Plasma Leptin Research Articles

Plasma Leptin, Nesfatin 1, NPY, and Zinc Levels in Obese and Metabolic Syndrome Children

Objective: The aim of this study is to investigate the relationship between leptin, nesfatin 1 and NPY hormones and zinc in boys and girls diagnosed with metabolic syndrome and obesity. Materials and Methods: This study included a total of 6 groups. Group 1 Boy Control, Group 2 Girl Control, Group 3 Obese Boys, Group 4 Obese Girls, Group 5 Boys with Metabolic Syndrome, Group 2 with Girls with Metabolic Syndrome. Plasma leptin, nesfatin-1, NPY (by ELISA method) and serum zinc (by AA method) levels were determined in blood samples obtained from the subjects. Results: Leptin and zinc levels were significantly higher both in boy and girl patients with metabolic syndrome than in obese and control children. Nesfatin-1 and NPY levels were significantly lower both in girl and boy obese and metabolic syndrome children compared to their control groups. Conclusion: In the current study a significant increase in plasma leptin and serum zinc levels and a significant decrease of plasma nesfatin-1 and NPY levels were observed in boys and girls with metabolic syndrome. The findings of our study show that leptin, nesfatin-1 and NPY levels may be important biomarkers in the assessment of metabolic syndrome risk in both girls and boys.

The obesity-linked human lncRNA AATBC stimulates mitochondrial function in adipocytes.

Adipocytes are critical regulators of metabolism and energy balance. While white adipocyte dysfunction is a hallmark of obesity-associated disorders, thermogenic adipocytes are linked to cardiometabolic health. As adipocytes dynamically adapt to environmental cues by functionally switching between white and thermogenic phenotypes, a molecular understanding of this plasticity could help improving metabolism. Here, we show that the lncRNA Apoptosis associated transcript in bladder cancer (AATBC) is a human-specific regulator of adipocyte plasticity. Comparing transcriptional profiles of human adipose tissues and cultured adipocytes we discovered that AATBC was enriched in thermogenic conditions. Using primary and immortalized human adipocytes we found that AATBC enhanced the thermogenic phenotype, which was linked to increased respiration and a more fragmented mitochondrial network. Expression of AATBC in adipose tissue of mice led to lower plasma leptin levels. Interestingly, this association was also present in human subjects, as AATBC in adipose tissue was inversely correlated with plasma leptin levels, BMI, and other measures of metabolic health. In conclusion, AATBC is a novel obesity-linked regulator of adipocyte plasticity and mitochondrial function in humans.

Leptin receptor expression in blood mononuclear cells of lactating women is associated with infant body weight: Potential role as a molecular biomarker.

Molecular biomarkers of maternal leptin resistance associated with infant weight are needed. To evaluate gene expression of leptin receptor (LEPR), suppressor of cytokine signalling 3 (SOCS3) and insulin receptor in peripheral blood mononuclear cells (PBMCs) of lactating women and their relationship with infant body weight and adiposity. At day 10 postpartum, maternal gene expression in PBMCs as well as leptin and insulin concentrations in plasma and milk were assessed (n = 68). Infant weight and BMI z-scores, skinfolds and arm circumference were obtained at 10 days and/or at 3 months old. In mothers with pre-pregnancy overweight or obesity (OW/OB), LEPR expression was reduced (p = 0.013) whereas plasma and milk leptin and milk insulin concentrations were elevated. LEPR expression was positively related with infant weight z-score (Beta (95% CI): 0.40 (0.17, 0.63), p = 0.001) but not with leptin concentrations. SOCS3 expression was positively related with infant weight z-score (Beta (95% CI): 0.28 (0.04, 0.51), p = 0.024) and arm circumference (Beta (95% CI): 0.57 (0.32, 0.82), p < 0.001). Relationships remained significant after adjusting for maternal and infant confounders. LEPR and SOCS3 gene expression in PBMCs are novel maternal molecular biomarkers that reflect leptin resistance and are associated with infant body weight and adiposity.

Longitudinal effects of FTO gene polymorphism on body composition, cardiorespiratory fitness, physical activity, inflammatory markers, and cardiovascular risk in children and adolescents. "The UP & DOWN study".

