β2-Adrenoceptor Deficiency Results in Increased Calcified Cartilage Thickness and Subchondral Bone Remodeling in Murine Experimental Osteoarthritis

PurposeRecent studies demonstrated a contribution of adrenoceptors (ARs) to osteoarthritis (OA) pathogenesis. Several AR subtypes are expressed in joint tissues and the β2-AR subtype seems to play a major role during OA progression. However, the importance of β2-AR has not yet been investigated in knee OA. Therefore, we examined the development of knee OA in β2-AR-deficient (Adrb2-/-) mice after surgical OA induction.MethodsOA was induced by destabilization of the medial meniscus (DMM) in male wildtype (WT) and Adrb2-/- mice. Cartilage degeneration and synovial inflammation were evaluated by histological scoring. Subchondral bone remodeling was analyzed using micro-CT. Osteoblast (alkaline phosphatase - ALP) and osteoclast (cathepsin K - CatK) activity were analyzed by immunostainings. To evaluate β2-AR deficiency-associated effects, body weight, sympathetic tone (splenic norepinephrine (NE) via HPLC) and serum leptin levels (ELISA) were determined. Expression of the second major AR, the α2-AR, was analyzed in joint tissues by immunostaining.ResultsWT and Adrb2-/- DMM mice developed comparable changes in cartilage degeneration and synovial inflammation. Adrb2-/- DMM mice displayed elevated calcified cartilage and subchondral bone plate thickness as well as increased epiphyseal BV/TV compared to WTs, while there were no significant differences in Sham animals. In the subchondral bone of Adrb2-/- mice, osteoblasts activity increased and osteoclast activity deceased. Adrb2-/- mice had significantly higher body weight and fat mass compared to WT mice. Serum leptin levels increased in Adrb2-/- DMM compared to WT DMM without any difference between the respective Shams. There was no difference in the development of meniscal ossicles and osteophytes or in the subarticular trabecular microstructure between Adrb2-/- and WT DMM as well as Adrb2-/- and WT Sham mice. Number of α2-AR-positive cells was lower in Adrb2-/- than in WT mice in all analyzed tissues and decreased in both Adrb2-/- and WT over time.ConclusionWe propose that the increased bone mass in Adrb2-/- DMM mice was not only due to β2-AR deficiency but to a synergistic effect of OA and elevated leptin concentrations. Taken together, β2-AR plays a major role in OA-related subchondral bone remodeling and is thus an attractive target for the exploration of novel therapeutic avenues.

Serum Leptin Levels, Nutritional Status, and the Risk of Healthcare-Associated Infections in Hospitalized Older Adults

We aimed to determine whether serum leptin levels are predictive of the occurrence of healthcare-associated infections (HAIs) in hospitalized older patients. In a prospective cohort, 232 patients had available data for leptin and were monitored for HAIs for 3 months. Admission data included comorbidities, invasive procedures, the Mini Nutritional Assessment (MNA), BMI, leptin, albumin and C-reactive protein levels, and CD4 and CD8 T-cell counts. Multivariate logistic regression modelling was used to identify predictors of HAIs. Of the 232 patients (median age: 84.8; females: 72.4%), 89 (38.4%) experienced HAIs. The leptin level was associated with the BMI (p < 0.0001) and MNA (p < 0.0001) categories. Women who experienced HAIs had significantly lower leptin levels than those who did not (5.9 μg/L (2.6–17.7) and 11.8 (4.6–26.3), respectively; p = 0.01; odds ratio (OR) (95% confidence interval): 0.67 (0.49–0.90)); no such association was observed for men. In a multivariate analysis of the women, a lower leptin level was significantly associated with HAIs (OR = 0.70 (0.49–0.97)), independently of comorbidities, invasive medical procedures, and immune status. However, leptin was not significantly associated with HAIs after adjustments for malnutrition (p = 0.26) or albuminemia (p = 0.15)—suggesting that in older women, the association between serum leptin levels and subsequent HAIs is mediated by nutritional status.

