Circulating Leptin Levels Research Articles

IL-6 Receptor Blockade Increases Circulating Adiponectin Levels in People with Obesity: An Explanatory Analysis.

Human obesity is associated with decreased circulating adiponectin and elevated leptin levels. In vitro experiments and studies in high fat diet (HFD)-fed mice suggest that interleukin-6 (IL-6) may regulate adiponectin and leptin release from white adipose tissue (WAT). Herein, we aimed to investigate whether IL-6 receptor blockade affects the levels of circulating adiponectin and leptin in obese human individuals. To this end, serum samples collected during a multicenter, double-blind clinical trial were analyzed. In the latter study, obese human subjects with or without type 2 diabetes were randomly assigned to recurrent placebo or intravenous tocilizumab (an IL-6 receptor antibody) administration during a 12-week exercise training intervention. Twelve weeks of tocilizumab administration (in combination with exercise training) trend wise enhanced the decrease in circulating leptin levels (−2.7 ± 8.2% in the placebo vs. −20.6 ± 5.6% in tocilizumab, p = 0.08) and significantly enhanced the increase in circulating adiponectin (3.4 ± 3.7% in the placebo vs. 27.0 ± 6.6% in tocilizumab, p = 0.01). In addition, circulating adiponectin levels were negatively correlated with the homeostatic model assessment of insulin resistance (HOMA-IR), indicating that increased adiponectin levels positively affect insulin sensitivity in people with obesity. In conclusion, IL-6 receptor blockade increases circulating adiponectin levels in people with obesity.

Relationship between Adipose Tissue Derived Hormones and Cardiometabolic Risk according to Obesity Status.

Adiponectin, and leptin are adipose tissue derived hormones affecting metabolic status. This study aimed to investigate the relationship between circulating adiponectin and leptin levels, and cardiometabolic parameters by obesity status among healthy women without metabolic disease. Finally 141 participants were included in the analyses and categorized into three groups by their body mass index (kg/m2) (normal weight: 18.5 ≤ body mass index [BMI] < 23.0, n=65; overweight: 23.0 ≤ BMI < 25.0, n=26; obesity: 25.0 ≤ BMI, n=50). Overweight and obesity groups were older, and had significantly higher levels of adiposity, blood pressure, fasting glucose, triglyceride, and high sensitivity C-reactive protein (hs-CRP), and lower levels of high density lipoprotein (HDL)-cholesterol than normal weight group. Circulating leptin levels, and leptin to adiponectin ratio were highest in obesity group, but circulating adiponectin levels were not statistically different among the three groups. Circulating leptin levels were negatively correlated with adiponectin levels, and leptin to adiponectin ratio. In addition, leptin levels were positively correlated with waist circumference, systolic blood pressure, insulin resistance, and hs-CRP, and negatively with HDL-cholesterol. However, circulating adiponectin levels were negatively correlated only with waist circumference, and hs-CRP. These patterns were retained after adjusted for confounding factors such as age, smoking and drinking habits, menopausal status and total calorie intake. In conclusion, circulating adiponectin and leptin levels according to obesity status were differently observed among healthy women, and circulating leptin levels may be a more sensitive parameter for cardiometabolic risk in healthy women.

Leptin regulation of hippocampal synaptic function in health and disease.

It is widely accepted that the metabolic hormone leptin regulates food intake and body weight via activation of hypothalamic leptin receptors. However, as leptin receptors are also highly expressed in other brain regions, such as the hippocampus, alterations in leptin responsiveness also impacts on key functions of the hippocampus, like learning and memory. Within the hippocampus, high levels of leptin receptors are expressed at excitatory synapses, and in accordance with a synaptic localization, leptin potently regulates synaptic transmission at both Schaffer collateral (SC) and temporoammonic (TA) inputs to CA1 pyramidal neurons. Increasing evidence from cellular and behavioral studies examining leptin action at CA1 synapses support the notion that leptin is a potential cognitive enhancer. However, the capacity of leptin to regulate synaptic efficacy at SC-CA1 and TA-CA1 synapses declines in an age-dependent manner. Moreover, clinical evidence that supports a link between circulating leptin levels and the risk of the age-related neurodegenerative disorder, Alzheimer's disease (AD) is accumulating. Consequently, it has been proposed that the leptin system is a potential therapeutic target in AD, and that boosting the hippocampal actions of leptin may be beneficial in the treatment of AD. Here we review recent progress in our understanding of the neuronal and hippocampal synaptic functions that are regulated by leptin and how alterations in the leptin system influence age-related CNS-related disorders like AD.

