Lower Leptin Levels Research Articles

Abstract 121: Leptin Restores Endothelial Function, Diminishes Vascular Adrenergic Contractility, but Does Not Alter Arterial Stiffness and Blood Pressure, in a Mouse Model of Congenital Generalized Lipodystrophy

Leptin which has been associated with cardiovascular disease in the context of obesity, is the current treatment for the metabolic disorders associated with congenital generalized lipodystrophy (CGL). However, the effects of chronic leptin infusion on vascular function and arterial pressure remain unknown in CGL. Here, we hypothesized that deletion in leptin will alter while leptin infusion will restore cardiovascular function via direct vascular mechanisms in CGL in male Berardinelli-Seip 2 gene deficient mice (gBscl2-/-), a mouse model of CGL. CGL mice exhibited reduced adipose mass and leptin levels (gBscl2+/+: 4.03 ± 0.3 vs gBscl2-/-: 0.38 ± 0.1*, ng/dL *P<0.05), as well as evidence of cardiovascular dysfunction including impaired endothelium-dependent relaxation, increased vascular contractility for phenylephrine (gBscl2+/+: 55.3 ± 1 vs gBscl2-/-: 106.2 ± 2.7*, Emax *P<0.05), augmented pulse wave velocity (PWV) (gBscl2+/+: 259.6 ± 20.4 vs gBscl2-/-: 412.4 ± 2.7*, cm/s *P<0.05), vascular fibrosis and elevated mean arterial pressure (MAP) (gBscl2+/+: 100.7 ± 1.4 vs gBscl2-/-: 109.5 ± 2*, mmHg *P<0.05). Blood vessels from CGL mice exhibit increased Nox1 expression gene expression (3 fold) and reactive oxygen species production. Nox1 inhibition (GKT771 10 -5 M) or PPARγ activator (Pioglitazone 10 -5 M) restored endothelial function. Remarkably, chronic (0.3mg/day/7 days) and acute leptin supplementation restored endothelial function and decreased Nox1 expression and ROS production. Selective genetic ablation of leptin receptors in endothelial cells promoted endothelial dysfunction, via Nox-1 dependent mechanisms. Furthermore, leptin reduced vascular adrenergic contractility, but did not reduce MAP, nor PWV or vascular fibrosis in CGL. In conclusion, leptin restores endothelial function via PPARγ-dependent decreases in Nox1, reduces vascular adrenergic contractility, but does not affect the blood pressure and vascular structure, in gBscl2-/- mice. These data reveal a new direct role of leptin receptors in the control of vascular homeostasis and present leptin as a potential therapy for the treatment of vascular disease associated with low leptin levels.

Leptin and the endocrine control of energy balance.

The discovery of leptin changed the view of adipose tissue from that of a passive vessel that stores fat to that of a dynamic endocrine organ that actively regulates behaviour and metabolism. Secreted by adipose tissue, leptin functions as an afferent signal in a negative feedback loop, acting primarily on neurons in the hypothalamus and regulating feeding and many other functions. The leptin endocrine system serves a critical evolutionary function by maintaining the relative constancy of adipose tissue mass, thereby protecting individuals from the risks associated with being too thin (starvation and infertility) or too obese (predation). In this Review, the biology of leptin is summarized, and a conceptual framework is established for studying the pathogenesis of obesity, which, analogously to diabetes, can result from either leptin hyposecretion or leptin resistance. Herein, these two states are distinguished with the terms 'type 1 obesity' and 'type 2 obesity': type 1 obesity describes a subset of obese individuals with low endogenous plasma leptin levels who respond to leptin therapy, whereas type 2 obesity describes most obese individuals, who are leptin resistant but might respond to leptin therapy in combination with other drugs, such as leptin sensitizers.

Has the adipokine profile an influence on the catch-up growth type in small for gestational age infants?

Infants born small for gestational age (SGA) are at increased risk of perinatal morbidity, persistent short stature, and metabolic alterations in later life. Moreover, the post-natal growth pattern of SGA infants may be an important contributor to health outcomes later in life, which can be influenced by adipokines. The aims of this study were to compare plasma adipokine profiles (leptin, adiponectin, vaspin, chemerin, and nephroblastoma overexpressed (NOV/CCN3)) among SGA newborns aged 3months, with low, normal, or high catch-up, to search for potential differences between males and females and to analyze the evolution of several adipokines in plasma from SGA newborns between 3 and 24months. This prospective, longitudinal study was addressed in SGA Caucasian subjects at Hospital Universitario de Álava-Txagorritxu. We observed that infants with fast catch-up showed significantly lower birth weight than the other two groups. As far as adipokines are concerned, they could have an influence on catch-up type because differences among the three experimental groups were found. It may be proposed that health prognoses in infants with slow and fast catch-up are opposite, not only in adulthood but also during their first months. Finally, adipokine evolution patterns during the first 24months of age differ, depending on the adipokine, and 24-month-old males show lower levels of leptin, adiponectin, and omentin than females.