Elevated Serum Leptin Levels in Patients With Eosinophilic Chronic Rhinosinusitis

Background: Eosinophilic chronic sinusitis (ECRS) is a subtype of CRS with nasal polyps (CRSwNP) that is frequently comorbid with asthma. Notably, ECRS patients often show a high recurrence of NPs after surgical resection. Leptin is a hormone produced by adipocytes that has been implicated in airway inflammatory diseases. However, to date, the role of leptin in ECRS has not been investigated.Objective: To determine whether the serum levels of leptin are altered in patients with ECRS.Methods: In total, 40 patients with ECRS, 15 patients with non-eosinophilic CRS (non-ECRS), and 12 individuals without CRS (control) were included in this study. Patient’s serum leptin levels were assessed, and the number of eosinophils in their NPs were measured through a histological evaluation of the three densest areas with cellular infiltrate beneath the epithelial surface. Finally, nasal fibroblast cultures established from NPs were stimulated with varying concentrations of recombinant leptin in vitro to determine whether leptin affects eotaxin-3 (Chemokine (C-C motif) ligand 26 :26: CCL26) expression.Results: The serum leptin levels in both the ECRS and non-ECRS groups were significantly higher than those in the control subjects (p &lt; 0.0001 vs. ECRS; p &lt; 0.05 vs. non-ECRS). Furthermore, ECRS patients displayed significantly elevated serum leptin levels compared to non-ECRS patients (p &lt; 0.001), although there was no difference in body mass index between the groups. Notably, serum leptin levels were correlated with the proportion of eosinophils in peripheral blood (r = 0.3575, p &lt; 0.01) and the number of eosinophils in NPs (r = 0.5109, p &lt; 0.0001). Serum leptin levels were also correlated with eotaxin-3 mRNA expression in NPs (r = 0.5374, p &lt; 0.01). Finally, leptin significantly augmented eotaxin-3 expression in nasal fibroblasts established in vitro from NPs in a leptin receptor-dependent manner (p &lt; 0.05).Conclusion: Leptin levels are elevated in ECRS patients and may both promote and indicate the severity of ECRS as well as systemic type 2-biased inflammatory responses. Combined, these data indicate that circulating leptin may play a significant role in the development of eosinophilic inflammation in NPs.

Serum Leptin and Earlier Stages of Nephropathy among Type 2 Diabetic Subjects in a Bangladeshi population

Objective: To evaluate the relationship of Serum Leptin and Early Nephropathy among uncontrolled type 2 Diabetes Mellitus patients of Bangladesh Institute of Research and Rehabilitation in Diabetes Endocrinology and Metabolism (BIRDEM), Dhaka and Endocrinology department of Sylhet MAG Osmani Medical College (SOMC) & Hospital Sylhet, Bangladesh. Methods: This study was carried out from January 2013 to December 2015 among 100 type 2 diabetic patients from the outpatient department (OPD) BIRDEM and SOMC hospital. Results: 16 out of 30 controls and 65 out of 100 people with diabetes have a family history of diabetes. Early retinopathy and neuropathy were observed in 45.5% and 36.5% diabetic subjects. Mean±SD of serum urea in control subjects was 28.65±6.27; in diabetic subjects was 30.21±7.67. Serum creatinine in controls was 1.12±0.24, in diabetic subjects was 1.13±0.25. Serum leptin levels in control subjects {1.65 (0.05-8.66)} was lower than diabetic counterpart {1.21 (0.11-13.3)}. Leptin levels in male controls {(1.29 (0.05-2.49)} was significantly (P 0.000) lower than the female controls {4.03 (0.05-8.66)}. Conclusion: It was evident that there was very little or no association between serum leptin level and the indices of renal function. No changes of circulating serum Leptin concentration in the earlier stages of Diabetic Nephropathy were found.

