Baseline Leptin Levels Research Articles

Effects of Chronotherapeutic Interventions in Adults With ADHD and Delayed Sleep Phase Syndrome (DSPS) on Regulation of Appetite and Glucose Metabolism

Background: ADHD is highly comorbid with Delayed Sleep Phase Syndrome (DSPS). Both are associated with obesity and diabetes, which can be caused by long-term dysregulations of appetite and glucose metabolism. This study explores hormones involved in these processes and the effects of chronotherapeutic interventions in a small sample of adults with ADHD and DSPS. Methods: Exploratory, secondary analysis of data from the PhASE study, a three-armed randomized clinical trial, are presented, including 37 adults (18–53 years) with ADHD and DSPS receiving three weeks of 0.5 mg/day (1) placebo, (2) melatonin, or (3) melatonin plus 30 minutes of bright light therapy (BLT). Leptin (appetite-suppressing), ghrelin (appetite-stimulating), insulin, insulin-like growth factor-1 (IGF-1), and glucose were measured from blood collected at 08:00 hours. Salivary cortisol was collected during the first 30 minutes after awakening and self-reported appetite was assessed. Results: Baseline leptin and IGF-1 levels were higher than reference ranges, and ghrelin and cortisol levels were lower, while insulin and glucose were normal. Melatonin treatment decreased leptin and insulin. Other outcomes remained unchanged and melatonin + BLT had no effects. Conclusion: Due to the small sample size and exploratory nature of the study, results should be interpreted with caution. Overall, these results show no strong indications for dysregulation of appetite and glucose metabolism to suggest high risk of obesity and diabetes in this small sample of adults with ADHD and DSPS. However, baseline appetite was suppressed, likely because measurements took place in the early morning which could be considered the biological night for this study population. Melatonin treatment seemed to cause subtle changes in appetite-regulating hormones suggesting increased appetite. Chronotherapeutic treatment may affect appetite-regulating hormones by advancing the biological rhythm and/or altering eating behaviors, but this remains to be investigated in larger samples using detailed food diaries.

Concurrent strength and aerobic exercise reduce plasma leptin and cortisol levels

To analyze the correlation between leptin and cortisol after a concurrent training (CT) session. Thirty male volunteers (age: 27.7 ± 5.1 years, BMI: 27.08 ± 1.42 kg/m2) were randomly assigned to an experimental group (EG: n=15) and a control group (CG: n=15). Baseline leptin and cortisol levels were determined by collecting blood samples. EG was subjected to CT (indoor cycling followed by strength training), whereas CG performed no exercise. After CT, blood samples were collected in EG and CG to determine the hormone variables. EG showed a significant decrease (p<0.05) intra and intergroup in leptin and cortisol levels. Only the EG showed a significant correlation (r=0.756; p<0.05) between leptin and cortisol levels. CT session is linked to in decreased leptin and cortisol levels, exhibiting a positive correlation between them.

Plasma Leptin and Alzheimer Protein Pathologies Among Older Adults

Many epidemiologic studies have suggested that low levels of plasma leptin, a major adipokine, are associated with increased risk of Alzheimer disease (AD) dementia and cognitive decline. Nevertheless, the mechanistic pathway linking plasma leptin and AD-related cognitive decline is not yet fully understood. To examine the association of plasma leptin levels with in vivo AD pathologies, including amyloid-beta (Aβ) and tau deposition, through both cross-sectional and longitudinal approaches among cognitively unimpaired older adults. This was a longitudinal cohort study from the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer Disease. Data were collected from January 1, 2014, to December 31, 2020, and data were analyzed from July 11 to September 6, 2022. The study included a total of 208 cognitively unimpaired participants who underwent baseline positron emission tomography (PET) scans for brain Aβ deposition. For longitudinal analyses, 192 participants who completed both baseline and 2-year follow-up PET scans for brain Aβ deposition were included. Plasma leptin levels as assessed by enzyme-linked immunosorbent assay. Baseline levels and longitudinal changes of global Aβ and AD-signature region tau deposition measured by PET scans. Among the 208 participants, the mean (SD) age was 66.0 (11.3) years, 114 were women (54.8%), and 37 were apolipoprotein E ε4 carriers (17.8%). Lower plasma leptin levels had a significant cross-sectional association with greater brain Aβ deposition (β = -0.04; 95% CI, -0.09 to 0.00; P = .046), while there was no significant association between plasma leptin levels and tau deposition (β = -0.02; 95% CI, -0.05 to 0.02; P = .41). In contrast, longitudinal analyses revealed that there was a significant association between lower baseline leptin levels and greater increase of tau deposition over 2 years (β = -0.06; 95% CI, -0.11 to -0.01; P = .03), whereas plasma leptin levels did not have a significant association with longitudinal change of Aβ deposition (β = 0.006; 95% CI, 0.00-0.02; P = .27). The present findings suggest that plasma leptin may be protective for the development or progression of AD pathology, including both Aβ and tau deposition.