The role of polymorphism rs9939609 of the FTO gene has been related with fat mass and cardiovascular risk in adults, but it remains unclear in children and adolescents. Hence, the main aim of this study was to determine the FTO polymorphism effects on body composition, cardiorespiratory fitness (CRF), physical activity (PA), inflammatory markers, and cardiovascular risk both in cross-sectional analysis and after two-years of follow-up in children and adolescents. A total of 2129 participants were included in this study. The rs9939609 polymorphism was genotyped. Body composition measurements, CRF, and moderate-to-vigorous PA (MVPA) were determined at baseline and after two-year of follow-up. Moreover, plasma leptin and adiponectin were also determined as inflammatory markers. Furthermore, an index of cardiovascular disease risk factors (CVDRF-I) was calculated. Codominant (TT vs. TA vs. AA) and dominant (AA+AT vs. TT) models were applied for statistical analysis. The results showed a main effect of the FTO genotype on body composition measures in both first and third year (p < 0.05), with lower adiposity in TT compared with AA or AA+AT group. These differences were maintained after accounting for pubertal maturity, sex, age, VO2 max, and MVPA. Moreover, lower leptin level was observed in TT compared to AA+AT group in the third year. An interaction in Gene*Time*Sex was found in height and neck circumference in dominant model (p = 0.047; p = 0.020, respectively). No differences were found in CRF, MVPA nor CVDRF-I between groups. Hence, homozygous TT allele could be a protective factor against weight gain from early childhood.

Maternal obesity and high leptin levels prime pro-inflammatory pathways in human cord blood leukocytes

IntroductionMaternal obesity alters the immune function in the offspring. We hypothesize that maternal obesity and pro-inflammatory pathways induce leptin-related genes in neonatal monocytes, whereby high leptin levels enhance their inflammatory response. MethodsTranscriptional profiles of cord blood leukocytes (CBL) in basal and pro-inflammatory conditions were studied to determine differentially expressed genes (DEG). The DNA methylation profile of CB monocytes (CBM) of neonates born to control BMI mothers and women with obesity was assayed to identify differentially methylated probes (DMP). CBM-derived macrophages were cultured with or without leptin (10–100 ng/ml) and then stimulated with lipopolysaccharide (LPS, 100 ng/ml) and interferon-gamma (20 ng/ml) to assess the induction of TNF-α and IL-10 transcripts. ResultsCBL from pregnancies with obesity (CBL-Ob) showed 12,183 DEG, affecting 49 out of 78 from the leptin pathway. Control CBM exposed to LPS showed 45 leptin-related DEG, an effect prevented by the co-exposure to LPS and IL-10. Conversely, CBM-Ob showed 5279 DMP enriched in insulin- and leptin-related genes, and Lasso regression of leptin-related DMP showed high predictive value for plasma leptin levels (r2 = 0.9897) and maternal BMI categories (AUC = 1). Chronic exposure to leptin increased TNF-α and decreased IL-10 levels in control BMI samples but not in Ob-CBM. Enhanced TNF-α induction after proinflammatory stimulation was observed in leptin-treated control BMI samples. DiscussionObesity in pregnancy is associated with a distinctive expression and DNA methylation profile of leptin-related genes in cord blood monocytes, meanwhile, leptin enhances the expression of pro-inflammatory cytokines upon stimulation with M1-skewing agents.

The lncOb rs10487505 polymorphism impairs insulin sensitivity and glucose tolerance in children and adolescents with obesity.

Leptin plays a key role in the regulation of body weight and other endocrine systems. Recently, impairment of leptin gene transcription due to genetic variations in a long noncoding RNA (lncOb) has been described. This retrospective study aims to characterize the clinical and metabolic phenotype of children and adolescents with obesity who were homozygous for the lncOb rs10487505 leptin lowering allele. Enrolled children underwent an anthropometrical evaluation, biochemical assessment, and genotyping for lncOb rs10487505. Plasma leptin levels were assessed in 150 participants. A total of 434 patients were included and divided into two groups according to rs10487505 recessive inheritance (CC vs. GG/GC). Children who were homozygous for the C allele showed higher fasting insulin (p = 0.01), homeostasis model assessment of insulin resistance (p = 0.01), lower whole-body insulin sensitivity index (p = 0.02), and lower disposition index (p = 0.03). Moreover, CC patients presented with a higher prevalence of prediabetes (9.3% vs. 3.4%, p = 0.04) and a 2.9-fold (95% CI: 1.1-7.9, p = 0.04) higher risk of prediabetes compared with G-carriers independently from confounders. Leptin plasma levels were significantly lower in the CC group (p = 0.002). Hormone levels correlated with BMI z score (r = 0.19, p = 0.04), fasting insulin (r = -0.34, p < 0.0001), homeostasis model assessment of insulin resistance (r = -0.33, p < 0.0001), and disposition index (r = 0.20, p = 0.04). The lncOb rs10487505 polymorphism affects leptin circulating levels, worsens insulin resistance, and heightens the risk of prediabetes in children and adolescents with obesity.