Examining the causal role of leptin in bone mineral density: A Mendelian randomization study.

Leptin, a small polypeptide hormone secreted by the adipocytes, controls body weight and gonadal function by binding to a special receptor located in the hypothalamus. Observational studies have demonstrated a controversial association between leptin and bone mineral density (BMD), and functional studies of the relationship between leptin and BMD still largely vary by different studies. Using SNPs strongly associated with leptin levels in 52,140 individuals, we conducted a two-sample Mendelian randomization study to identify whether genetically lowered leptin levels were associated with BMD by using an inverse-variance weighted method, a weighted median method, MR-Egger and Robust Adjusted Profile Score. We found that circulating leptin levels may causally decrease lumbar spine BMD (effect size = -0.45, 95% CI: -0.82, -0.083; p value = 0.016). The association estimates of circulating leptin levels on femoral neck, forearm and total body BMD were not significant. Our study suggests that genetically predicted higher circulating leptin was associated with lower LS-BMD.

GLP-1 induces alpha cell proliferation and overrides leptin suppression induced by negative energy balance in vagotomized rats.

Glucagon-like peptide-1 (GLP-1) influences energy balance by exerting effects on food intake and glucose metabolism, through mechanisms that are partially dependent on the vagal pathway. The aim of this study was to characterize the effects of chronic GLP-1 stimulation on energy homeostasis and glucose metabolism in the absence of vagal innervation Truncal vagotomized (VGX) and sham operated rats (SHAM) received an intraperitoneal GLP-1 infusion (3.5 pmol/kg/min) trough mini-osmotic pumps. To dissect the effects derived from vagal denervation on food intake, an additional group was included consisting of sham operated rats that were PAIR FED to VGX. Food intake and body weight were recorded throughout the experimental period, while the percentage of white and brown adipose tissue, fasting glucose, insulin, gastro-intestinal hormonal profile, hypothalamic, and BAT gene expression were assessed at endpoint. VGX rats had significantly lower food intake, body weight gain, and leptin levels when compared with SHAM rats. Despite having similar body weight, PAIR-FED rats had lower fasting leptin, insulin and insulin resistance, while having higher ghrelin levels than VGX. GLP-1 infusion did not influence food intake or body weight, but was associated with lower leptin levels in VGX and lower pancreatic α-cells ki-67 staining in SHAM. Concluding, this study corroborates that the vagus nerve may modulate whole body energy homeostasis by acting in peripheral signals. Our data suggest that in the absence of vagal or parasympathetic tonus, GLP-1 mediated inhibition of cell proliferation markers in α-cells is prevented, meanwhile leptin suppression, associated with a negative energy balance, is partially overridden.

Lower levels of leptin are associated with severity parameters in visceral leishmaniasis patients.

Visceral leishmaniasis (VL) is the most severe clinical form of leishmaniasis, and if untreated may be fatal. It affects important organs of the immune system and is characterized by a specific immunosuppression, along with intense cellular activation and cytokine storm. Moreover, VL is now recognized as a systemic inflammatory response syndrome (SIRS), in which multiple cytokines and other pro-inflammatory molecules are released. The action of these inflammatory mediators may be considered risk factors for poor prognosis and death. Leptin, a hormone derived from adipose tissue, has been described with several immunoregulatory functions in vitro and in vivo Leishmania infection models, particularly for enhancing the macrophage microbicidal mechanisms. Considering that evaluation of immunologic parameters that may be associated with this clinical scenario may help to decrease VL lethality, we evaluated whether leptin is associated with VL pathogenesis. Thirty-one patients were recruited in the active phase of VL, of which 22 were followed up until one month after therapy (1mpt). Except for creatinine levels, all clinical parameters were altered in active VL patients, especially leucocyte counts and albumin and hemoglobin levels. Also, elevated levels of lipopolysaccharide (LPS), immunoglobulins (Ig)G1 and G3 anti-Leishmania and interleukins (IL)-6 and -10 were higher than in healthy individuals. In contrast, active VL patients presented diminished serum leptin levels and positive correlation with leukocytes counts and hemoglobin and albumin levels. After 1mpt, VL patients showed a significant increase in leptin levels, reaching values similar to healthy volunteers. As expected, only LPS levels remained elevated after 1mpt. These findings suggest that leptin levels are affected in Leishmania infection and the correlation with important parameters associated with the prognosis of VL points to the involvement of this molecule in VL immunopathogenesis. Additional studies are needed to evaluate the possibility of leptin as a prognostic marker of VL.