Dysregulated appetitive leptin signaling in male rodent offspring from post-bariatric dams.

Bariatric surgery produces significant positive benefits to recipients such as resolution of various obesity-related comorbidities, including improved reproductive function. Females of childbearing age seek bariatric surgical remedies to improve their chance of successful pregnancy; however, limited knowledge exists on the impact of surgical weight loss to subsequently born offspring.We previously reported that circulating leptin levels were reduced in pregnant females having previously received vertical sleeve gastrectomy (VSG) in comparison to control dams having received Sham surgery. Furthermore, the levels of leptin receptors in the VSG placenta were also reduced in comparison to controls in. These data suggest there may be a significant difference in leptin signaling during pregnancy that may produce an altered developmental environment for the offspring.Here, we investigate the adult offspring of dams having received VSG or Sham-VSG prior to pregnancy. Endogenous fasting plasma leptin levels were not different between Sham and VSG offspring. Fasting leptin receptor mRNA in the medial basal hypothalamus (MBH) was elevated in VSG offspring in comparison to Sham. Intraperitoneal administration of exogenous leptin produced reductions in acute food intake in male Sham offspring, but did not reduce food intake at any time point measured in male VSG offspring. Using Western blot, we identified elevated pSTAT3 and pSTAT3/STAT3 ratios in the MBH of post-VSG offspring in comparison to controls. Using immunohistochemistry, we found an increased number of pSTAT positive cells in the arcuate nucleus in the Sham offspring in comparison to VSG. In contrast, within the paraventricular and ventromedial hypothalamic nuclei the VSG offspring had elevated numbers of pSTAT-positive cells in comparison to controls. Collectively, these data support our hypothesis that leptin signaling is dysregulated in VSG offspring and may be partially responsible for the long-term impact of maternal bariatric surgery on the metabolic health of offspring.

Mid‐life obesity and metabolic dysfunction in a genetically diverse mouse model of Alzheimer’s disease

AbstractBackgroundAge and genetic background are the greatest risk factors for Alzheimer’s disease, but obesity and metabolic syndrome increase the risk of developing AD, as increased BMI at mid‐life is associated with an earlier age at onset for AD dementia. Furthermore, many AD patients also present with non‐cognitive symptoms associated with metabolic dysfunction, such as weight loss, changes in appetite, and low circulating leptin levels, which often occur prior to the onset of cognitive decline. Thus, systemic metabolic function may be an important, causal factor in the etiology of AD in humans. However, the mechanisms underlying this dysfunction and its relationship to disease onset, progression, and severity are poorly understood.MethodsWe assessed metabolic function in mice from our recently developed model of human AD, the AD‐BXD genetic reference panel (Neuner, et al 2019). Metabolic function was measured in 39 AD‐ and non‐transgenic (Ntg) strains using indirect calorimetry in Promethion metabolic cages to measure energy expenditure, VO2and VCO2, respiratory exchange rate (RER), locomotor activity, food and water intake, and sleep. To model mid‐life obesity, a subset of age‐ and sex‐matched AD‐ and Ntg‐BXD mice were fed a high‐fat/high‐sugar diet (HFD) starting at ∼2.5 months of age.ResultsAD‐BXD mice weigh less than their non‐transgenic counterparts; assessment of body composition indicates this is due primarily to a loss of fat mass. AD‐BXD strains also exhibited an increase in rearing behavior, which may indicate hypervigilance. Female AD‐BXD strains exhibited increased energy expenditure and locomotor activity and failed to develop diet‐induced obesity when fed HFD. Mice fed HFD generally displayed changes in RER consistent with a shift to fat metabolism; we further observed changes in patterns of food intake.ConclusionsOur data indicate that AD‐BXD mice exhibit some degree of metabolic dysfunction and that this is exacerbated by HFD. Analyses indicate that metabolic dysfunction at cognitively presymptomatic ages is correlated with memory deficits later in life. Ongoing work will quantify the impact of genetic background on these traits and relationships between metabolic and cognitive phenotypes.