Plasma adiponectin as a predictor of the effectiveness of coronary heart disease therapy in patients with metabolic syndrome

BACKGROUND: Adiponectin, an adipose tissue protein, plays a crucial role in the development of metabolic syndrome and atherosclerosis. As a potential therapeutic target, this adipokine can be considered in the context of treatment strategies.&#x0D; AIM: The aim of this study was to assess the correlation between changes in plasma adiponectin concentration during coronary heart disease therapy and the effectiveness of the treatment, as well as to examine the relationship between initial adiponectin levels and treatment outcomes in patients with metabolic syndrome.&#x0D; MATERIALS AND METHODS: The study included 31 patients with coronary heart disease and metabolic syndrome (age 59.7 5.9 years, 21 women) which underwent the reexamination after 23 years. Most patients received statins (n = 26), while some received fibrates (n = 4) and hypoglycemic drugs (n = 4). Additionally, the patients were on hypotensive and antithrombotic therapies. The effectiveness of coronary heart disease therapy was assessed by evaluating changes in the functional class of angina pectoris and exercise tolerance measured through cycle ergometry. Plasma samples were collected at the initial and reexamination periods to determine glucose, insulin, adiponectin, leptin, and lipidogram parameters.&#x0D; RESULTS: The study revealed improvements in insulin sensitivity and plasma lipid spectrum, along with reduced levels of plasma leptin and increased adiponectin levels during the course of therapy. In addition, some patients showed enhanced exercise tolerance. Among the biochemical parameters, changes in insulin resistance during therapy correlated with improvements in exercise performance indicators during cycle ergometry (r = 0.320.36, p 0.05). Moreover, multiple regression analysis indicated that the initial adiponectin concentration independently determined changes in inotropic reserve and the amount of work performed ( = 0.44, p = 0.04 and = 0.64, p = 0.008).&#x0D; CONCLUSIONS: The studys findings regarding the association of plasma adiponectin concentration with changes in exercise tolerance during coronary heart disease therapy suggest the potential for developing specific approaches to raise adiponectin levels in the future.

Metabolic mitochondrial alterations prevail in the female rat heart 8 weeks after exercise cessation.

The consumption of high-caloric diets strongly contributes to the development of non-communicable diseases (NCDs), including cardiovascular disease, the leading cause of mortality worldwide. Exercise (along with diet intervention) is one of the primary non-pharmacological approaches to promote a healthier lifestyle and counteract the rampant prevalence of NCDs. The present study evaluated the effects of exercise cessation after a short period training on the cardiac metabolic and mitochondrial function of female rats. Seven-week-old female Sprague-Dawley rats were fed a control or a high-fat, high-sugar (HFHS) diet and, after 7 weeks, the animals were kept on a sedentary lifestyle or submitted to endurance exercise for 3 weeks (6 days per week, 20-60 min/day). The cardiac samples were analysed 8 weeks after exercise cessation. The consumption of the HFHS diet triggered impaired glucose tolerance, whereas the HFHS diet and physical exercise resulted in different responses in plasma adiponectin and leptin levels. Cardiac mitochondrial respiration efficiency was decreased by the HFHS diet consumption, which led to reduced ATP and increased NAD(P)H mitochondrial levels, which remained prevented by exercise 8 weeks after cessation. Exercise training-induced cardiac adaptations in redox balance, namely increased relative expression of Nrf2 and downstream antioxidant enzymes persist after an eight-week exercise cessation period. Endurance exercise modulated cardiac redox balance and mitochondrial efficiency in female rats fed a HFHS diet. These findings suggest that exercise may elicit cardiac adaptations crucial for its role as a non-pharmacological intervention for individuals at risk of developing NCDs.

Association between LEPR Genotype and Gut Microbiome in Healthy Non-Obese Korean Adults.