Association between leptin levels and severity of suicidal behaviour in schizophrenia spectrum disorders.

ObjectiveAssociations between suicidality and lipid dysregulation are documented in mental illness, but the potential role of leptin remains unclear. We examined the association between leptin and suicidal behaviour in schizophrenia, together with the influence of other clinical and biological indices.MethodWe recruited a sample of 270 participants with schizophrenia spectrum diagnoses. Blood samples were analysed for leptin, while symptom severity was assessed by Positive and Negative Syndrome Scale (PANSS) and Inventory of Depressive Symptomatology (IDS‐C). Patients' history of suicidal behaviour was categorized into three subgroups based on IDS‐C suicide subscale: No suicidal behaviour, mild/moderate suicidal behaviour and severe suicidal behaviour with/without attempts.ResultsMild/moderate suicidal behaviour was present in 17.4% and severe suicidal behaviour in 34.8%. Both groups were significantly associated with female gender (OR = 6.0, P = 0.004; OR = 5.9, P = 0.001), lower leptin levels (OR = 0.4, P = 0.008; OR = 0.5, P = 0.008) and more severe depression (OR = 1.2, P < 0.001; OR = 1.1, P < 0.001) respectively. Smoking (OR = 2.6, P = 0.004), younger age of onset (OR = 0.9, P = 0.003) and less use of leptin‐increasing medications (OR = 0.5, P = 0.031) were associated with severe/attempts group, while higher C‐reactive protein CRP (OR = 1.3, P = 0.008) was associated with mild/moderate group.ConclusionLower leptin levels were associated with higher severity of suicidal behaviour in schizophrenia.

Abstract MP54: Sex-Related Differences in the Association of Social Isolation With Plasma Leptin Concentration

Introduction: Studies have reported a positive associations of depression and psychosocial stress and plasma leptin concentration. Social isolation has been linked to increased leptin signaling in male rats, but this association has not been investigated in humans. Methods: We investigated the cross-sectional association of social isolation and plasma leptin concentration among 2,729 Framingham Offspring Cohort participants at the 7 th examination (1999-2001, mean age = 60.1 years, 42% men). Social isolation was measured using the Berkman-Syme Social Network Index: we assigned 1 point for being married, 1 point each for &gt;2 close friends and &gt;2 close relatives, 1 point for participation is social groups, and 1 point for participation in religious meetings ≥1-2 times per month. Social isolation was defined as a total of 0 points. Non-fasting plasma leptin levels were measured using a commercial immunoassay. The primary outcome was plasma leptin concentration. Secondary outcomes included caloric intake, measured by food frequency questionnaire, and volumes of abdominal subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT), measured by CT among 1,210 of the subjects between 2002 and 2005. Leptin concentration and adipose tissue volume were log-transformed due to skewed distributions. We estimated the associations of social isolation with all outcomes using linear regression. Models included age, body mass index, years of education, smoking status, physical activity index, hypertension, high blood glucose, and CES-D score as covariates. Because leptin levels and responses to social stress may vary among men and women, analyses were stratified by sex. Results: Socially isolated participants were younger and had higher CES-D scores than those who were not. Other characteristics were similar between the two groups. Plasma leptin concentration was 20% lower among socially isolated men (95% CI: -31, -6%) compared with men who were not isolated. Social isolation was also associated with lower caloric intake as well (β = -144.5 kcal, 95% CI: -287.1, -1.87 kcal). Among the subset of men for whom we had adipose tissue depot volume measurements (n=552), VAT volume appeared to be 10% lower among socially isolated men compared with non-isolated men (95% CI: -19, 1%), but this was not true of SAT (β = 1%, 95% C: -9, 10%). We did not observe differences in leptin concentration (β = -1%, 95% CI: -10, 15%), caloric intake (β = -39.1 kcal, 95% CI: -136.0, 57.7 kcal) or SAT β=4%, 95% CI: -3, 14%) according to social isolation among women. Socially isolated women appeared to have higher VAT (β = 10, 95% CI: -1, 10%) Conclusions: In our population of middle-aged and older adults, social isolation was associated with lower leptin levels among men, but not women. The lower leptin concentration observed among isolated men may reflect decreased caloric intake in response to social stress.

Dysregulation of a long noncoding RNA reduces leptin leading to a leptin-responsive form of obesity.