Recurrent Ethanol Treatment does not Produce a Cumulative Effect on Plasma Leptin Levels in Rats

Background: Hypoleptinemia is a potent orexigenic signal. Chronic ethanol (EtOH) consumption is associated with weight gain in humans, and acute ethanol treatment leads to reductions in leptin concentrations in both fasted humans and rats. The objective of this study was to determine whether short-term recurrent ethanol treatment has a cumulative effect on plasma leptin levels in rats, and whether treatment in the fed or fasted state influences the leptin lowering effect of EtOH. We hypothesized that recurrent EtOH treatment would have a cumulative effect on leptin levels, and that these effects would be more pronounced in the fed state, when leptin levels are highest. Methods: Two separate groups of male Sprague Dawley rats were exposed to either oral or intravenous (IV) treatment with EtOH (2g/kg via oral gavage or 0.067 g/kg/min IV for 30 min; n=7/group) on three consecutive days. Each rat served as its own control and received saline treatment either 7 d prior to or 7 d following exposure to EtOH. The oral group was fasted 12-14 h (overnight) prior to treatment, while the IV group was not fasted. Plasma leptin and EtOH levels were measured each day at baseline and 3 h following EtOH treatment. Data are expressed as mean ± SEM. A two-way repeated measures ANOVA was used to test for differences in plasma leptin and EtOH levels due to treatment (saline vs. EtOH) or day (cumulative effect of treatment). Results: Post-treatment ethanol levels in the oral and IV groups (55 ± 6.9 and 45 ± 6.3 mM, respectively) were higher than saline-treated rats (p>0.001). Baseline leptin levels in the oral treatment (fasted) group were 3.4 ± 0.3 and 3.9 ± 0.2 ng/mL under saline and leptin treated conditions, respectively. There was a significant main effect of treatment but not of day in the oral group (p=0.04 and p=0.38, respectively). In the oral group, average daily change in leptin levels 3 h post treatment in saline and leptin treated rats were -0.18 ± 0.05 and -0.72 ± 0.1 ng/mL, respectively. Baseline leptin levels in the IV group (fed) were 7.8 ± 0.3 and 6.7 ± 0.1 ng/mL, in saline and leptin treated rats respectively. There was no significant main effect of treatment or day in the IV group (p=0.17 and p=0.41, respectively). In the IV group, average daily changes in leptin levels 3 h following treatment in saline and leptin treated rats were -1.7 ± 0.2 and -1.3 ± 0.3 ng/mL, respectively. Conclusion: Although we were able to replicate previous work indicating reduced leptin levels following acute EtOH treatment in fasted rats, our results do not support a cumulative leptin-lowering effect of recurrent EtOH treatment. Furthermore, IV EtOH treatment in the fed state did not have any impact on leptin levels. This suggests that the leptin-lowering effects of EtOH may either require the fasted state or may require ingestion and exposure of the GI system to EtOH. NIH R01 DK131165-01A1. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

High Salt Diet Induces Aldosterone Synthase Elevation in Adrenal and Visceral Adipose Tissue - A Potential Culprit for Unsuppressed Aldosterone Levels in Female BALB/c Mice

Women are more salt-sensitive than men, irrespective of age, menopausal status, or ethnic background. Nonetheless, the mechanisms predisposing women to salt sensitivity of blood pressure (SSBP) are poorly understood, notably due to the diffculty in finding appropriate animal models. Previously, we demonstrated that female BALB/c mice spontaneously develop SSBP, likely through an inability to reduce the expression of adrenal aldosterone synthase (CYP11B2) appropriately, which leads to unsuppressed aldosterone levels in response to high salt intake. Herein, we aim to decipher the mechanism involved in SSBP in female BALB/c mice by comparing them to female salt-resistant C57BL/6 mice. Eleven-week-old female BALB/c and C57BL/6J mice were fed either a normal (0.4%, NSD) or a high salt diet (4%, HSD) for seven days. HSD significantly reduced adrenal aldosterone synthase transcript and protein expression in female C57BL/6 mice compared to those on a NSD. Conversely, HSD substantially increased CYP11B2 levels in BALB/c female mice when compared to strain-matched NSD and C57BL/6 NSD mice (2-way ANOVA, p<0.05). HSD induced a more significant aldosterone drop in C57BL/6 versus BALB/c mice (C57BL/6: 72% vs. BALB/c: 49%). Remarkably, HSD led to an increase in CYP11B2 in the visceral adipose tissue (VAT) of BALB/c mice in comparison to strain-matched NSD mice, while no such alteration was observed between C57BL/6 NSD and HSD. We previously showed that leptin regulates CYP11B2 expression. We report here that HSD increased leptin receptor (lepR) expression in adrenal and VAT from BALB/c mice in comparison to both strain-matched NSD and C57BL/6 NSD. Baseline levels of leptin were similar in C57BL/6 and BALB/c mice. However, BALB/c mice on HSD displayed increased levels of leptin compared to its strain-matched NSD mice, while no such alteration was observed in C57BL/6 mice. Furthermore, female BALB/c mice on HSD displayed elevated endothelial cell-specific mineralocorticoid receptor (ECMR) expression compared to female C57BL/6 NSD and HSD mice (2-way ANOVA, p<0.05). Endothelium-dependent relaxation to acetylcholine was significantly reduced in the female BALB/c mice on HSD compared to strain-matched NSD and C57BL/6 NSD (n = 3, 2-way ANOVA, P < 0.05). Interestingly, on NSD, C57BL/6 mice present a better endothelial function than BALB/c, which was not altered by HSD. Collectively, our data supports an overactivation of the leptin-CYP11B2-aldosterone axis in both adrenals and VAT, leading to inappropriate aldosterone levels, which, associated with higher ECMR expression, induce endothelial dysfunction in BALB/c mice. Together, these mechanisms are likely the cause of SSBP in female BALB/c mice. Funding: R01HL130301, R01HL155265 (E.J.B.). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Weight loss induces changes in adaptive thermogenesis in female and male physique athletes.