The LEPR (leptin receptor) genotype is associated with obesity. Gut microbiome composition differs between obese and non-obese adults. However, the impact of LEPR genotype on gut microbiome composition in humans has not yet been studied. In this study, the association between LEPR single nucleotide polymorphism (rs1173100, rs1137101, and rs790419) and the gut microbiome composition in 65 non-obese Korean adults was investigated. Leptin, triglyceride, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol levels were also measured in all participants. Mean ± SD (standard deviation) of age, body mass index, and leptin hormone levels of participants was 35.2 ± 8.1 years, 21.4 ± 1.8 kg/m2, and 7989.1 ± 6687.4 pg/mL, respectively. Gut microbiome analysis was performed at the phylum level by 16S rRNA sequencing. Among the 11 phyla detected, only one showed significantly different relative abundances between LEPR genotypes. The relative abundance of Candidatus Saccharibacteria was higher in the G/A genotype group than in the G/G genotype group for the rs1137101 single nucleotide polymorphism (p=0.0322). Participant characteristics, including body mass index, leptin levels, and other lipid levels, were similar between the rs1137101 G/G and G/A genotypes. In addition, the relative abundances of Fusobacteria and Tenericutes showed significant positive relationship with plasma leptin concentrations (p=0.0036 and p=0.0000, respectively). In conclusion, LEPR genotype and gut microbiome may be associated even in normal-weight Korean adults. However, further studies with a greater number of obese adults are needed to confirm whether LEPR genotype is related to gut microbiome composition.

Longitudinal Changes in Body Weight of Breastfeeding Mothers in the First Year after Delivery and its Relationship with Human Milk Composition: a Combined Longitudinal and Cross-sectional Cohort Study

ObjectivePostpartum weight retention (PPWR) is a common problem among women after childbirth. The main objectives of this study are to understand the changes in body weight of breastfeeding mothers during long-term follow-up and preliminarily explore the relationship between maternal body weight and human milk composition, including macronutrients, leptin, and adiponectin. Methods: The study included a longitudinal cohort (122 mothers), and a cross-sectional cohort (37 mothers). The human milk, maternal weight, and dietary surveys were collected in the longitudinal cohort at different follow-up time points (1−14 days postpartum, 2−4 months postpartum, 5−7 months postpartum, and 12−17 months postpartum). The maternal body weight was analyzed using the responses in the survey questionnaires. A milk analyzer based on the mid-infrared spectroscopy (MIRS) was used to determine milk composition, and nutrition analysis software evaluated dietary intakes. In the cross-sectional cohort, participating mothers were asked to provide blood and human milk samples and pertinent information related to maternal body composition. Maternal body composition was measured by bioelectrical impedance analysis (BIA), while ELISA analyzed leptin and adiponectin in milk and serum. Results: At 5−7 months postpartum, the PPWR of breastfeeding mothers was (2.46 ± 3.59) kg. At 12−17 months postpartum, the PPWR was (0.98 ± 4.06) kg. PPWR was found to be negatively correlated with milk fat content within 14 days postpartum and positively correlated at 2−4 months postpartum. In addition, the maternal weight and body muscle mass were positively correlated with leptin and adiponectin in milk. Plasma leptin was positively correlated with the mother's body weight, body mass index (BMI), FAT percentage, and body fat mass, while plasma adiponectin did not correlate with any parameter. The results also indicate that the PPWR did not correlate with leptin and adiponectin in plasma or milk. Conclusions: Breastfeeding mothers may retain considerable weight gain one year after delivery. Human milk composition may be related to changes in maternal body weight. Leptin and adiponectin in breast milk and leptin in plasma are associated with the maternal body composition. This study supports the notion that maternal nutritional status may affect offspring health through lactation, and future research should focus on exploring weight management of postpartum mothers.

Effect of Supplementation with Coffee and Cocoa By-Products to Ameliorate Metabolic Syndrome Alterations Induced by High-Fat Diet in Female Mice.

Coffee and cocoa manufacturing produces large amounts of waste. Generated by-products contain bioactive compounds with antioxidant and anti-inflammatory properties, suitable for treating metabolic syndrome (MetS). We aimed to compare the efficacy of aqueous extracts and flours from coffee pulp (CfPulp-E, CfPulp-F) and cocoa shell (CcShell-E, CcShell-F) to ameliorate MetS alterations induced by a high-fat diet (HFD). Bioactive component content was assessed by HPLC/MS. C57BL/6 female mice were fed for 6 weeks with HFD followed by 6 weeks with HFD plus supplementation with one of the ingredients (500 mg/kg/day, 5 days/week), and compared to non-supplemented HFD and Control group fed with regular chow. Body weight, adipocyte size and browning (Mitotracker, confocal microscopy), plasma glycemia (basal, glucose tolerance test-area under the curve, GTT-AUC), lipid profile, and leptin were compared between groups. Cocoa shell ingredients had mainly caffeine, theobromine, protocatechuic acid, and flavan-3-ols. Coffee pulp showed a high content in caffeine, protocatechuic, and chlorogenic acids. Compared to Control mice, HFD group showed alterations in all parameters. Compared to HFD, CcShell-F significantly reduced adipocyte size, increased browning and high-density lipoprotein cholesterol (HDL), and normalized basal glycemia, while CcShell-E only increased HDL. Both coffee pulp ingredients normalized adipocyte size, basal glycemia, and GTT-AUC. Additionally, CfPulp-E improved hyperleptinemia, reduced triglycerides, and slowed weight gain, and CfPulp-F increased HDL. In conclusion, coffee pulp ingredients showed a better efficacy against MetS, likely due to the synergic effect of caffeine, protocatechuic, and chlorogenic acids. Since coffee pulp is already approved as a food ingredient, this by-product could be used in humans to treat obesity-related MetS alterations.