Quantitative changes in leptin concentration lead to alterations in food intake and body weight, but the regulatory mechanisms that control leptin gene expression are poorly understood. Here we report that fat-specific and quantitative leptin expression is controlled by redundant cis elements and trans factors interacting with the proximal promoter together with a long noncoding RNA (lncOb). Diet-induced obese mice lacking lncOb show increased fat mass with reduced plasma leptin levels and lose weight after leptin treatment, whereas control mice do not. Consistent with this finding, large-scale genetic studies of humans reveal a significant association of single-nucleotide polymorphisms (SNPs) in the region of human lncOb with lower plasma leptin levels and obesity. These results show that reduced leptin gene expression can lead to a hypoleptinemic, leptin-responsive form of obesity and provide a framework for elucidating the pathogenic mechanism in the subset of obese patients with low endogenous leptin levels.

High serum free fatty acids and low leptin levels: Plausible metabolic indicators of negative energy balance in early lactating Murrah buffaloes.

Lactation is a highly demanding event in mammals, including buffaloes. It modulates the partitioning of nutrients, energy utilization, and food intake of the mother to meet her own and infant's energy needs. Failure to satisfy these energy needs leads to Negative Energy Balance (NEB). Currently, the only available indirect NEB indicator is Body Condition Score (BCS). However, direct dependency of the BCS on the peak depletion of body fat causes its inefficient use in a dairy farm. Thus, to establish objective NEB indicators in buffaloes, the serum levels of biochemical (serum β-hydroxybutyrate [BHBA] and free fatty acids [FFAs]), and endocrine (Growth Hormone [GH], insulin-like growth factor1 [IGF1], Insulin, and leptin) parameters were estimated in buffaloes. Our results revealed that serum FFA levels were significantly (p < 0.05) higher in high milk yielders (HMY) than low milk yielders (LMY) and heifers (H) during the 3rd and the 4th weeks of postpartum. The serum FFA levels were also significantly (p < 0.001) higher in the postpartum buffaloes with BCS < 3 in the field conditions. Further, serum leptin levels were significantly (p < 0.05) lower in HMY than LMY during the 3rd week of postpartum. However, the BHBA, GH, IGF1, and insulin levels were not significantly different between lactating buffaloes and H. These observations indicated that the NEB condition is probably restricted to the first month of early lactation in buffaloes. In conclusion, the simultaneous higher FFA and lower leptin levels could act as direct plausible metabolic indicators of NEB in buffaloes.

Baseline serum leptin predicts peritoneal dialysis adequacy: a single-center prospective, longitudinal study

Hyperleptinemia is often observed in peritoneal dialysis (PD) patients. But, there are few studies on the relationship between blood leptin level and PD survival, and, some of them contradict each other. The present study aimed to investigate the impact of PD initiation on the serum leptin concentrations and its association with PD adequacy. Method. A total of 23 patients with end-stage renal disease (ESRD), who started the treatment with continuous ambulatory peritoneal dialysis (CAPD), were included in this prospective single-center observational longitudinal study. Among the patients, there were 15 men and 8 women; the average age of the patient population was 52.4 ± 12.3 years. The treatment with CAPD was performed using Dianeal PD 4 with glucose concentration of 1.36% and 2.27%. The patients were screened before PD initiation and after 3- and 12- month PD treatment. Leptin levels were determined in all patients using ELISA-method. Results. The median serum leptin concentration at study entry was 10.6 [5.6-21.9] ng/mL. Leptin level and its dynamics during the year after PD treatment initiation were dependent on body mass index (BMI). The overweight or obese patients had ever-increasing leptin levels after 3- and 12- month PD treatment. Whereas in the PD patients with normal weight, we observed a significant decrease of leptin levels after 12-month PD treatment. Serum leptin concentration in the women was significantly higher compared with the men (46.4 [1.1-95] vs 9.8 [3.2-14.5] ng/mL; p = 0.02). Blood cholesterol levels had a positive correlation with serum leptin concentrations after 3- and 12- month PD treatment: r = 0.53, p = 0.01 and r = 0.56, p = 0.008, respectively. However, we did not find a statistically significant association of leptin with PD adequacy parameters after 3- and 12- month PD treatment of the patients. In the Cox proportional hazard model adjusted for gender, serum leptin level demonstrated itself as the effective factor in PD adequacy survival: HR 5.3 (95% CI 1.7; 16.3). PD adequacy survival was better in the patients with leptin concentrations above the median (≥10.6 ng/mL) compared with the patients who had serum leptin levels below the median (log rank test, χ2 = 8.2; p = 0.0042). Conclusions. Our study have demonstrated markedly elevated serum leptin level in the overweight PD patients and its strong decrease during 12 months in the patients with normal weight. Low serum leptin level before PD initiation is associated with inadequate PD.