Physique athletes lose substantial weight preparing for competitions, potentially altering systemic metabolism. We investigated sex differences in body composition, resting energy expenditure (REE), and appetite-regulating and thyroid hormone changes during a competition preparation among drug-free physique athletes. The participants were female (10 competing (COMP) and 10 nondieting controls (CTRL)) and male (13 COMP and 10 CTRL) physique athletes. COMP were tested before they started their diet 23 weeks before competing (PRE), during their diet one week before competing (MID), and 23 weeks after competing (POST), whereas CTRL were tested at similar intervals but did not diet. Measurements included body composition by dual-energy X-ray absorptiometry, muscle size, and subcutaneous fat thickness (SFA) by ultrasound, REE by indirect calorimetry, circulating ghrelin, leptin T3, and T4 hormone analysis. Fat mass (FM) and SFA decreased in both sexes (p<0.001), while males (p<0.001) lost more lean mass (LM) than females (p<0.05). Weight loss, decreased energy intake, and increased aerobic exercise (p<0.05) led to decreased LM- and FM-adjusted REE (p<0.05), reflecting metabolic adaptation. Absolute leptin levels decreased in both sexes (p<0.001) but more among females (p<0.001) due to higher baseline leptin levels. These changes occurred with similar decreases in T3 (p<0.001) and resting heart rate (p<0.01) in both sexes. CTRL, who were former or upcoming physique athletes, showed no systematic changes in any measured variables. In conclusion, while dieting, female and male physique athletes experience REE and hormonal changes leading to adaptive thermogenesis. However, responses seemed temporary as they returned toward baseline after the recovery phase. ClinicalTrials.gov (NCT04392752).

Effect of flavonoid intake on circulating levels of adiponectin and leptin: A systematic review and meta-analysis of randomized controlled clinical trials.

This meta-analysis of randomized controlled trials (RCTs) was conducted to explore the effects of flavonoid intake on adiponectin and leptin levels. The PubMed, EMBASE, and Cochrane Library databases were searched on March 1, 2021. Random-effects, subgroup, sensitivity, and meta-regression analyses were conducted on 40 publications. Flavonoid intake significantly increased circulating adiponectin (0.54 μg/ml, 95% CI [0.20, 0.88], p=.002; I2 =86.4%) and significantly reduced leptin levels (weighted mean difference: -0.79 ng/ml, 95% CI [-1.33, -0.25], p=.004; I2 =87.7%). Subgroup analysis demonstrated that flavonoid intervention produced a significant elevation in adiponectin levels only in studies that lasted more than 12 weeks, conducted in Asian regions, were parallel-designed, involved obese or overweight participants and participants with type 2 diabetes mellitus (T2DM) or cardiovascular diseases, used tea catechins, and used a dietary supplement intervention. A significantly negative effect on leptin levels was observed in studies conducted in Asian countries, with healthy participants and participants with T2DM, used whole food interventions, and involved participants with lower baseline leptin levels. In conclusion, flavonoid intake significantly increased circulating adiponectin and decreased leptin levels; however, study heterogeneity was very high. Future well-designed trials are required to address heterogeneous study designs and clarify the efficacy of plants in regulating adiponectin and leptin levels.

Soy isoflavones plus soy protein effects on serum concentration of leptin in adults: A systematic review and meta-analysis of randomized clinical trials.

