Juergen Kratzsch

Elevated serum levels of leptin and soluble leptin receptor in patients with advanced chronic heart failure.

Patients with chronic heart failure (CHF) have metabolic abnormalities, leading to a catabolic syndrome, with progressive loss of skeletal muscle in advanced stages of the disease. Leptin, the product of an obesity gene, has been associated with energy expenditure and weight regulation. The aim of this study was to assess serum levels of leptin and its soluble receptor in relation to exercise intolerance and neurohumoral activation in patients with CHF. We investigated 53 patients with CHF left ventricular ejection fraction (LVEF) 25±1%, age 56.6±1.3 years, Maximal oxygen uptake (VO2 max) 16.3±0.6 ml/min·kg) sub‐classified according to peak oxygen consumption of > or ≤14 ml/min·kg and 11 age‐matched controls (LVEF 70±1, age 60.5±4.0 years, (VO2max) 26.9±1.6 ml/min·kg). Body mass index‐adjusted serum levels of leptin and soluble leptin receptor were increased in patients with CHF compared to the controls (0.28±0.03 vs. 0.22±0.04 ng·m2/ml·kg and 32.6±1.9 ng/ml vs. 22.9±2.3, P<0.05). This increase was even more pronounced in patients with CHF and severe exercise intolerance (0.43±0.08 vs. 0.21±0.02 and 0.22±0.04 ng·m2/ml·kg; P<0.01 vs. VO2max>14 ml/min·kg and controls). Elevated levels of leptin correlated with an increased serum concentration of TNFα (r=0.749, P<0.01) in this subgroup of patients with CHF. We conclude that patients with advanced CHF show elevated serum levels of leptin and its soluble receptor. This finding indicates that leptin may participate in the catabolic state leading to the development of cardiac cachexia in the course of CHF.

Thyroid gland development and defects.

During the functional ontogenesis of the thyroid gland an increasing number of transcription factors play fundamental roles in thyroid-cell differentiation, maintenance of the differentiated state, and thyroid-cell proliferation. The early growth and development of the fetal thyroid appears to be generally independent of thyroid-stimulating hormone (TSH). TSH and thyroxine (T4) levels increase from the 12th week of gestation until delivery, whereas triiodothyronine (T3) levels remain relatively low. At birth, a cold-stimulated short-lived TSH surge is observed, followed by a TSH decrease until day 3 or 4 of life by T4 feedback inhibition. Disorders of thyroid gland development and/or function are relatively common, affecting approximately one newborn infant in 2000-4000. The most prevalent disease, congenital hypothyroidism, is frequently caused by genetic defects of transcription factors involved in the development of the thyroid or pituitary gland. A major cause of congenital hyperthyroidism is the transplacental passage of stimulating thyrotropin antibodies from the mother to the fetus. Hypothyroxinaemia or hypotriiodthyroninaemia is frequently observed in preterm infants with or without severe non-thyroidal illness. Whereas congenital hypo- and hyperthyroidism may be treated successfully with T4 or thyrostatic drugs, there is still insufficient evidence on whether the use of T4 for treatment of the latter condition results in changes in neonatal morbidity or reductions in neurodevelopmental impairment.

Serum levels of the myokine irisin in relation to metabolic and renal function.

OBJECTIVE Irisin has recently been introduced as a novel myokine which reverses visceral obesity and improves glucose metabolism in mice. However, regulation of irisin in humans in relation to renal and metabolic disease has not been comprehensively studied. DESIGN AND METHODS Serum irisin levels were quantified by ELISA and correlated with anthropometric and biochemical parameters of renal function, glucose and lipid metabolism, as well as inflammation, in 532 patients with stages 1-5 of chronic kidney disease (CKD). RESULTS Median serum irisin levels adjusted for age, gender, and BMI significantly decreased with increasing CKD stage and lowest concentrations were seen in patients with CKD stage 5. Furthermore, irisin concentrations were associated with facets of the metabolic syndrome including diastolic blood pressure, markers of impaired glucose tolerance, and dyslipidemia in univariate analysis. Moreover, markers of renal function, e.g. glomerular filtration rate, and insulin resistance, e.g. homeostasis model assessment of insulin resistance, remained independently associated with circulating irisin levels in robust multivariate analysis. CONCLUSIONS We show that irisin serum concentrations decrease with increasing CKD stage and are independently and positively predicted by renal function and insulin resistance. The physiological relevance of our findings, as well as the factors contributing to irisin regulation in humans, needs to be further defined in future experiments.

Obesity and age affect male fertility potential

A case-cohort study of 2,157 patients, aged 17-67 years was performed to assess the impact of body mass index and age on male fertility. Using a multiple regression analysis across the total cohort, only age correlated significantly with all spermiogram parameters and serum hormones, but in patients aged 20-30 years (n = 617) the total sperm count was significantly negatively correlated with body mass index.