Metabolic dysfunctions following chronic oral corticosterone are modified by adolescence and sex in mice

Adolescence is a period of development in which shifts in responses to glucocorticoids is well-documented. Obesity and metabolic syndrome are substantial health issues whose rates continue to rise in both adult and adolescent populations. Though many interacting factors contribute to these dysfunctions, how these shifts in glucocorticoid responses may be related remain unknown. Using a model of oral corticosterone (CORT) exposure in male and female mice, we demonstrate differential responses during adolescence (30–58 days of age) or adulthood (70–98 day of age) in endpoints relevant to metabolic function. Our data indicate that CORT resulted in significant weight gain in adult- and adolescent-exposed females and adult-exposed males, but not adolescent-exposed males. Despite this difference, all animals treated with high levels of CORT showed significant increases in white adipose tissue, indicating a dissociation between weight gain and adiposity in adolescent-treated males. Similarly, all experimental groups showed significant increases in plasma insulin, leptin, and triglyceride levels, further suggesting potential disconnects between overt weight gain, and underlying metabolic dysregulation. Finally, we found age- and dose-dependent changes in the expression of hepatic genes important in glucocorticoid receptor and lipid regulation, which showed different patterns in males and females. Thus, altered transcriptional pathways in the liver might be contributing differentially to the similar metabolic phenotype observed among these experimental groups. We also show that despite little CORT-induced changes in the hypothalamic levels of orexin-A and NPY, we found that food and fluid intake were elevated in adolescent-treated males and females. These data indicate chronic exposure to elevated glucocorticoid levels results in metabolic dysfunction in both males and females, which can be further modulated by developmental stage.

Distinct inflammatory signatures of upper and lower body adipose tissue and adipocytes in women with normal weight or obesity.

Upper and lower body fat accumulation poses an opposing obesity-related cardiometabolic disease risk. Depot-differences in subcutaneous adipose tissue (SAT) function may underlie these associations. We aimed to investigate the inflammatory signatures of abdominal (ABD) and femoral (FEM) SAT in postmenopausal women with normal weight or obesity. We included 23 postmenopausal women with normal weight (n = 13) or obesity (n = 10). In vivo secretion of adipokines from ABD and FEM SAT was measured using the arterio-venous balance technique. Adipokine gene expression and adipocyte morphology were examined in ABD and FEM SAT. Furthermore, adipokine expression and secretion were investigated in vitro using differentiated human primary ABD and FEM subcutaneous adipocytes derived from the study participants. Plasma leptin and plasminogen activator inhibitor (PAI)-1 concentrations were higher, and ABD and FEM adipocytes were larger in women with obesity than normal weight. No differences in adipocyte size and blood flow were apparent between ABD and FEM SAT. We found significant release of leptin and monocyte chemoattractant protein (MCP)-1 from ABD and FEM SAT, with higher fractional release of MCP-1 from ABD than FEM SAT. Gene expression of leptin, PAI-1, and tumor necrosis factor-α was lower in ABD than FEM SAT and higher in women with obesity than normal weight. In ABD adipocytes, interleukin-6, PAI-1, and leptin gene expression were higher, while adiponectin and dipeptidyl-peptidase-4 gene expression were lower than in FEM adipocytes. Finally, ABD adipocytes secreted less MCP-1 compared to FEM adipocytes. These findings demonstrate that upper and lower body SAT and adipocytes are characterized by distinct inflammatory signatures in postmenopausal women, which seem independent of adipocyte size.