Some studies conducted on soy isoflavones and soy protein reflected that leptin can be reduced by soy isoflavones or soy protein. The aim of present study is to assess the effect of soy isoflavones plus soy protein on serum concentration of leptin among adults. To find randomized clinical trails (RCTs) assessing the effect of soy isoflavones containing soy protein on serum concentration of leptin in participants with age ≥18 years old, databases including PubMed, Scopus, ISI Web of Science, Cochrane and ClinicalTrials.gov were searched up to March 2021. We calculated the effect size by the mean change from baseline of leptin concentrations and its standard deviation for intervention and comparison groups. DerSimonian and Laird random effects model was used to estimate the overall summary effect and the heterogeneity. Risk of bias was conducted by Cochrane Collaboration's tool. Study protocol was registered in PROSPERO (No. CRD42021228366). Eight articles with 421 participants and six articles with 336 participants were known to be eligible for systematic review and meta-analysis, respectively. A pooled analysis revealed that the combination of soy isoflavones and soy protein had a borderline non-significant on serum concentration of leptin (weighted mean difference (WMD):-1.03ng/ml, 95% confidence interval (CI):-2.11, 0.05ng/ml). This combination reduced serum leptin levels in studies with baseline levels of leptin ≤22ng/ml, in short-term trials (≤56 days), studies that used soy isoflavones with dose ≤96mg/day and among subjects with health risk factors or diseases. Soy isoflavones plus soy protein had a non-significant decreasing effect on the serum concentration of leptin. However, making firm conclusion needs more studies on participants with different health condition, and different soy isoflavones doses and intervention duration.

LEPTIN AS A PREDICTOR OF CARDIOPROTECTIVE EFFICIENCY OF RENAL DENERVATION IN PATIENTS WITH RESISTANT HYPERTENSION AND TYPE 2 DIABETES MELLITUS

Objective: To evaluate serum leptin level before renal denervation (RDN) and to assess whether this baseline metabolic marker predicts cardioprotective efficacy in patients with resistant hypertension (RHTN) and type 2 diabetes mellitus (T2DM). Design and method: The study included 25 patients with RHTN and T2DM (mean age 60.9 ± 7.1 years, 16 women, mean 24-hour (24-h) blood pressure (BP) (systolic/diastolic) 158.8 ± 16.5/81.1 ± 13.1 mm Hg, mean HbA1c 7.4 ± 1.5%). All patients were enrolled in the prospective interventional study with RDN (NCT02667912 and NCT01499810 at ClinicalTrials.gov). Office BP and ABPM, tissue Doppler echocardiography with assessment of diastolic function, serum leptin level were performed at baseline and 6-months after RDN. Twenty patients completed a 6-month follow-up. Results: RDN led to a significant reduction in systolic and diastolic 24-h BP (-13.4/-7.6 mm Hg, p = 0.001/0.002). The baseline leptin level correlated with the mean E/e ‘ratio at baseline (R = 0.52, p = 0.015) and its dynamics after 6 months (R = 0.71, p = 0.001). Depending on the degree of decrease in average E/e’ ratio, the patients were retrospectively divided into 2 groups: 1st (with improvement) (persons with a decrease in average E/e’ ratio by 1 unit or more, n = 10 (50%)) and 2nd (without improvement) (with a lesser degree of decrease in average E/e’ ratio). Initially, the pts of 1st group not differed from those of 2nd group by age, BP and HbA1c level. At the same time, pts of the 1st group had higher baseline leptin level (60.4 ± 24.05 and 35.8 ± 9.82 ng/ml, p = 0.008) than pts of the 2nd group. A ROC analysis showed that the best cut-off value of the leptin level is 47.4 ng/ml with 70% sensitivity and 85% specificity (AUC: 0.84; 95% CI:0.64–1.04; p = 0.001). Conclusions: Estimation of the leptin allows predicting the cardioprotective efficacy of renal denervation in patients with resistant hypertension and type 2 diabetes mellitus.

Therapeutic indications and metabolic effects of metreleptin in patients with lipodystrophy syndromes: Real-life experience from a national reference network.

AimTo describe baseline characteristics and follow‐up data in patients with lipodystrophy syndromes treated with metreleptin in a national reference network, in a real‐life setting.Patients and MethodsClinical and metabolic data from patients receiving metreleptin in France were retrospectively collected, at baseline, at 1 year and at the latest follow‐up during treatment.ResultsForty‐seven patients with lipodystrophy including generalized lipodystrophy (GLD; n = 28) and partial lipodystrophy (PLD; n = 19) received metreleptin over the last decade. At baseline, the median (interquartile range [IQR]) patient age was 29.3 (16.6‐47.6) years, body mass index was 23.8 (21.2‐25.7) kg/m2 and serum leptin was 3.2 (1.0‐4.9) ng/mL, 94% of patients had diabetes (66% insulin‐treated), 53% had hypertension and 87% had dyslipidaemia. Metreleptin therapy, administered for a median (IQR) of 31.7 (14.2‐76.0) months, was ongoing in 77% of patients at the latest follow‐up. In patients with GLD, glycated haemoglobin (HbA1c) and fasting triglyceride levels significantly decreased from baseline to 1 year of metreleptin treatment, from 8.4 (6.5‐9.9)% [68 (48‐85) mmol/mol] to 6.8 (5.6‐7.4)% [51(38‐57) mmol/mol], and 3.6 (1.7‐8.5) mmol/L to 2.2 (1.1‐3.7) mmol/L, respectively (P < 0.001), with sustained efficacy thereafter. In patients with PLD, HbA1c was not significantly modified (7.7 [7.1‐9.1]% [61 (54‐76) mmol/mol] at baseline vs. 7.7 [7.4‐9.5]% [61(57‐80) mmol/mol] at 1 year), and the decrease in fasting triglycerides (from 3.3 [1.9‐9.9] mmol/L to 2.5 [1.6‐5.3] mmol/L; P < 0.01) was not confirmed at the latest assessment (5.2 [2.2‐11.3] mmol/L). However, among PLD patients, at 1 year, 61% were responders regarding glucose homeostasis, with lower baseline leptin levels compared to nonresponders, and 61% were responders regarding triglyceridaemia. Liver enzymes significantly decreased only in the GLD group.ConclusionsIn this real‐life setting study, metabolic outcomes are improved by metreleptin therapy in patients with GLD. The therapeutic indication for metreleptin needs to be clarified in patients with PLD.