Abstract 17361: How Leptin Harms the Heart in High Fat Diet-Induced Obesity

Introduction: Sedentary lifestyle and excessive calorie intake are risk factors for CVD. We have demonstrated the cardioprotective effect of exercise in aged mice and the critical role of visceral adiposity and its profibrotic secretome in increasing cardiovascular risks in obesity and aging. The association between exercise, lowered plasma leptin and reduced inflammatory leukocytes has been recently shown in patients with atherosclerosis. It remains unclear whether elevated plasma leptin can preserve or alter cardiovascular function in obesity. Methods: We analyzed the effect of high fat diet (HFD) in C57BL/6J male mice on the heart in terms of function, structure, histology and key molecular markers. Two interventions were used: 1) active fat mass loss via exercise (daily swimming) during HFD; 2) passive fat mass loss via surgical removal of the visceral adipose tissue (VAT lipectomy) followed by HFD. Results: HFD increased body weight and adiposity, leading to higher plasma leptin, glucose and insulin levels, compared to control diet (CD) mice. HFD impaired left ventricle (LV) structure (hypertrophy, interstitial fibrosis) and cardiac function (echocardiography, in vivo hemodynamics). Atria of HFD mice had enhanced pro-inflammatory protein production. Exercise reduced circulating leptin levels in HFD mice by 50%, in line with fat mass loss. In contrast, lipectomy reduced visceral fat mass, but body weight, adiposity and plasma leptin did not change. Both exercise and VAT lipectomy improved cardiac contractility, reversed collagen deposition and oxidative stress in HFD mice. Both interventions downregulated LV pro-inflammatory markers. We proved the role of leptin in cardiac remodeling in vitro by incubating primary cardiac fibroblasts with hyperleptinemic plasma from HFD mice. Remarkably, plasma from HFD-EX (exercise) suppressed the fibro-proliferative and pro-inflammatory responses of cardiac fibroblasts. Conclusions: Leptin directly contribute to cardiac fibrosis in obesity via activation and proliferation of cardiac fibroblasts. Understanding how leptin signals to the heart might have implications in a wide range of CVD, potentially helping early stratification and personalized care.

Leptin modulates gene expression in the heart and cardiomyocytes towards mitigating ischemia-induced damage

Leptin, an adipocyte-derived satiety hormone, has been previously linked to cardioprotection. We have shown before that leptin conferred resistance to ischemic damage in the heart in long-lived transgenic αMUPA mice overexpressing leptin compared to the wild type (WT) FVB/N control mice. To better understand the contribution of leptin to the ischemic heart, we measured here the expression of genes encoding leptin and ischemia-related proteins in αMUPA and WT mice in the heart vs adipose tissue after MI. In addition, we investigated gene expression in neonatal rat cardiomyocytes under hypoxia in the absence and presence of exogenously added leptin or a leptin antagonist. We used real time RT-PCR and ELISA or Western blot assays to measure, respectively, mRNA and protein levels. The results have shown that circulating leptin levels and mRNA levels of leptin and heme oxygenase-1 (HO-1) in the heart were elevated in both mouse genotypes after 24 h myocardial infarction (MI), reaching higher values in αMUPA mice. In contrast, leptin gene expression in the adipose tissue was significantly increased only in WT mice, but reaching lower levels compared to the heart. Expression of the proinflammatory genes encoding TNFα and IL-1β was also largely increased after MI in the heart in both mouse types, however reaching considerably lower levels in αMUPA mice indicating a mitigated inflammatory state. In cardiomyocytes, mRNA levels of all aforementioned genes as well as HIF-1α and SOD2 genes were elevated after hypoxia. Pretreatment with exogenous leptin largely reduced the mRNA levels of TNFα and IL-1β after hypoxia, while enhancing expression of all other genes and reducing ROS levels. Pretreating the cells with a leptin antagonist increased solely the levels of leptin mRNA, suggesting a negative regulation of the hormone on the expression of its own gene. Overall, the results have shown that leptin affects expression of genes in cardiomyocytes under hypoxia in a manner that could mitigate inflammation and oxidative stress, suggesting a similar influence by endogenous leptin in αMUPA mice. Furthermore, leptin is likely to function in the ischemic murine heart more effectively in an autocrine compared to paracrine manner. These results suggest that leptin can reduce ischemic damage by modulating gene expression in the heart.