Leptin in maternal serum and breast milk: association with infants' body weight gain in a longitudinal study over 6 months of lactation.

The adipokine leptin has been detected in human breast milk, but its effect on postnatal growth and development remains largely unclear. We hypothesized that leptin could affect infants body weight gain during early lactation in the first 6 mo of life. Therefore, we evaluated leptin levels in maternal serum and breast milk of 23 healthy, lactating mothers and their neonates in a prospective, longitudinal study. Leptin concentration was quantified by a commercially available human leptin RIA. Our results showed that leptin levels in breast milk were 22-fold lower than in maternal serum, but both parameters were positively correlated to each other (r = 0.431, p = 0.001) and to maternal BMI (serum: r = 0.512, p < 0.001; milk: r = 0.298, p < 0.001) over 6 mo of lactation. A negative association was found between breast milk leptin levels during the first week after delivery and the infant weight gain from the end of the first to the sixth month (r = −0.681, p = 0.007). This suggests that milk-borne leptin provides a link between maternal body composition and infant growth and development and plays a critical role in regulating appetite and food intake during early infancy.

High Circulating Leptin Receptors with Normal Leptin Sensitivity in Liver-specific Insulin Receptor Knock-out (LIRKO) Mice

Liver-specific insulin receptor knock-out (LIRKO) mice display hyperinsulinemia, abnormal glucose metabolism, and progressive liver dysfunction. In addition, circulating leptin levels appear to be increased more than 10-fold. However, food intake, body weight, and adipose mass are not significantly altered in LIRKO mice compared with wild-type littermates. Using a ligand immunofunctional assay, we found that the apparent increase in circulating leptin in LIRKO mice is because of an 80-fold increased serum level of soluble leptin receptor. Gene expression analysis by microarray and real time PCR reveals the liver as the source of soluble leptin receptor in LIRKO mice, with an increase in expression of the short (Ob-Ra), long (Ob-Rb), and soluble (Ob-Re) forms of the leptin receptor. Direct control of leptin receptor expression by insulin could also be demonstrated in isolated hepatocytes from normal mice. Despite the markedly increased levels of leptin receptor in their circulation, LIRKO mice exhibit normal or even enhanced leptin sensitivity, as assessed by their physiological and molecular responses to exogenous leptin administration and their lower base-line hypothalamic levels of SOCS3 mRNA. Thus, insulin signaling in the liver plays an important role in control of leptin receptor expression and shedding. In the LIRKO mouse, this is lost, leading to markedly increased leptin receptors into the circulation. These high levels of circulating leptin receptor bind leptin and likely alter its clearance, but do not inhibit leptin action and may actually potentiate leptin action. In this manner, insulin signaling in liver plays an important role in leptin homeostasis and fine modulation of leptin action.

Novel regulatory mechanisms for generation of the soluble leptin receptor: implications for leptin action.

Background The adipokine leptin realizes signal transduction via four different membrane-anchored leptin receptor (Ob-R) isoforms in humans. However, the amount of functionally active Ob-R is affected by constitutive shedding of the extracellular domain via a so far unknown mechanism. The product of the cleavage process the so-called soluble leptin receptor (sOb-R) is the main binding protein for leptin in human blood and modulates its bioavailability. sOb-R levels are differentially regulated in metabolic disorders like type 1 diabetes mellitus or obesity and can, therefore, enhance or reduce leptin sensitivity. Methodology/Principal Findings To describe mechanisms of Ob-R cleavage and to investigate the functional significance of differential sOb-R levels we established a model of HEK293 cells transiently transfected with different human Ob-R isoforms. Using siRNA knockdown experiments we identified ADAM10 (A Disintegrin And Metalloproteinase 10) as a major protease for constitutive and activated Ob-R cleavage. Additionally, the induction of lipotoxicity and apoptosis led to enhanced shedding shown by increased levels of the soluble leptin receptor (sOb-R) in cell supernatants. Conversely, high leptin concentrations and ER stress reduced sOb-R levels. Decreased amounts of sOb-R due to ER stress were accompanied by impaired leptin signaling and reduced leptin binding. Conclusions Lipotoxicity and apoptosis increased Ob-R cleavage via ADAM10-dependent mechanisms. In contrast high leptin levels and ER stress led to reduced sOb-R levels. While increased sOb-R concentrations seem to directly block leptin action, reduced amounts of sOb-R may reflect decreased membrane expression of Ob-R. These findings could explain changes of leptin sensitivity which are associated with variations of serum sOb-R levels in metabolic diseases.