Baseline serum biomarkers of inflammation, bone turnover and adipokines predict spinal radiographic progression in ankylosing spondylitis patients on TNF inhibitor therapy

ObjectiveTo analyze whether biomarker levels at baseline or their change after 3 months or 2 years predict radiographic spinal progression in ankylosing spondylitis (AS) patients treated with TNF-α inhibitors (TNFi). Methods137 AS patients from the Groningen Leeuwarden Axial Spondyloarthritis (GLAS) cohort were included before starting TNFi. Serum biomarkers were measured at baseline, 3 months and 2 years: Markers of inflammation (calprotectin, matrix metalloproteinase-3, vascular endothelial growth factor), bone turnover markers (bone-specific alkaline phosphatase, serum C-terminal telopeptide fragments of type I collagen (sCTX), osteocalcin, osteoprotegerin, procollagen type I and II N-terminal propeptide, sclerostin) and adipokines (high-molecular-weight adiponectin, leptin, visfatin). Spinal radiographs were scored at baseline, 2 and 4 years. Logistic regression was performed to examine the association between biomarker values and radiographic spinal progression, adjusting for known risk factors for radiographic progression. ResultsBaseline calprotectin and visfatin levels were associated with mSASSS progression ≥2 points (OR 1.195 [95%CI 1.055–1.355] and 1.465 [1.137–1.889], respectively), while calprotectin was also associated with new syndesmophyte formation after 2 years (OR 1.107 [1.001–1.225]). Baseline leptin level was associated with mSASSS progression ≥4 points after 4 years (OR 0.614 [0.453–0.832]), and baseline sCTX level with syndesmophyte formation after 4 years (OR 1.004 [1.001–1.008]). Furthermore, change of visfatin and leptin levels over the first 2 years showed significant association with radiographic progression after 4 years. ConclusionIndependent of known risk factors, serum levels of biomarkers at baseline are able to predict radiographic spinal progression over 2 and 4 years in AS patients on TNFi therapy.

Changes of Metabolic Biomarker Levels upon One-Year Anti-TNF-α Therapy in Rheumatoid Arthritis and Ankylosing Spondylitis: Associations with Vascular Pathophysiology.

Background: Cardiovascular (CV) morbidity, mortality, and metabolic syndrome are associated with rheumatoid arthritis (RA) and ankylosing spondylitis (AS). Here, lipids and other metabolic markers in relation to vascular function and clinical markers were evaluated in RA and AS patients undergoing one-year anti-TNF therapy. Patients and methods: Fifty-three patients including 36 RA patients treated with either etanercept (ETN) or certolizumab pegol (CZP) and 17 AS patients treated with ETN were included in a 12-month follow-up study. Various lipids, paraoxonase (PON) and arylesterase (ARE) activities, myeloperoxidase (MPO) and adipokine levels were determined overtime. Ultrasonography was performed to determine flow-mediated vasodilation (FMD), common carotid intima-media thickness (ccIMT), and arterial pulse-wave velocity (PWV) in all patients. All assessments were performed at baseline and 6 and 12 months after treatment initiation. Results: Anti-TNF therapy decreased ARE activity, MPO, adiponectin, and chemerin levels after 12 months (p < 0.05). Lipids, PON activity, and leptin remained unchanged. Regression analyses suggested variable associations of IMT, PWV, and FMD with ARE, MPO, leptin, and lipids (p < 0.05). On the other hand, these metabolic parameters were significantly associated with disease duration, CV history, CRP, obesity, PWV, and IMT (p < 0.05). One-year anti-TNF treatment together with baseline leptin (p = 0.039) or CRP (p = 0.016) levels determined 12 months of lipid changes overtime. TNF inhibition together with baseline disease activity determined ARE activity changes (p = 0.046). Anti-TNF therapy and baseline chemerin levels determined IMT changes overtime (p = 0.003). Conclusions: Assessment of various metabolic parameters together with disease activity, CRP, and ultrasound-based techniques may exert additional value in determining CV burden and in monitoring the effects of biologics on preclinical vascular pathophysiology.

Leptin as a Biomarker of Stress: A Systematic Review and Meta-Analysis.