Circulating leptin levels in patients with myalgic encephalomyelitis, chronic fatigue syndrome or fibromyalgia: a systematic review protocol.

The objective of the review is to evaluate circulating levels of leptin in people diagnosed with myalgic encephalomyelitis chronic fatigue syndrome or fibromyalgia syndrome and to investigate the differences compared with healthy controls. Myalgic encephalomyelitis chronic fatigue syndrome is a condition that has major symptoms, including self-reported fatigue, post-exertional malaise, and unexplained pain across the body. The widespread pain is measured in a systematic way and is often referred to as fibromyalgia. The two disorders have many similarities, but their association with leptin has indicated that leptin may affect the role of pro-inflammatory cytokines and symptom severity. This review will consider observational studies of varying study designs including prospective and retrospective cohort studies, case-control studies, time-series, and analytical cross-sectional studies that include both cases and healthy comparators. Cases will include a diagnosis of myalgic encephalomyelitis, chronic fatigue syndrome, and/or fibromyalgia. Controls are people without this diagnosis, usually healthy participants. Only studies published in English will be included due to limited resources for translation. This protocol will be reported based on the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) checklist and will follow the JBI methodology for systematic reviews of etiology and risk. A comprehensive search strategy will include PubMed, Embase, Scopus, Science Direct, and PsycINFO. Two reviewers will screen, critically appraise eligible articles, and extract data using a standardized data extraction tool informed by JBI SUMARI. The authors will complete a quantitative analysis that synthesizes findings across studies using pooled effect sizes and confidence intervals of the measures provided. PROSPERO CRD42020169903.

Association of Leptin Promoter 2548G/A variant with Serum Leptin, Lipid Profile and Type 2 Diabetes Mellitus

Background: A common 2548G/A promoter variant of the human leptin gene has been implicated in circulating leptin levels variations and pathogenesis of type 2 diabetes mellitus but available data are still conflicting. Objective: To explore potential associations between LEP 2548G/A of leptin with T2DM and the effect of this variation on serum leptin levels. Patients and Methods: Sixty two patients with T2DM and fifty non-diabetic controls were included in the study. Blood samples were collected from subjects for biochemical analysis and Genotyping was performed by polymerase chain reaction reaction–restriction fragment length polymorphism (PCR-RFLP). Results: The genotype frequencies for LEP 2548G/G, LEP 2548G/A LEP 2548A/A were 46%, 32% and 22% in control group, and 19.4%, 33.9% and 46.7% in diabetic group, respectively. The A allele and GA/AA genotype of LEP 2548G/A was found to be more frequent than the G allele and GG genotype in T2DM patients compares to the controls. Subjects with the GA + AA genotype of LEP 2548G/A were at increased risk for T2DM (P=0.0001, OR = 1.78; 95% CI: 1.19–2.38). The serum leptin concentration of GA + AA genotype carriers was significantly higher from that of the GG genotype in the diabetic group. Conclusion: A allele carrier who have higher serum concentrations of leptin may have an association with the risk of T2DM development in the Erbi population.

Abstract 10: Mouse Recombinant Soluble PRR-induced Increase Of Blood Pressure Is Sex-dependant In High Fat-fed Mice