Loss of epidermal glucocorticoid receptor protects against whole body metabolic dysfunction upon chronic corticosterone treatment

ObjectiveGlucocorticoid (GC) excess contributes to the development of metabolic syndrome, defined by visceral obesity, abnormal glucose tolerance, and dyslipidemia. While it is accepted that loss of metabolic control is causative of cutaneous diseases, the systemic effects of epidermal dysfunction have received limited attention. Importantly, independent of GC blood levels, skin synthesis of these hormones can provide tissue-specific variations that may affect global homeostasis. We aimed to assess whether the epidermal-specific loss of the GC receptor (GR) had an impact on the dermal white adipose tissue (dWAT), a specialized fat depot functionally different from other fat pads, as well as on whole body homeostasis. MethodsGR epidermal KO (GREKO) and control female mice were treated with oral corticosterone (CORT) for 4 weeks, a protocol inducing metabolic dysfunction. Metabolic parameters including body weight, visceral and hepatic fat accumulation, blood glucose and insulin levels, glucose tolerance tests upon fasting, and triglycerides levels, were determined. Systemic alterations of soluble factors with known roles in immunity and inflammation were also assessed by a multiplex antibody array system containing selected cytokines, chemokines, and growth factors. The levels of cutaneous GCs and the profile of skin-secreted factors were determined in tissue explants by ELISA and the multiplex array system. Morphometric studies quantitated changes in dWAT thickness and adipocyte size in both genotypes, basally and at the end of CORT treatment. The expression of adipocyte markers was assessed in purified dermal adipocytes in vehicle and CORT-treated GREKOvs controls. ResultsDespite similar circulating levels of GCs, GREKO mice were highly resistant to CORT-induced systemic metabolic anomalies including body weight gain, visceral and hepatic fat, hyperglycemia, insulinemia, and elevated levels of plasma triglycerides, leptin, FGF-21, PAI-1, and CCL11. GREKO mice featured constitutively enhanced levels of cutaneous GCs relative to controls at least partially due to keratinocyte-specific increased expression of the critical steroidogenic enzyme Cyp11b1. Also, the higher ratio of skin-secreted protective vs inflammatory adipokines in GREKOvs controls, correlated with higher capacity of adipogenic conversion in experiments using conditioned media from tissue explants. Following CORT treatment, relative to controls, GREKO mice featured reduced dWAT hyperplasia and adipocyte hypertrophy, with increased Adipoq and decreased Lipocalin 2 expression in purified dermal adipocytes. ConclusionsOverall data suggest that epidermal GR loss results in paracrine actions on dermal adipocytes as well as endocrine actions on key metabolic tissues that significantly improve the whole body metabolism in a mouse model of metabolic dysfunction.

27-LB: A Prediction Model for Diabetic Retinopathy Based on Plasma Adipokines among Patients with Type 2 Diabetes

Background: Accumulating evidence has suggested a link between adipokines and diabetic retinopathy (DR). This study aimed to investigate the risk factors for sight-threatening DR (STDR) and establish a prognostic model for predicting STDR among patients with type 2 diabetes mellitus (T2DM). Methods: In the case-control set, principal component analysis (PCA) was performed to select optimal predictive cytokines for STDR. Support vector machine (SVM) was used to examine the possible combination of baseline plasma adipokines to discriminate the mild participants who will later develop STDR. An individual prospective cohort with a follow-up period of 3 years was used for the external validation. Results: In both training and testing sets, comprised of 306 patients with DR, median levels of plasma adiponectin, leptin, and fatty acid-binding protein 4 (FABP4) were significantly higher in the STDR group than those in mild DR. Except for adipsin, the other three adipokines, FABP4, adiponectin, and leptin, were selected by PCA and integrated into SVM. The accuracy of the multivariate SVM classification model was acceptable in both the training set (AUC = 0.81, sensitivity = 71%, specificity = 91%) and the testing set (AUC = 0.77, sensitivity = 61%, specificity = 92%). 110 T2DM mild NPDR patients were enrolled for external validation. High- and low-risk groups were grouped by the median value of adiponectin, FABP4, and leptin. More STDR occurred in the high-risk group than in the low-risk group among the three predictors. SVM demonstrated acceptable performance, with the AUC, sensitivity, and specificity of 0.77, 64%, and 91%, respectively. Conclusions: Adiponectin, leptin, and FABP4 were demonstrated to be associated with the severity of DR and maybe good predictors for STDR, suggesting that adipokines may play an important role in the pathophysiology of DR development. Disclosure Y. An: None. J. Ke: None. D. Zhao: None.