Pharmacokinetics and pharmacodynamics of GH: dependence on route and dosage of administration

OBJECTIVE Pharmacokinetic and pharmacodynamic data after recombinant human GH (rhGH) administration in adults are scarce, but necessary to optimize replacement therapy and to detect doping. We examined pharmacokinetics, pharmacodynamics, and 20 kDa GH after injection of rhGH at different doses and routes of administration. DESIGN Open-label crossover study with single boluses of rhGH. METHODS Healthy trained subjects (10 males, 10 females) received bolus injections of rhGH on three occasions: 0.033 mg/kg s.c., 0.083 mg/kg s.c., and 0.033 mg/kg i.m. Concentrations of 22 and 20 kDa GH, IGF-I, and IGF-binding proteins (IGFBP)-3 were measured repeatedly before and up to 36 h after injection. RESULTS Serum GH maximal concentration (Cmax) and area under the time-concentration curve (AUC) were higher after i.m. than s.c. administration of 0.033 mg/kg (Cmax 35.5 and 12.0 microg/l; AUC 196.2 and 123.8). Cmax and AUC were higher in males than in females (P < 0.01) and pharmacodynamic changes were more pronounced. IGFBP-3 concentrations showed no dose dependency. In response to rhGH administration, 20 kDa GH decreased in females and remained suppressed for 14-18 h (low dose) and 30 h (high dose). In males, 20 kDa GH was undetectable at baseline and throughout the study. CONCLUSIONS After rhGH administration, pharmacokinetic parameters are mainly influenced by route of administration, whereas pharmacodynamic variables and 20 kDa GH concentrations are determined mainly by gender. These differences need to be considered for therapeutic use and for detection of rhGH doping.

Cerebrospinal Fluid Melanin-Concentrating Hormone (MCH) and Hypocretin-1 (HCRT-1, Orexin-A) in Alzheimer’s Disease

Ancillary to decline in cognitive abilities, patients with Alzheimer’s disease (AD) frequently suffer from behavioural and psychological symptoms of dementia (BPSD). Hypothalamic polypeptides such as melanin-concentrating hormone (MCH) and hypocretin-1 (HCRT-1, orexin-A) are promoters of sleep-wake regulation and energy homeostasis and are found to impact on cognitive performance. To investigate the role of MCH and HCRT-1 in AD, cerebrospinal fluid (CSF) levels were measured in 33 patients with AD and 33 healthy subjects (HS) using a fluorescence immunoassay (FIA). A significant main effect of diagnosis (F(1,62) = 8.490, p<0.01) on MCH levels was found between AD (93.76±13.47 pg/mL) and HS (84.65±11.40 pg/mL). MCH correlated with T-tau (r = 0.47; p<0.01) and P-tau (r = 0.404; p<0.05) in the AD but not in the HS. CSF-MCH correlated negatively with MMSE scores in the AD (r = −0.362, p<0.05) and was increased in more severely affected patients (MMSE≤20) compared to HS (p<0.001) and BPSD-positive patients compared to HS (p<0.05). In CSF-HCRT-1, a significant main effect of sex (F(1,31) = 4.400, p<0.05) with elevated levels in females (90.93±17.37 pg/mL vs. 82.73±15.39 pg/mL) was found whereas diagnosis and the sex*diagnosis interaction were not significant. Elevated levels of MCH in patients suffering from AD and correlation with Tau and severity of cognitive impairment point towards an impact of MCH in AD. Gender differences of CSF-HCRT-1 controversially portend a previously reported gender dependence of HCRT-1-regulation. Histochemical and actigraphic explorations are warranted to further elucidate alterations of hypothalamic transmitter regulation in AD.

Serum levels of adipocyte fatty acid binding protein are increased in gestational diabetes mellitus

OBJECTIVE Adipocyte fatty acid binding protein (AFABP) was recently introduced as a novel adipokine, serum levels of which independently correlate with the development of the metabolic syndrome and cardiovascular disease in humans. In the current study, we investigated serum concentrations of AFABP in patients with gestational diabetes mellitus (GDM) as compared with healthy pregnant controls matched for gestational age and fasting insulin. DESIGN AND METHODS AFABP was determined by ELISA in controls (n=80) and GDM patients (n=40) and correlated to clinical and biochemical measures of renal function, glucose and lipid metabolism, as well as inflammation, in both groups. RESULTS Median serum AFABP concentrations were significantly elevated in subjects with GDM (22.9 microg/l) as compared with healthy pregnant controls (18.3 microg/l; P<0.05). Furthermore, GDM was independently associated with AFABP concentrations in multiple regression analysis (P<0.05). In addition, markers of adiposity (body mass index, serum leptin), triglycerides and serum creatinine were independently associated with circulating AFABP (P<0.05). CONCLUSIONS Maternal AFABP concentrations are significantly increased in GDM. The adipokine might contribute to the increased metabolic and cardiovascular risk of the disease.