Obesity is a major risk factor for hypertension. Although the renin-angiotensin system (RAS) contributes to the sex difference of blood pressure (BP) control, whether the prorenin receptor (PRR) and its soluble form (sPRR) play a role in the sexual dimorphism of BP is not clear. We previously demonstrated that, in high fat (HF)-fed male C57BL/6 mice, the infusion of mouse recombinant sPRR increased systolic blood pressure (SBP) by the sympatho-excitatory effects of leptin on BP. Therefore, in the present study, we aim to address whether mouse recombinant sPRR influences the BP in HF-fed female mice. To test this hypothesis, C57BL/6 female mice were fed a HF diet for 32 weeks and were implanted with radiotelemetry transmitter. After 24 weeks of high fat feeding, female mice (5-6/group) were implanted with osmotic pumps and infused with either saline (veh) or sPRR for 3 to 4 weeks. In contrast to male mice, the infusion of sPRR (30 μg/kg/day) did not change significantly the SBP (24hSBP; veh: 135 ± 7; sPRR: 134 ± 4 mmHg; P&gt;0.05) and the baroreflex sensitivity. The decrease in BP mediated by chlorisondamine treatment was not significantly different between female mice infused with vehicle or sPRR (ΔSBP; veh: -11 ± 9; sPRR: -16 ± 7 mmHg; P&gt;0.05). In addition, sPRR infusion did not affect the bradycardic or tachycardic responses after propranolol or atropine treatment respectively. Moreover, the decrease of SBP induced by losartan was similar in mice infused with vehicle or sPRR (ΔSBP; veh: -9 ± 4; sPRR: -10 ± 3 mmHg; P&gt;0.05). Similar results were obtained using higher dose of sPRR (60 μg/kg/day). In female mice, sPRR infusion did not increase significantly the body weight (veh: 32.7 ± 2.5 g; sPRR: 35.8 ± 4.2 g; P&gt;0.05), the white adipose tissue weight (WAT; veh: 3.0 ± 0.7g; sPRR: 3.7 ± 1.6 g; P&gt;0.05) or circulating leptin levels (veh: 12.0 ± 7.6 ng/ml; sPRR: 15.5 ± 9.5 ng/ml; P&gt;0.05). In conclusion, in contrast to male, female mice are protected from sPRR-induced increase in BP. sPRR did not increase circulating leptin suggesting that sPRR-induced leptin increase is regulated in a sex-dependent manner. Other pathways could participate to the protection against sPRR-induced increase in BP in female mice such as the vasodilator arm of the RAS and/or the hormonal status of the female mice.

Short-term metreleptin treatment of patients with anorexia nervosa: rapid on-set of beneficial cognitive, emotional, and behavioral effects

To examine the hypothesis that normalization of low circulating leptin levels in patients with anorexia nervosa ameliorates hyperactivity, three seriously ill females with hyperactivity were treated off-label with metreleptin (recombinant human leptin) for up to 14 days. Drive for activity, repetitive thoughts of food, inner restlessness, and weight phobia decreased in two patients. Surprisingly, depression improved rapidly in all patients. No serious adverse events occurred. Due to obvious limitations of uncontrolled case series, placebo-controlled clinical trials are mandatory to confirm the observed rapid onset of beneficial effects. Our findings suggest an important role of hypoleptinemia in the mental and behavioral phenotype of anorexia nervosa.

Effect of Lactobacillus rhamnosus GG on Energy Metabolism, Leptin Resistance, and Gut Microbiota in Mice with Diet-Induced Obesity.

Obesity is closely associated with various metabolic disorders, including leptin resistance, which is characterized by high circulating leptin levels. Probiotics can decrease circulating leptin levels by alteration of the gut microbiota. Thus, they may have anti-obesogenic effects. In this study, the effects of administration of a probiotic bacterium, Lactobacillus rhamnosus GG (LGG), on gut microbiota and modulation of leptin resistance were evaluated in mice. Male Balb/C mice aged 7 weeks were fed either a normal diet (ND), high-fat diet (HFD), HFD supplemented with low-dose LGG (108 CFU/mouse/day), or HFD supplemented with high-dose LGG (1010 CFU/mouse/day) for 10 weeks. Significantly increased body weight, epididymal fat weight, and decreased leptin responsiveness to exogenous leptin treatment and ratio of villus height to crypt depth were observed in the HFD-fed mice compared to the ND-fed mice. Moreover, a remarkable increase in the proportion of Proteobacteria and ratio of Firmicutes/Bacteroidetes in the fecal microbiota were also observed in the HFD-fed mice. Supplementation of HFD with high-dose LGG restored exogenous leptin responsiveness, increased the ratio of villus height to crypt depth, and decreased the proportion of Proteobacteria in fecal microbiota. These findings suggest that LGG supplementation might alleviate leptin resistance caused by an HFD through the improvement of the digestive health of the host.

Relationship between circulating leptin levels and arterial stiffness: a systematic review and meta-analysis of observational studies.