Background: Leptin is a satiety hormone mainly produced by white adipose tissue. Decreasing levels have been described following acute stress. Objective: To conduct a systematic review and meta-analysis to determine if leptin can be a biomarker of stress, with levels decreasing following acute stress. Methods: PubMed, Cochrane Library, Embase, and ScienceDirect were searched to obtain all articles studying leptin levels after acute stress on 15 February 2021. We included articles reporting leptin levels before and after acute stress (physical or psychological) and conducted random effects meta-analysis (DerSimonian and Laird approach). We conducted Meta-regressions and sensitivity analyses after exclusion of groups outside the metafunnel. Results: We included seven articles—four cohort and three case-control studies—(28 groups) from 27,983 putative articles. Leptin levels decreased after the stress intervention (effect size = −0.34, 95%CI −0.66 to −0.02) compared with baseline levels, with a greater decrease after 60 min compared to mean decrease (−0.45, −0.89 to −0.01) and in normal weight compared to overweight individuals (−0.79, −1.38 to −0.21). There was no difference in the overweight population. Sensitivity analyses demonstrated similar results. Levels of leptin after stress decreased with sex ratio—i.e., number of men/women—(−0.924, 95%CI −1.58 to −0.27) and increased with the baseline levels of leptin (0.039, 0.01 to 0.07). Conclusions: Leptin is a biomarker of stress, with a decrease following acute stress. Normal-weight individuals and women also have a higher variation of leptin levels after stress, suggesting that leptin may have implications in obesity development in response to stress in a sex-dependent manner.

Serum leptin is associated with increased pulse pressure and the development of arterial stiffening in adult men: results of an eight-year follow-up study

High leptin levels are associated with an unfavorable cardiometabolic risk profile. A number of studies found a positive association between leptin and vascular damage, but to date, no observational study has evaluated a potential predictive role of leptin for arterial stiffening. Therefore, the aim of this study was to estimate the role of leptin in the incidence of arterial stiffening (pulse pressure >60 mmHg) and changes in pulse pressure in an 8-year follow-up of a sample of adult men (The Olivetti Heart Study). The analysis included 460 men without baseline arterial stiffening and antihypertensive treatment at baseline and at follow-up (age: 50.0 years, BMI: 26.5 kg/m2). At the end of the follow-up period, the incidence of arterial stiffening was 8%. Baseline leptin was significantly greater in the group that developed arterial stiffening and was significantly correlated with pulse pressure changes over time (p < 0.05). According to the median plasma leptin distribution of the whole population, the sample was stratified into two groups: one with leptin levels above the median and the other with leptin levels below the median. Those who had baseline leptin levels above the median had a greater risk of developing arterial stiffening (odds ratio: 2.5, p < 0.05) and a greater increase in pulse pressure over time (beta: 2.1, p < 0.05), also after adjustment for confounders. The results of this prospective study indicate a predictive role of circulating leptin levels for vascular damage, independent of body weight and blood pressure.

Effect of obesity therapy in women of reproductive age on leptin level and hormonal ovarian function

Hypothesis/aims of study. Ovarian insufficiency is present in more than 30% of reproductive-age obese women. The role of leptin in the pathogenesis of ovarian insufficiency is not yet established and has to be clarified. It is of interest to study the effect of obesity therapy on hyperleptinemia, hormonal and ovulatory function in reproductive-age women with alimentary obesity. The aim of this study was to assess the effect of obesity therapy on leptin level and hormonal ovarian function in women of reproductive age.&#x0D; Study design, materials and methods. All studied women underwent a clinical and laboratory examination, including: medical history, anthropometry (height and weight measurement, waist and hip circumferences, body mass index calculation), blood pressure measurement, gynecological examination, ultrasound examination of the pelvic organs, osteodensitometry, determination of serum gonadotropins, sex hormones, insulin, leptin, and blood biochemical parameters, morning fasting blood glucose, and glucose after the glucose tolerance test. The survey and objective examination data were recorded in a specially developed application form, including the following parameters: the patients age, menarche age, the type of the menstrual cycle, data on pregnancies, childbirth and reproductive plans, gynecological and somatic diseases.&#x0D; Results. The relationship between the initial levels of leptin, estradiol, HOMA-IR, the number of follicles in the ovaries and the restoration of ovulatory function after the weight loss was revealed. The analysis produced a mathematical model to estimate the predictive value of these indicators in relation to the recovery of ovulation after the weight loss. An analysis was made of the effectiveness of drugs used to treat excess body weight (metformin and sibutramine).&#x0D; Conclusion. The predictive value of the baseline levels of leptin and estradiol, the number of antral follicles and insulin resistance in relation to the achievement of ovulation after the reduction of body weight in patients with anovulation caused by excess body weight and obesity has been established. Ovulation recovery did not depend on the choice of a drug used to treat excess body weight. When comparing the groups of women who received medication for alimentary obesity using metformin and sibutramine, no significant differences in the frequency of ovulation recovery were found.