Leptin and Adiponectin as markers for preeclampsia in obese pregnant women, a cohort study.

Preeclampsia (PE) is a serious complication of pregnancy, the pathogenesis of which is largely unknown. We hypothesize that adipocytokines may play a role in the pathogenesis of PE, particularly in obese women, and evaluate leptin and adiponectin as potential first trimester markers for predicting PE. A cohort of 2503 pregnancies, containing 93 PE pregnancies, was divided into women with normal weight, moderate, or severe obesity. All pregnancies had serum adiponectin and leptin measured in first trimester. Logistic regression was used to model PE with maternal characteristics and concentrations of the biomarkers. In obese women a lower concentration of adiponectin was found in PE pregnancies; the concentration was lowest in the severely obese (p = 0.005). No association was found in normal weight women (p = 0.72). Leptin concentration had no association with PE in normal weight and moderately obese (p = 0.175-0.072), however in women with severe obesity a lower level of leptin was found (p = 0.049). The AUC was 0.73 for the ROC curve of combined maternal characteristics and adiponectin. Using adiponectin in women with moderate to severe obesity the sensitivity was 72.9% and the specificity was 49%. In severely obese women, PE is associated with low serum adiponectin and leptin concentrations in first trimester. This indicates that the inability of adipokine regulation to adapt to severe obesity may play a role in the pathogenesis of PE. Adipocytokines may contribute in identification of risk pregnancies among severe obese.

Pre-Conditioning Serum Leptin Levels Predict Early Relapse Rates of High Risk AML after Allogeneic Stem Cell Transplantation

Background: Allogeneic stem cell transplantation (alloSCT) is an effective treatment for many hematologic diseases including intermediate- and high-risk acute myeloid leukemia (AML). Relapse of the original disease continues to be the most common cause of treatment failure following alloSCT for AML. The factors governing relapse and non-relapse mortality (NRM) following alloSCT are poorly understood. We have previously reported that weight loss prior to conditioning therapy is a risk factor for relapse of myeloid diseases following alloSCT (1). The peptide hormone Leptin is a key regulator of food intake and body weight (2). Moreover, it has known roles in regulation of metabolism and immune homeostasis (3). This retrospective study evaluates Leptin as a predictor of survival, relapse and NRM following alloSCT for hematologic malignancies.Methods: Clinical data and Leptin serum levels measured prior to start of conditioning were collected retrospectively in a cohort of patients transplanted for acute leukemias (AML and ALL, n=206). Findings from this cohort were validated in an independent validation cohort of AML patients transplanted in another institution (n=367). Distribution of serum Leptin levels was highly skewed and thus log2-transformation was applied.Results: We identified low serum Leptin as an independent predictor for early relapse following alloSCT for intermediate and advanced stage acute leukemia (AML and ALL) as defined by the EBMT score (4). Multivariate analysis of Leptin and known covariables (age at transplantation, HLA mismatch, conditioning intensity, in-vivo T cell depletion with ATG, recipient and donor sex) revealed a hazard ratio (HR) for relapse of 0.75 per log2 increase (0.59-0.96, p=0.020) for Leptin. We observed an increased risk of NRM with higher leptin serum levels with an HR of 1.63 (1.15-2.31, p=0.006) while no statistically significant effect on OS was found. In order to visualize the effect of the continuous variable on the distribution of survival times, the quartiles of serum Leptin levels with regards to relapse, NRM and OS are shown in Figure 1. This effect on relapse was similar in intermediate and advanced stage AML patients from an independent cohort with an HR of 0.84 (0.72-0.97, p=0.020) while no statistically significant effects on NRM and OS were found. Pre-conditioning serum Leptin was confirmed as a predictor for early relapse by fitting the Cox model to the validation data.Conclusion: Low pre-conditioning serum Leptin levels appear to be an independent risk factor for early relapse following alloSCT for intermediate and advanced stage AML. Pre-conditioning serum Leptin should be explored to guide nutritional intervention in AML patients undergoing alloSCT in order to improve transplant success.ReferencesDietrich S, Radujkovic A, Stolzel F, Falk CS, Benner A, Schaich M, et al. Pretransplant metabolic distress predicts relapse of acute myeloid leukemia after allogeneic stem cell transplantation. Transplantation. 2015;99(5):1065-71.Elmquist JK, Elias CF, Saper CB. From lesions to leptin: hypothalamic control of food intake and body weight. Neuron. 1999;22(2):221-32.Procaccini C, La Rocca C, Carbone F, De Rosa V, Galgani M, Matarese G. Leptin as immune mediator: Interaction between neuroendocrine and immune system. Developmental and comparative immunology. 2017;66:120-9.Gratwohl A, Stern M, Brand R, Apperley J, Baldomero H, de Witte T, et al. Risk score for outcome after allogeneic hematopoietic stem cell transplantation: a retrospective analysis. Cancer. 2009;115(20):4715-26. [Display omitted] DisclosuresBeelen:Medac: Consultancy, Other: Travel Support.