Alteration of serum leptin and LEP/LEPR promoter methylation in Prader-Willi syndrome

Prader-Willi syndrome (PWS) is a rare neurodevelopmental disorder based on a loss of paternally expressed but maternally imprinted genes in chromosome region 15q11-13. During child development, PWS usually results in insatiable appetite with subsequent obesity representing the major mortality factor. The neurobiological basis of PWS-typical hyperphagia has remained poorly understood. Many PWS-typical abnormalities are based on hypothalamic dysregulation, the region in which hunger and satiety are hormonally regulated, with the hormone leptin being a main long-term regulator of satiety. Previous studies in PWS have inconsistently shown leptin alterations solely in early childhood, without investigating the leptin system on an epigenetic level. The present study investigates serum leptin levels (S-leptin) and methylation of the leptin (LEP) and leptin receptor gene (LEPR) promoter in 24 individuals with PWS compared to 13 healthy controls matched for sex, age, and body mass index (BMI) and relates the results to the extent of hyperphagia in PWS. S-Leptin levels were obtained by Enzyme-linked Immunosorbent Assay. LEP/LEPR-promoter methylation was assessed by DNA-bisulfite-sequencing, hyperphagia by Hyperphagia Questionnaire for Clinical Trials (HQ-CT). PWS and control groups differed significantly in S-leptin levels with higher S-leptin in PWS. Methylation analysis showed significant differences in mean promoter methylation rate both for LEP and LEPR with a lower methylation rate in PWS. LEPR, but not LEP methylation correlated with S-leptin levels. S-leptin and both LEP and LEPR methylation did not correlate with HQ-CT scores in PWS. The present study is the first to show significantly elevated S-leptin levels in an adult PWS cohort combined with an altered, downregulated LEP and LEPR promoter methylation status compared to BMI-matched controls. Analogous to previous studies, no link to the behavioral dimension could be drawn. Overall, the results suggest an increased leptin dysregulation in PWS, whereby the findings partly mirror leptin resistance seen in non-syndromic obesity.

Maternal Serum and Cord Blood Leptin Concentrations at Delivery in Normal Pregnancies and in Pregnancies Complicated by Intrauterine Growth Restriction

<b><i>Introduction:</i></b> Leptin is a polypeptide hormone, and in pregnancy, it is secreted by the placenta and maternal and fetal adipose tissues. Normal leptin production is a factor responsible for uncomplicated gestation, embryo development, and fetal growth. The study compared maternal serum and cord blood leptin concentrations at delivery in normal pregnancies and in pregnancies complicated by intrauterine growth restriction (IUGR). <b><i>Methods:</i></b> The study was performed in 25 pregnant women with isolated IUGR and in 194 pregnant women without any complications. Leptin concentrations in maternal serum and in cord blood samples collected at delivery were measured by ELISA and subsequently analyzed by maternal body mass index (BMI), mode of delivery, and infant gender and birth weight. For comparative analyses of normally distributed variables, parametric tests were used, that is, the Student <i>t</i> test and a one-way ANOVA. The nonparametric Mann-Whitney test was used when the distribution was not normal. The Pearson correlation coefficient was calculated to assess the correlation between normally distributed variables (<i>p</i> &#x3c; 0.05). <b><i>Results:</i></b> In pregnancies complicated by IUGR, the mean maternal serum leptin concentration at delivery was significantly higher (52.73 ± 30.49 ng/mL) than in normal pregnancies (37.17 ± 28.07 ng/mL) (<i>p</i> = 0.01). The mean cord blood leptin concentration in pregnancies complicated by IUGR was 7.97 ± 4.46 ng/mL and significantly lower than in normal pregnancies (14.78 ± 15.97 ng/mL) (<i>p</i> = 0.04). In normal pregnancies, but not in pregnancies complicated by IUGR, a statistically significant correlation was established between maternal serum leptin concentrations and maternal BMI at delivery (<i>r</i> = 0.22; <i>p</i> = 0.00). No statistically significant correlation was found between cord blood leptin concentrations and maternal BMI in either study subjects or controls. In normal pregnancies, but not in pregnancies complicated by IUGR, a strong correlation was observed between cord blood leptin concentrations and birth weight (<i>r</i> = 0.23; <i>p</i> = 0.00). <b><i>Conclusions:</i></b> Elevated maternal blood leptin concentrations in pregnancies complicated by IUGR may indicate a significant adverse effect of elevated leptin on fetal growth. The differences in leptin concentrations, measured in maternal serum and in cord blood, between the study subjects and controls suggest that deregulated leptin levels may increase the risk of obstetric complications associated with placental insufficiency.