SUN-607 Iron Parameters in Patients with Partial Lipodystrophy and Impact of Metreleptin Therapy

Introduction Intriguing rodent studies and epidemiological data suggest that iron metabolism and adipocytokines crosstalk to regulate glucose metabolism and fuel storage. Iron parameters have not been previously studied in patients with lipodystrophy whereas increased iron stores have been associated with type 2 diabetes. In this study, we sought to investigate the status of iron parameters in patients with partial lipodystrophy (PL) and to interrogate whether the adipocyte hormone leptin can modulate iron metabolism. Methods Serum samples of 19 patients with PL (age: 42, IQR: 34-57, M/F: 3/16) were used from an open-label study previously performed at the University of Michigan evaluating the efficacy of metreleptin in nonalcoholic steatohepatitis (NCT01679197) to measure ferritin, hepcidin, iron, and transferrin soluble receptor levels. High-sensitivity C-reactive protein (hs-CRP) levels were also determined as broader changes in inflammatory pathways may potentially impact circulating ferritin levels. Results were integrated into an existing database of metabolic parameters. Data are presented as median, IQR. Results At baseline, ferritin levels were positively correlated with fasting glucose (r = 0.533; p = 0.023) and HbA1c (r = 0.510; p = 0.031). During the 6 months of therapy period, HbA1c (9.2%, 7.3-10.3 vs. month-3: 8.6%, 7.7-9.6; p = 0.099; and month-6: 8.5%, 6.8-9.5; p = 0.264), triglyceride levels (346 mg/dL, 240-1771 vs. month-3: 346 mg/dl, 237-479; p = 0.047; and month-6: 295 mg/dl, 207-495; p = 0.091), and hepatic fat (12.7%, 9.8-20.6 vs. month-6: 8.9%, 7.0-11.0; p = 0.031)} decreased. Reductions were observed in serum ferritin after metreleptin treatment (83.23 ng/mL, 76.43-178.97 vs. month-3: 73.79 ng/ml, 68.30-78.59; p = 0.007; and month-6: 61.03 ng/mL, 46.45-157.74; p = 0.004). There was a tendency for hepcidin and iron to be decreased, but this did not reach statistical significance. On the other hand, there were notable reductions in hs-CRP levels at 6 months compared to baseline (2.94 mg/L, 1.30-4.80 vs. 1.6 mg/L, 1.00-6.30; p = 0.012). Baseline leptin level was inversely correlated with percent reduction in hs-CRP at month-6 (r = -0.685; p = 0.001). Also, modest correlations were observed between changes in serum iron and triglycerides (r = 0.491, p = 0.033) and hepatic fat (r = 0.412, p = 0.079). Conclusions We observed a significant relationship between ferritin and glucose control in a group of patients with PL. Metreleptin therapy was associated with improvements in triglycerides and hepatic fat and there were also significant decreases in ferritin and hs-CRP levels. These results raise the possibility that metreleptin therapy influences iron metabolism. However, whether the decrease in ferritin indicates a decrease in iron stores or is mediated by an effect on inflammation remains unknown.

Leptin Serum Levels are Associated With GLP-1 Receptor Agonist-Mediated Effects on Glucose Metabolism in Clozapine- or Olanzapine-Treated, Prediabetic, Schizophrenia Patients

Abstract Background We previously demonstrated that the glucagon-like peptide-1 receptor agonist (GLP-1RA) liraglutide significantly reduced glucometabolic disturbances and body weight vs placebo in prediabetic, overweight, or obese schizophrenia-spectrum disorder patients treated with clozapine or olanzapine. Here, we aimed to identify potential biomarkers of prediabetes and the GLP-1RA-induced effects on glucose tolerance in schizophrenia patients treated with clozapine or olanzapine. Methods Multiplexed immunoassays were used to measure 8 proteins (adiponectin, C-reactive protein, interleukin-1 receptor antagonist, leptin, macrophage migration inhibitory factor, prolactin, receptor for advanced glycation end products, and vascular endothelial growth factor [VEGF]) in fasting prediabetic and non-prediabetic patients with schizophrenia-spectrum disorder, the prediabetic patients receiving 16-week randomized treatment with liraglutide or placebo. Results Serum adiponectin (P = .004) and VEGF (P = .019) levels were significantly lower in prediabetic (n = 81) than non-prediabetic schizophrenia-spectrum disorder patients (n = 32). Adiponectin levels increased significantly (P = .022) and leptin levels decreased significantly (P = .017) following treatment with liraglutide (n = 39) vs placebo (n = 42). Importantly, patients receiving liraglutide who had higher baseline leptin levels showed significantly larger reductions in the primary endpoint, the 75-g oral glucose tolerance test value, than patients with lower baseline leptin levels (P = .009). Conclusion These results provide new evidence for metabolic alterations associated with prediabetes and GLP-1RA treatment in the context of schizophrenia. They suggest that leptin may be a valuable biomarker predicting GLP-1RA-induced improvement in glucose tolerance in overweight or obese schizophrenia-spectrum disorder patients with prediabetes treated with clozapine or olanzapine. These findings require further validation in larger numbers of individuals.

