147) with NSCLS susceptibility. In total, 1193 NSCLC cases and 1056 controls were included. SNPscan™ genotyping method was used to analyze the genotypes of LEPR polymorphisms. Compared to rs6588147 GG in LEPR gene, this study identified a protective role of LEPR rs6588147 GA and GA/AA for the occurrence of NSCLC (GA vs. GG [p = 0.021] and GA/AA vs. GG [p = 0.030]). As well, we found that a protective role of LEPR rs6588147 for the occurrence of non-SCC subgroup (p < 0.05). By logistic regression analysis, we found that the rs6588147 A allele related genotypes might play a protective role for the occurrence of NSCLC in drinking, BMI ≥24 kg/m2, smoking and male subgroups. We also found that the rs1137101 A allele related genotypes played a protective role for the occurrence of NSCLC in male, younger participants (under 59 years) and overweight/obesity (BMI ≥24 kg/m2) subgroups. We found that LEPR Ars1037100Ars1037101Ars6588147 haplotype might play a protective role for the occurrence of NSCLC (p = 0.013). In addition, our findings indicated that LEPR rs1137100 G>A SNP might increase the risk of lymph node metastases (p = 0.038). This study highlights that LEPR rs6588147, rs1137101 genotypes and LEPR Ars1037100Ars1037101Ars6588147 haplotype are correlated with the occurrence of NSCLC. LEPR rs1137100 G>A SNP increases the risk of lymph node metastases.

Central inhibition of HDAC6 re-sensitizes leptin signaling during obesity to induce profound weight loss

Leptin resistance during excess weight gain significantly contributes to the recidivism of obesity to leptin-based pharmacological therapies. The mechanisms underlying the inhibition of leptin receptor (LepR) signaling during obesity are still elusive. Here, we report that histone deacetylase 6 (HDAC6) interacts with LepR, reducing the latter's activity, and that pharmacological inhibition of HDAC6 activity disrupts this interaction and augments leptin signaling. Treatment of diet-induced obese mice with blood-brain barrier (BBB)-permeable HDAC6 inhibitors profoundly reduces food intake and leads to potent weight loss without affecting the muscle mass. Genetic depletion of Hdac6 in Agouti-related protein (AgRP)-expressing neurons or administration with BBB-impermeable HDAC6 inhibitors results in a lack of such anti-obesity effect. Together, these findings represent the first report describing a mechanistically validated and pharmaceutically tractable therapeutic approach to directly increase LepR activity as well as identifying centrally but not peripherally acting HDAC6 inhibitors as potent leptin sensitizers and anti-obesity agents.

Salvia officinalis Improves Glycemia and Suppresses Pro-inflammatory Features in Obese Rats with Metabolic Syndrome.

Obesity is regarded as the main cause of metabolic diseases and a core factor for all-cause mortality in the general population, notably from cardiovascular disease. The majority of people with type 2 diabetes have obesity and insulin resistance. Some evidence indicates that an individual with obesity is approximately 10 times more likely to develop type 2 diabetes than someone with moderate body weight. One of the most significant therapeutic herbs, Salvia officinalis (Lamiaceae) (SAGE), possesses potent medicinal importance. The aim of this article was to evaluate the anti-diabetic and antiobesity activity of SAGEAE against HFD-induced obesity in rats. Thirty adult albino rats were randomly divided into five equal groups: control, High-fat Diet (HFD) administrated rats, HFD + Salvia officinalis Aqueous Extract (SAGEAE) (150 mg/kg.bw.), HFD + SAGEAE (300 mg/kg.bw.) and HFD + metformin (500 mg/kg.bw.). Body weight, plasma biochemical parameters, oxidative stress, inflammatory indicators, hepatic Phosphoenolpyruvate Carboxykinase 1 (PCK1), Glucokinase (GK), brain Leptin Receptor (LepRb), Glucose Transporter-4 (GLUT4), Sirtuin 1 (SIRT1) and mRNA33-5P gene signalling mRNA levels were all assessed after 8 weeks. A histological examination of the liver was also performed to check for lipid accumulation. The administration of HFD resulted in increased body weight, glucose, insulin, leptin, Total Cholesterol (TC), Triglycerides (TG), Thiobarbaturic Acid Reactive Substances (TBARS), Monocyte Chemoattractant Protein-1 (MCP1), Interleukine-6 (IL-6) and tumor necrosis factor-α (TNF- α) as well as hepatic PCK1, brain LepRb and adipose tissue mRNA33-5P gene expression. However, our findings revealed a significant reduction in adiponectin, High-density Lipoproteincholesterol (HDL-C), reduced glutathione (GSH) and Superoxide Dismutase (SOD) levels as well as the expression of hepatic GK and adipose tissue SIRT1 and GLUT4 genes. Also, administration of SAGEAE significantly normalized body weight, glucose, insulin, leptin, adiponectin, TC, TG, HDL-C, TBARs, SOD, IL-6, MCP-1 and TNF-α in plasma and liver tissue of HFD-treated rats. On the other hand, PCK1, GK, LepRb, SIRT1, GLUT4 and mRNA33-5P gene expression was enhanced in obese rats when administrated with SAGEAE. Histological and US studies support the biochemical, PCR and electrophoretic results. The findings imply that SAGEAE could be used as a new pharmaceutical formula in the treatment of obesity.

The Association Between the 5-Hydroxytryptamine Receptor 2A Gene Variants rs6311 and rs6313 and Obstructive Sleep Apnea in the Iranian Kurdish Population.

Introduction: Sleep is one of the most significant parts of everyone's life. Most people sleep for about one-third of their lives. Sleep disorders negatively impact the quality of life. Obstructive sleep apnea (OSA) is a severe sleep disorder that significantly impacts the patient's life and their family members. This study aimed to investigate the relationship between rs6313 and rs6311 polymorphisms in the serotonin receptor type 2A gene and OSA in the Kurdish population. Materials and Methods: The study's population comprises 100 OSAsufferers and 100 healthy people. Polysomnography diagnostic tests were done on both the patient and control groups. The polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) was used to investigate the relationship between OSAand LEPR gene polymorphisms. Results: Statistical analysis showed a significant relationship between genotype frequencies of patient and control groups of rs6311 with OSAin dominant [odds ratio (OR) = 5.203, p < 0.001) and codominant models (OR = 9.7, p < 0.001). Also, there was a significant relationship between genotype frequencies of patient and control groups of rs6313 with OSAin dominant (OR = 10.565, p < 0.001) and codominant models (OR = 5.938, p < 0.001). Conclusions: Findings from the study demonstrated that the two polymorphisms rs6311 and rs6313 could be effective at causing OSA; however, there was no correlation between the severity of the disease and either of the two polymorphisms.