Leptin is associated with cardiovascular risk. Some studies analyzed the potential association between leptin and arterial stiffness, an independent cardiovascular risk factor. However, the studies that investigated this association provided inconsistent and heterogeneous results. We performed a systematic review and a meta-analysis of the available studies on the relationship between leptin and arterial stiffness to achieve definitive conclusions. A systematic search of the on-line databases available (up to December 2019) was conducted including the observational studies that reported the evaluation of the relationship between non-invasively assessed arterial stiffness (expressed by carotid-femoral pulse wave velocity) and leptin. For each study, the effect size was standardized and pooled using a random effect model. Sensitivity analysis, heterogeneity, publication bias, meta-regression and sub-group analyses were also assessed. Ten studies met the pre-defined inclusion criteria and provided 11 cohorts with 7,580 total participants. Leptin levels were positively and significantly associated with risk of increased arterial stiffness (odds ratio 1.04; p < 0.01), with no significant heterogeneity among studies. Likewise, pooled analysis of correlation showed a significant and positive association between leptin and pulse wave velocity (z = 0.27, p < 0.01), with significant heterogeneity among studies. The results of this meta-analysis indicate that leptin is positively associated with arterial stiffness. This association significantly adds to the recognized value of leptin in cardiovascular disease.

Using proximity extension proteomics assay to discover novel biomarkers associated with circulating leptin levels in patients with type 2 diabetes

We aimed to discover novel associations between leptin and circulating proteins which could link leptin to the development of cardiovascular disease in patients with type 2 diabetes (T2DM). In a discovery phase, we investigated associations between 88 plasma proteins, assessed with a proximity extension assay, and plasma leptin in a cohort of middle-aged patients with T2DM. Associations passing the significance threshold of a False discovery rate of 5% (corresponding to p < 0.0017) were replicated in patients with T2DM in an independent cohort. We also investigated if proteins mediated the longitudinal association between plasma leptin and the incidence of major cardiovascular events (MACE). One protein, adipocyte fatty acid binding protein (A-FABP), was significantly associated with leptin in both the discovery phase [95% CI (0.06, 0.17) p = 0.00002] and the replication cohort [95% CI (0.12, 0.39) p = 0.0003]. Multiplicative interaction analyses in the two cohorts suggest a stronger association between A-FABP and leptin in men than in women. In longitudinal analyses, the association between leptin and MACE was slightly attenuated after adding A-FABP to the multivariate model. Our analysis identified a consistent association between leptin and A-FABP in two independent cohorts of patients with T2DM, particularly in men.Trial registration: ClinicalTrials.gov identifier NCT 01049737.

Interaction of FTO rs9939609 and the native American-origin ABCA1 p.Arg230Cys with circulating leptin levels in Mexican adolescents diagnosed with eating disorders: Preliminary results

Eating disorders (ED) are characterized by disruption of eating behaviour and alteration of food intake. Leptin, is one of the main hormones that modulate food intake and are altered in individuals diagnosed with ED. Genetic risk variants for obesity, like those reported inFTO and ABCA1, have also been associated to ED disorders. The present study aimed to analysed leptin circulating levels and the interaction between obesity-risk variants in FTO and ABCA1, in adolescents diagnosed with ED. A total of 99 individuals diagnosed with ED were genotype using Taqman probes for FTO (rs9939609) and ABCA1 (p.Arg230Cys, rs9282541). Commercial enzyme-linked immunosorbent assays were utilized to determined circulating leptin. Differences in leptin concentration were analysed by t-Student or ANOVA test. Gene-gene interaction were analysed using general estimation equations. Circulating leptin levels differed between the three diagnostic groups, lead by individuals diagnosed with binge eating-disorder. In individuals with more than 3 of episodes of binge-eating per week having the highest leptin levels. Also, we found that carriers of both risk alleles had the highest leptin levels. Our observations found an interaction between FTO rs9969609 and the native American-origin ABCA1 p.Arg230Cys to modulate circulating leptin levels in Mexican adolescents diagnosed with eating-disorders.

Elevated serum leptin levels are associated with low muscle strength and muscle quality in male patients undergoing chronic hemodialysis.