Leptin, Ghrelin, and Leptin/Ghrelin Ratio in Critically Ill Patients.

The objective of this study was to evaluate leptin, ghrelin, and leptin/ghrelin ratio in critically ill patients and association of leptin/ghrelin ratio with outcomes. This is a sub-study of the PermiT trial (ISRCTN68144998). A subset of 72 patients who were expected to stay >14 days in the Intensive care unit were enrolled. Blood samples were collected on days 1, 3, 5, 7, and 14. Samples were analyzed for leptin and active ghrelin in addition to other hormones. Baseline leptin/ghrelin ratio was calculated, and patients were stratified into low and high leptin/ghrelin ratio based on the median value of 236. There was a considerable variation in baseline leptin level: Median 5.22 ng/mL (Q1, Q3: 1.26, 17.60). Ghrelin level was generally low: 10.61 pg/mL (Q1, Q3: 8.62, 25.36). Patients with high leptin/ghrelin ratio compared to patients with low leptin/ghrelin ratio were older, had higher body mass index and more likely to be diabetic. There were no differences in leptin/ghrelin ratio between patients who received permissive underfeeding and standard feeding. Multivariable logistic regression analysis showed that age and body mass index were significant independent predictors of high leptin–ghrelin ratio. Leptin–ghrelin ratio was not associated with 90-day mortality or other outcomes. Age and body mass index are predictors of high leptin/ghrelin ratio. Leptin/ghrelin ratio is not affected by permissive underfeeding and is not associated with mortality.

Serum leptin, a potential predictor of long-term angiographic progression in Takayasu's arteritis.

AimIn patients with Takayasu's arteritis (TA), current biomarkers that properly reflect the progression of the vascular structure remain absent. We aimed to determine the serum leptin level to investigate its relationship with imaging changes and assess its value as a predictor for long‐term radiological progression.MethodThis study included 34 untreated TA patients and 40 age‐matched healthy controls. At baseline and during the 5‐year follow‐up, we assessed disease activity using Kerr's criteria and Indian Takayasu Clinical Activity Score (ITAS2010) and monitored laboratory biomarkers as well as imaging findings. Serum leptin levels were measured by enzyme‐linked immunosorbent assay.ResultsThe baseline serum leptin levels were significantly higher in TA patients than in healthy controls. Leptin was significantly positively correlated with triglyceride and high‐density lipoprotein cholesterol levels and negatively correlated with fibrinogen and C‐reactive protein levels. Patients were subdivided into three groups based on their baseline leptin level. During a 5‐year follow‐up, patients in the high and medium leptin groups showed more radiological progression compared to those in the low leptin group. Cox proportional hazard regression analysis showed that a high serum leptin level was a positive predictor of radiological progression.ConclusionLeptin is a potential biomarker for assessing TA structural progression. Untreated patients with elevated serum leptin levels are at a higher risk of progression in the aorta. Thus, the leptin level can be a predictor of long‐term radiological progression.

Childhood Habitual Sleep Duration Modifies the Polygenic Risk for Obesity through Leptin Pathway—A Longitudinal Study

Sleep disruption is known to be an obesity risk factor, however, little is known about its interplay with genetic predisposition and pathways involved in obesity pathogenesis, especially in the longitudinal setting. Leveraging a large cohort from the Beijing Child and Adolescent Metabolic Syndrome (BCAMS) study, we aimed to examine a possible sleep-gene interaction for childhood obesity risk, including longitudinal assessment in a 10-year follow-up and further test if there is any mediation through the leptin pathway. A total of 3,211 children (6-18 years) were recruited from this cohort study. Baseline leptin levels and twelve established adult BMI loci were examined for the associations with habitual sleep duration. After adjusting for pubertal stages, diet score and activity, short sleep duration at baseline was significantly associated with increased overweight/obesity risk at both baseline and follow-up. Genetic predisposition scores, particularly consisting of the central nervous system (CNS) gene variation (GPSCNS), were robustly correlated with baseline overweight/obesity in children who slept ≤8h/day (P&amp;lt;0.001), whereas the association was ablated in those who slept ≥10h/day (P&amp;gt;0.05). Comparable observations were made at follow-up. Mediation analysis revealed a modest direct effect of the GPSCNS-sleep interaction on BMI at baseline, while an indirect effect of this interaction was found to be mediated principally through elevated leptin (52.6%); moreover, the mediation effect via leptin remained stable over 10 years. This study provides longitudinal evidence that short sleep duration in children has a long-term impact on the association of polygenic risk for obesity from childhood to young adulthood and leptin pathway explains a key mechanism via a modification effect. Therefore, adequate sleep duration during childhood is important for the early prevention of obesity, especially if there is a genetic predisposition to this trait. Disclosure M. Li: None. J. Fu: None. L. Han: None. G. Li: None. S. Gao: None. S.F. Grant: None.