Exercise Increases Adiponectin and Reduces Leptin Levels in Prediabetic and Diabetic Individuals: Systematic Review and Meta-Analysis of Randomized Controlled Trials.

It is speculated that lifestyle interventions known to improve diabetic metabolic state may exert their effects via adipokines. The aim of this systematic review and meta-analysis was to evaluate the chronic effects of physical exercise on adiponectin and leptin levels in adult prediabetic and diabetic individuals. PubMed, Embase, Scopus, The Cochrane Library, clinicaltrials.gov, and WHO Clinical Trials Registry were searched for randomized controlled trials. Pooled effects of interventions were assessed as mean difference (MD) with random effects model. Sensitivity analysis was conducted to test data robustness and subgroup analysis for study heterogeneity. Twenty-two trials with 2996 individuals were included in the meta-analysis. Physical exercise increased levels of adiponectin (MD: 0.42 µg/mL; 95% confidence interval (CI), 0.23, 0.60, p < 0.00001, n = 19 trials) and reduced leptin levels (MD: −1.89 ng/mL; 95% CI, −2.64, −1.14, p < 0.00001, n = 14 trials). These results were robust and remained significant after sensitivity analysis. Study heterogeneity was generally high. As for physical exercise modalities, aerobic exercise, but not other modalities, increased adiponectin and reduced leptin levels. In conclusion, physical exercise and, specifically, aerobic exercise, leads to higher adiponectin and lower leptin levels in prediabetic and diabetic adults. However, cautious interpretation of current findings is warranted.

Race/Ethnicity-Specific Associations between Smoking, Serum Leptin, and Abdominal Fat: The Multi-Ethnic Study of Atherosclerosis.

Smoking is a well-known cardiovascular risk factor associated with weight loss. We aimed to evaluate the association between smoking, serum leptin levels, and abdominal fat. Cross-sectional. Data from examinations 2 or 3 (2002-2005) of the Multi-Ethnic Study of Atherosclerosis (MESA). 1,875 asymptomatic, community-dwelling adults. We used multivariable linear regression models to assess the race/ethnicity-specific associations between smoking, serum logeleptin levels, and computed tomography ascertained abdominal fat. Results were adjusted for demographic and relevantclinical covariates. Participants (mean age 64.5±9.6 years; 50.6% women; 42.2% former, 11.4% current smokers) were White (40.1%), Hispanic (25.8%), African American (21.1%), and Chinese (13.0%). Overall, median (25th - 75th percentile) leptin levels were significantly lower among current (11.14 ng/mL; 4.13 - 26.18) and former smokers (11.68 ng/mL; 4.72 - 27.57), as compared with never smokers (15.61 ng/mL; 3.05 - 30.12) (P<.001). The difference in median leptin levels between current and never smokers were significantly higher for Hispanics (Δ9.64 ng/mL) and African Americans (Δ8.81 ng/mL) than Whites (Δ2.10 ng/mL) and Chinese (Δ4.70 ng/mL) (P<.001). After adjustment for total abdominal fat, loge-leptin levels remained lower for former (-.14 [-.22 - -.07]) and current (-.17 [-.28 - -.05]) smokers, compared with never smokers. Results differed by race/ethnicity, with significantly lower loge-leptin levels observed only among current and former African Americans and Hispanic smokers, compared with their never smoker counterparts. (Ps for interaction <.05). Among smokers, leptin levels significantly vary by race/ethnicity. Former and current smoking are associated with lower leptin levels, although this may be restricted to Hispanics and African Americans.