Metformin Affects Plasma Levels of Soluble Leptin Receptors in Type 2 Diabetes Mellitus and Metabolic Syndrome Patients

Background: Obesity and insulin resistance elevate plasma leptin, while it lowers plasma levels of soluble leptin receptors (sOB-R).Objectives: To measure the levels of sOB-R in patients with type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS) and compare it to healthy controls. The study also aimed to investigate the influence of metformin on the levels of sOB-R in patients with T2DM and MetS. Materials and Methods: A cross-sectional study was conducted on 66 participants (33 patients and 33 controls). Patients were divided into two groups; Group I included 17 newly diagnosed T2DM patients, and Group II included 16 patients with MetS. Patients were studied before and 3 months after treatment with 850 mg metformin treatment. Group III included 33 non-obese healthy individuals as a control group. Measurements such as height, weight, waist circumference, hip circumference, blood pressure examination, and biochemical tests including fasting blood sugar, HbA1c, total cholesterol (Ch), triglyceride, high-density lipoprotein (HDL), insulin level, plasma sOB-R levels were performed. Ch/HDL ratio, non-HDL cholesterol, Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), Waist Hip Ratio (WHR), and Body Mass Index (BMI) were calculated.Results: No statistically significant difference was found among the groups regarding sOB-R levels initially, but after metformin treatment, T2DM patients showed a significantly higher level (10.19 ng/ml). There was a significant increase in the levels of sOB-R after metformin treatment, as it increased from 7.82 ng/ml to 10.19 ng/ml in T2DM, and from 6.92 ng/ml to 7.82 ng/ml in MetS patients. Conclusion: Metformin significantly increases the plasma levels of sOB-R in T2DM patients but only slightly increases these levels in MetS patients.

#2665 EFFECT OF RENAL DENERVATION ON THE PLASMA LEPTIN CONCENTRATION IN PATIENTS WITH RESISTANT HYPERTENSION

Abstract Background and Aims Leptin is mainly produced by adipose tissue and has hypertensinogenic properties. In patients with arterial hypertension, plasma concentration of leptin is higher than in healthy subjects. Percutaneous ablation of the sympathetic nervous system fibers located in the wall of the renal arteries by radio frequency waves (renal denervation - RDN), was introduced as a method of invasive treatment of resistant arterial hypertension. The aim of this single center, interventional, clinical study was to assess the effect of RDN on the plasma leptin concentration in patients with resistant arterial hypertension. Method Eighteen patients (9 women, 9 men) aged 53.2±6.5 years with resistant hypertension who underwent RDN using Simplicity catheters (Medtronic, Inc., Northridge, CA) were enrolled in the study. Plasma leptin concentration was determined using the Human Leptin RIA HL-81K (Linco Research, Inc., Missouri, USA) before RDN denervation and 6 months after RDN. Additionally, patients were divided into two subgroups: responders (systolic and diastolic blood pressure - BP reduction 6 months after RDN &amp;gt;25 mmHg and &amp;gt;12 mmHg, respectively; n=9) and low responders (systolic and diastolic BP reduction 6 months after RDN ≤25 mmHg and ≤12 mmHg, respectively; n=9). Results Systolic and diastolic BP was significantly reduced after RDN (196.6±28.2 and 162.9±15.6; p&amp;lt;0.001 and 117.9±26.4 and 90.7±8.6 mmHg; p&amp;lt;0.001, respectively). Body mass index (BMI) before RDN and 6 months after RDN was similar (31.0±4.4 and 31.3±4.4 kg/m2; P = .8, respectively). Mean plasma leptin concentration before RDN and 6 months after RDN did not change significantly in the entire studied group (27.2±14.3 and 24.6±13.1 [ng/mL], NS), as well as both in responders (29.9±14.4 and 28.2±12.9 [ng/mL, NS) and low-responders subgroups (24.4±14.7 and 21.0±12.9 [ng/mL], NS), respectively. Conclusion Renal denervation is effective in the treatment of patients with resistant hypertension, however this effect is not mediated by the influence on plasma leptin concentration.

Influence of Gender on Plasma Leptin Levels, Fat Oxidation, and Insulin Sensitivity in Young Adults: The Mediating Role of Fitness and Fatness.

It is unknown how plasma leptin affects fat oxidation depending on sex in young adults. Therefore, the present cross-sectional study aimed to examine the associations of plasma leptin with resting fat oxidation (RFO), maximal fat oxidation during exercise (MFO), and insulin sensitivity, considering the different responses in men and women, and the mediating role of fatness and cardiorespiratory fitness (CRF). Sixty-five young adults (22.5 ± 4.3 years; body mass index = 25.2 ± 4.7 kg·m-2, 23 females) participated in this study. Fasting plasma glucose, insulin, and leptin were analyzed. Variables related to insulin resistance (HOMA1-IR, HOMA2-IR), secretion (HOMA-%β), and sensitivity (HOMA-%S, QUICKI) were computed. RFO and MFO were determined through indirect calorimetry. A peak oxygen uptake (VO2peak) test was performed until exhaustion after the MFO test. The MFO was relativized to body mass (MFO-BM) and the legs' lean mass divided by the height squared (MFO-LI). In men, leptin was negatively associated with MFO-BM and positively with HOMA-%β (p ≤ 0.02 in both). In women, leptin was positively associated with RFO and QUICKI, and negatively with MFO-BM (p < 0.05 in all). The association between leptin and MFO was mediated by CRF (p < 0.05), but not by fat mass (p > 0.05). Plasma leptin is associated with fat oxidation and insulin secretion/sensitivity, with different responses within each sex. The association between leptin and fat oxidation is mediated by cardiorespiratory fitness.