Objectives:Low muscle strength and poor muscle quality are highly prevalent in patients with chronic hemodialysis (HD), which lead to an increased risk of poor clinical outcomes. Leptin dysregulation is common in HD patients. Given that leptin receptors are abundant in skeletal muscle, there may be a link between leptin and muscle strength. The cross-sectional study aimed to explore the correlation of serum leptin levels with muscle strength and muscle quality in patients with chronic HD.Materials and Methods:A total of 118 chronic HD patients were included in this study. Basic characteristics, handgrip strength, body composition were assessed, and blood samples for serum leptin levels and other biochemical test were obtained. We defined skeletal muscle index (SMI) as skeletal muscle mass/height2 (kg/m2) and muscle quality as handgrip strength divided by mid-arm muscle circumference (MAMC). Patients were classified into tertile groups, according to sex-specific leptin levels.Results:We observed that patients in the higher leptin tertile tend to have a higher body weight, body mass index (BMI), body fat mass, MAMC, and SMI, while the handgrip strength and muscle quality were significantly lower. Bodyweight (r = 0.30; P = 0.001), BMI (r = 0.45; P = 0.001), body fat mass (r = 0.57;P < 0.001), and SMI (r = 0.22; P = 0.018) were positively and handgrip strength (r = −0.27; P = 0.003) and muscle quality (r = −0.35;P < 0.001) were negatively correlated with serum leptin levels, respectively. After adjusting multiple confounding factors, logarithmically transformed serum leptin levels were independently associated with handgrip strength (β = −3.29, P = 0.005) and muscle quality (β = −0.14, P = 0.009). However, gender-stratified models showed the associations were observed only in male, but not in female.Conclusion:We concluded that higher serum leptin levels are associated with low handgrip strength and poor muscle quality in male patients on chronic HD. Further studies are needed to clarify the gender differences and to evaluate the casual relationship between circulating leptin levels and muscle strength.

Effects of leptin and adiponectin on the cardiovascular system

Elevated circulating leptin levels have been associated with an increased cardiovascular risk in humans. However, recent meta-analyses show that certain epidemiological studies did not find this association, suggesting distinct effects of leptin depending on the pathophysiological context. Studies performed in mice deficient in leptin or in leptin receptors are often contradictory, showing both protective and deleterious effects of leptin. These effects appear to vary depending on the genetic background of the animal and the doses of leptin administered, making interpretation of the results difficult. In humans, elevated adiponectinemia is associated with a favourable cardiovascular risk profile. Adiponectin exerts protective effects at all stages of development of atherosclerotic plaque. However, our knowledge of the pathophysiological mechanisms involved in these protective effects has been established from cellular models, which do not necessarily reproduce the pathology in all its complexity. In addition, mouse models have a very different lipoprotein metabolism from humans, which does not always allow extrapolation of results to humans. Finally, epidemiological studies evaluating adiponectin as a marker of cardiovascular risk show paradoxical results since a high serum adiponectin concentration has not been associated with a reduction in the number of cardiovascular events but with an increase of cardiovascular and all causes mortality in healthy subjects and coronary patients. These observations illustrate the paradox of adipokines actions and show the complexity to use these biomarkers in cardiovascular diseases. Resistance to the action of these adipokines is one of the hypotheses put forward to explain these discrepancies.

Recent advances in understanding the role of leptin in energy homeostasis.

The hormone leptin plays a critical role in energy homeostasis, although our overall understanding of acutely changing leptin levels still needs improvement. Several developments allow a fresh look at recent and early data on leptin action. This review highlights select recent publications that are relevant for understanding the role played by dynamic changes in circulating leptin levels. We further discuss the relevance for our current understanding of leptin signaling in central neuronal feeding and energy expenditure circuits and highlight cohesive and discrepant findings that need to be addressed in future studies to understand how leptin couples with physiological adaptations of food intake and energy expenditure.

BDNF Val66Met polymorphism alters food intake and hypothalamic BDNF expression in mice.

Obesity, a rising public health burden, is a multifactorial disease with an increased risk for patients to develop several pathological conditions including type 2 diabetes mellitus, hypertension, and cardiovascular disease. Increasing evidence suggests a relationship between the human brain-derived neurotrophic factor (BDNF) Val66Met single-nucleotide polymorphism (SNP) and obesity, although the underlying mechanisms of this connection are still not completely understood. In the present study, we found that homozygous knock-in BDNFMet/Met mice were overweight and hyperphagic compared to wildtype BDNFVal/Val mice. Increased food intake was associated withreduction of total BDNF and BDNF1, BDNF4 and BDNF6 transcripts in the hypothalamus of BDNFMet/Met mice. Incontrast, in the white adipose tissue total BDNF and Glut4 expression levels were augmented, while sirtuin 1 and leptin receptor (Ob-R) expression levels were reduced in BDNFMet/Met mice. Moreover, plasmatic leptin levels were decreased in BDNFMet/Met mice. However, BDNFVal/Val and BDNFMet/Met mice showed a similar response to the insulin tolerance test and glucose tolerance test. Altogether, these results suggest that BDNF Val66Met SNP strongly contributes to adipose tissue pathophysiology, resulting in reduced circulating leptin levels and hypothalamic expression of BDNF, which, in turn, promote increased food intake and overweight in BDNFMet/Met mice.