Genetic variants upstream of TNFAIP3 in the 6q23 region are associated with liver disease severity in HIV/HCV-coinfected patients: A cross-sectional study

BackgroundTNFAIP3 is a crucial hepatoprotective factor due to its anti-inflammatory, anti-apoptotic, anti-oxidant and pro-regenerative functions. The aim of this study was to analyze the associations between genetic variants upstream of TNFAIP3 (rs675520, rs9376293 and rs6920220) and liver fibrosis severity and inflammation in HIV/HCV-coinfected patients. MethodsA cross-sectional study was carried out in 215 HIV/HCV-coinfected patients, who underwent a liver biopsy. TNFAIP3 polymorphisms were genotyped using GoldenGate® assay. Outcome variables were: a) liver fibrosis (Metavir score) [fibrosis stage (F0, F1, F2, F3 and F4) and advanced fibrosis and cirrhosis (F ≥ 3 and F4, respectively)]; b) non-invasive indexes [FIB-4, APRI, and their cut-offs (FIB-4 ≥ 3.25 and APRI≥1.5)]; c) inflammation-related biomarkers (leptin, HGF, NGF, sFasL, sFas, MIF, HA, Ang-2, TIMP1, MMP1 and MMP2). ResultsPatients with rs675520 AG/GG genotypes had decreased odds of having cirrhosis (F4) and advanced fibrosis (FIB-4 ≥ 3.25 and APRI≥1.5) [adjusted Odd Ratio (aOR) = 0.30 (p = 0.025), aOR = 0.20 (p = 0.014), and aOR = 0.34 (p = 0.017), respectively] and lower levels of FIB-4 and APRI [adjusted arithmetic mean ratio (aAMR) = 0.76 (p = 0.003) and aAMR = 0.72 (p = 0.006), respectively]. Patients with rs9376293 CT/CC genotypes had decreased odds of APRI≥1.5 [aOR = 0.39 (p = 0.030)] and lower levels of APRI [aAMR = 0.77 (p = 0.018)]. Patients with rs6920220 AG/AA genotypes had higher odds of having FIB-4 ≥ 3.25 [aOR = 3.72 (p = 0.043)]. Moreover, rs675520 AG/GG genotypes, compared to AA genotype, were associated with lower levels of leptin and NGF (p = 0.002 and p = 0.001, respectively) and higher levels of sFas, MIF, TIMP1 and MMP2 (p = 0.004, p = 0.007, p = 0.020 and p = 0.036, respectively). Also, rs9376293 CT/CC genotypes were related to lower leptin levels (p = 0.026) and higher sFas, MIF, TIMP1 and MMP2 levels (p = 0.029, p = 0.040, p = 0.022 and p = 0.024, respectively). ConclusionsGenetic variants upstream of TNFAIP3 were associated with the liver fibrosis severity and inflammation in HIV/HCV-coinfected patients.

Relationship Between Leptin Level, Inflammation, and Volume Status in Maintenance Hemodialysis Patients.

Maintenance hemodialysis (HD) patients often experience fluctuations of volume status. Although hypervolemia possibly induces systemic inflammation, the relationship between volume status and leptin has not yet been well defined. The aims of this study were to determine the levels of leptin, C-reactive protein (CRP), and ferritin in relation to volume status and to assess the relationship between leptin and volume and inflammatory status in chronic HD patients. This prospective study included 93 HD patients divided, based on evaluation using the body composition monitor, into normovolemic and hypervolemic groups (overhydration/extracellular water [OH/ECW] ≤ 15% and OH/ECW > 15%, respectively). The levels of leptin and inflammatory markers (CRP, ferritin) were determined during a mid-week dialysis session in all patients. There were more hypervolemic patients after 12 months of follow up than at baseline (41% vs. 38%). Hypervolemic patients had significantly lower leptin levels (11.42 ± 19.24 ng/mL vs. 34.53 ± 40.32 ng/mL at baseline and 13.41 ± 22.04 ng/mL vs. 41.54 ± 21.78 ng/mL at 12 months), longer time on dialysis, and poorer nutritional status than normovolemic patients. Inflammation was present regardless of the volume status, but hypervolemic patients had significantly higher CRP and ferritin than normovolemic patients. A statistically significant reverse correlation was found between leptin level, hyperhydration index, and OH/ECW. No significant correlation was found between leptin and inflammatory markers CRP and ferritin.

High fat diet modulates inflammatory parameters in the heart and liver during acute Trypanosoma cruzi infection