Blocking soluble TNF decreases diet‐induced hyperglycemia and modulates immune alterations in 5xFAD animal model of Alzheimer’s disease

AbstractBackgroundRegulatory interactions between the gut and the brain are essential for energy homeostasis across systems. Current evidence indicates high‐fat, high‐carbohydrate diets (HFHC) impact Alzheimer’s disease (AD) pathophysiology, however, the mechanisms underlying this association are poorly understood. We hypothesize that (1) Tumor Necrosis Factor (TNF) mediates metabolic inflammation in an obesogenic environment with impacts across the gut‐brain axis and (2) that HFHC interacts with an AD‐relevant genetic background to promote metabolic and immune dysregulation that accelerates pathological and behavioral dysfunction in an animal model of AD.MethodTo investigate the effects of chronic systemic inflammation on AD‐associated pathology, 2‐month old female 5xFAD mice were fed HFHC or a control diets (CD) for 8 weeks. One month following dietary intervention, the brain‐permeant soluble TNF inhibitor XPro1595 or a brain‐impermeant pan (sol and membrane‐bound) TNF inhibitor Etanercept (Enbrel, Amgen‐Wyeth) or vehicle (saline) were dosed twice weekly for 4 weeks. Behavioral test were performed to assess cognitive parameters. Plasma, brain and gut were collected for evaluation of insulin impairment, metabolic and immune parameters. Cortical tissues were subjected to RNAseq analysis to determine gene pathways modified by interactions between diet, genotype, and TNF inhibition.ResultHFHC promoted metabolic syndrome features associated with increases in adiposity, body weight, and plasma glucose, cholesterol, leptin, and insulin. TNF inhibition did not rescue diet‐induced insulin increases, however XPro specifically reduced plasma glucose, while Enbrel increased HOMA‐IR in HFHC‐fed mice. HFHC diet increased circulating IL‐6, CXCL1, CXCL2 and CCL2 and TNF neutralization with either drug decreased IL‐6 in HFHC‐fed groups. In the colon, HFHC diet decreased CCL3 and TNF blockade increased colonic IL‐15 in HFHC‐fed mice. Ongoing behavioral assessment, cortical transcriptional analysis, and hippocampal protein profiles of insulin signaling and inflammatory markers will determine additional effects of TNF and HFHC in the 5XFAD animal model of AD.ConclusionCollectively, these results suggest that TNF modulates systemic metabolic and inflammatory pathways induced by HFHC consumption and associated with neurodegeneration and neuroinflammation. Blocking soluble TNF decreases hyperglycemia triggered during diet‐induce obesity. Future studies focusing on the impact of TNF on energy homeostasis and inflammation will provide targets for new therapeutics against neurological disease.

NPFFR2-deficient mice fed a high-fat diet develop strong intolerance to glucose.

A previous study on neuropeptide FF receptor 2 (NPFFR2)-deficient mice has demonstrated that NPFFR2 is involved in the control of energy balance and thermogenesis. Here, we report on the metabolic impact of NPFFR2 deficiency in male and female mice that were fed either a standard diet (STD) or a high-fat diet (HFD) and each experimental group consisted of ten individuals. Both male and female NPFFR2 knockout (KO) mice exhibited severe glucose intolerance that was exacerbated by a HFD diet. In addition, reduced insulin pathway signaling proteins in NPFFR2 KO mice fed a HFD resulted in the development of hypothalamic insulin resistance. HFD feeding did not cause liver steatosis in NPFFR2 KO mice of either sex, but NPFFR2 KO male mice fed a HFD had lower body weights, white adipose tissues, and liver and lower plasma leptin levels compared with their wild-type (WT) controls. Lower liver weight in NPFFR2 KO male mice compensated for HFD-induced metabolic stress by increased liver PPARα and plasma FGF21 hepatokine, which supported fatty acid β-oxidation in the liver and white adipose tissue. Conversely, NPFFR2 deletion in female mice attenuated the expression of Adra3β and Pparγ, which inhibited lipolysis in adipose tissue.