S11. PLASMA LEPTIN AND ANTHRANILIC ACID IN SCHIZOPHRENIA PATIENTS: NEW BIOMARKERS OF PREDISPOSITION TO METABOLIC ABNORMALITIES

BackgroundLeptin was implicated in pathophysiology of schizophrenia (Sz) and in increased risk of Sz patients for overweight and hyperlipidemia, especially in patients treated with anti-psychotic medications known to elevate plasma leptin levels. Our finding of increased plasma levels of anthranilic (ANA) and kynurenic (KYNA) acids in leptin-receptors deficient Zucker fatty rats [Oxenkrug et al., 2016], and causative association between KYNA and major psychopathology of Sz [Erhard et al., 2007; Schwarcz et al., 2001] warranted our further evaluation of plasma levels of leptin and tryptophan – kynurenine pathway metabolites in Sz patients.MethodsTryptophan (Trp), kynurenine (Kyn), ANA, KYNA, 3-hydroxykynurenine (3HK), and xanthurenic acid (XA) were evaluated by HPLC–mass spectrometry [Oxenkrug et al., 2015] in fasting plasma samples of fifty-two [19 drug-naïve first-episode and 33 previously-treated, but not medicated for, at least, 6 weeks] acutely ill Sz patients (DSM-IV) and fifty-two healthy subjects matched for age, gender, body mass index (BMI), and waist circumference [Steiner et al., 2017]. Plasma leptin levels, and other metabolic markers were previously assessed in study participants [Steiner et al., 2017]. The study was approved by the University of Magdeburg Review Board and Tufts Medical Center IRB, and written informed consent was obtainedResultsThe main (and, to the best of our knowledge, original) finding of our study is the strong correlation of leptin plasma levels with ANA (but not with other studied kynurenines) in Sz patients (r=0.44, p<0.006, Spearman’s rank correlations, two-tailed). There was a high tendency to such a correlation in control subjects (r=0.26, p=0.06). In patients (but not in controls) plasma levels of leptin and ANA correlated with waist circumference (r=0.27, p<0.004 and r=0.37, p<0.01, resp.) and BMI (r=0.30, p<0.03 and r=0.34, p<0.01, resp.). Plasma leptin and ANA levels did not differ between Sz patients and control subjects (Mann-Whitney U test).DiscussionThe strong positive correlation between plasma leptin and ANA (but not other kynurenines) might be explained by the shift of Kyn down-stream metabolism from formation of 3HK toward production of ANA and KYNA by adipocytes, the major source of leptin production. Notably, literature data pointed out to elevation of leptin and decrease of ANA levels after treatment with antipsychotic medications suggesting a switch from positive to negative correlation between leptin and ANA after treatment. A different regulation of ANA compared to other kynurenines in relation to leptin has previously been described in obesity: weight loss was accompanied by drop of circulating leptin levels while ANA was the only Kyn metabolite increased after weight loss [Theofylaktopoulou et al., 2013]. Our data further support the special role of ANA in leptin involvement in energy regulation in Sz patients. Evaluation of plasma leptin/ANA correlation may be useful in identification of Sz patients at increased risk for the development of metabolic abnormalities.ReferencesErhardt S, Schwieler L, Nilsson L. 2007. Physiol Behav 92:203Oxenkrug G. 2015. Mol Neurobiol. 52:805Oxenkrug G, Cornicelli J, van der Hart M, et al. 2016. Integr Mol Med, 3: 761Schwarcz, R., Rassoulpour, A., Wu, H.Q., et al. 2001. Biol. Psychiatry 50: 521Steiner J, Berger M, Guest PC, et al. 2017. JAMA Psychiatry, 74:968Theofylaktopoulou D, Midttun O, Ulvik A, et al. Clin Exp Immunol. 2013;173:121