The high fat diet (HFD) can trigger metabolic and cardiovascular diseases. Trypanosoma cruzi infection induces progressive inflammatory manifestations capable to affect the structure and the function of important organs such as the heart and liver. Here we aimed to investigate the effects of a HFD on the immune response and matrix metalloproteinase (MMP) activities during acute infection with the T. cruzi strain VL-10. The VL-10 strain has cardiac tropism and causes myocarditis in mice. Male C57BL/6 mice were treated with either: (i) regular diet (Reg) or (ii) HFD for 8 weeks, after which mice in each group were infected with T. cruzi. Mice were euthanized on day 30 after infection, and the liver and heart were subjected to histology and zymography to determine MMP-2 activities and plasma levels of IL-10, TNF, CCL2, and CCL5. T. cruzi-infected HFD animals had higher parasitemia, LDL and total cholesterol levels. Regardless of diet, plasma levels of all inflammatory mediators and cardiac MMP-2 activity were elevated in infected mice in contrast with the low plasma levels of leptin. HFD animals presented micro- and macrovesicular hepatic steatosis, while cardiac leukocyte infiltration was mainly detected in T. cruzi-infected mice. Our findings suggested that a HFD promotes higher circulating T. cruzi load and cardiac and liver immunopathogenesis in an experimental model using the VL-10 strain of the T. cruzi.

Abstract P140: Leptin Supplementation Restores Endothelial Function and Vascular Adrenergic Tone via Direct Endothelial Mechanisms and Sympato-Activation, Respectively, in a Mouse Model of Congenital Lipodystrophy

Absence of adipose tissue in congenital generalized lipodystrophy (CGL) leads to metabolic and cardiovascular disease and reduced leptin levels. We tested the hypothesis that leptin supplementation restores endothelial function and reduces vascular adrenergic response respectively via acting directly on endothelial cells (EC) and desensitizing vascular adrenergic response, in CGL mice. Deletion of Berardinelli-Seip gene (Bscl2) was used to mimic the human pathology in mice. Bscl2-/- mice showed reduced adipose mass [% of fat: wild-type (WT): 8.6 ± 0.3 vs Bscl2-/-: 2.4 ± 0.1, P&lt;0.05], leptin levels [ng/mL: WT: 4.0 ± 0.3 vs Bscl2-/-: 0.3 ± 0.1, *P&lt;0.05], impaired aortic endothelium-dependent relaxation to acetylcholine (Ach): [% relaxation: WT: 71.9 ± 1 vs Bscl2-/-: 49.9 ± 2*, *P&lt;0.05], increased vascular contractility to phenylephrine (Phe), associated with upregulation of α-adrenergic receptors, high mean arterial pressure (MAP) and reduced heart rate (HR): [(mmHg: WT: 100.7 ± 5 vs Bscl2-/-: 109.5 ± 6*), (bpm: WT: 592.7 ± 9 vs Bscl2-/-: 542.9 ± 15*) *P&lt;0.05]. Moreover, Bscl2-/- mice shown increase in Nox1 gene expression and increases in vascular - O 2 and H 2 O 2 levels. Both chronic (in vivo) and acute (organ bath) leptin supplementation or NOX 1 inhibition (GKT771, 10μM) restored endothelial function in addition to reducing endothelial Nox1 expression and ROS production, which suggest a direct role for leptin in endothelial cells. EC leptin receptor deficiency induced an endothelial dysfunction in mice, which was restored by Nox1 inhibition, further supporting a direct role of leptin in endothelial cells. In parallel, leptin supplementation reduced vascular adrenergic tone and aortic α-adrenergic receptors and increased in HR without changing MAP. Our data show that leptin replacement restores endothelial function and reduces vascular adrenergic tone in mouse model of congenital lipodystrophy by acting directly in EC and desensitizing vascular adrenergic response, respectively. This highlight the importance of leptin in the maintenance of vascular homeostasis and presents leptin as a potential therapeutic avenue for the treatment of vascular diseases associated with low leptin levels.

Psoriasis,Cardiovascular Disease,and Adipokines

Psoriasis usually combines with metabolic diseases,and the prevalence of cardiovascular disease remarkably increases in psoriatic patients. Adipokines,which play an important role in the cardiovascular diseases,also express abnormally in psoriasis and may induce or exacerbate the skin lesion. The adipokines associated with psoriasis and cardiovascular disease include adiponectin,leptin,resistin,omentin,visfatin,chemerin,and retinoid binding protein 4 (RBP-4). The levels of adiponectin and omentin apparently decrease in psoriatic patients compared to healthy controls,and thus they may play protective roles for psoriasis. Similarly,adiponectin plays a protective role in cardiovascular disease,but the role of retina in cardiovascular disease is still controversial. However,the concentrations of leptin,resistin,visfatin,chemerin,and RBP-4 in patients with psoriasis or cardiovascular disease are significantly higher than those of the controls;therefore,they may serve as the pathogenic factors for both diseases. Low adiponectin,leptin,visfatin,and chemerin levels may induce or aggravate psoriasis by activating plasmacytoid dendritic cells or T cells,as demonstrated in in vitro experiments. However,in vitro experiments also have shown that visfatin may inhibit cardiomyocyte apoptosis.