RESEARCH AIM:Nicotinamide phosphoribosyltransferase (Nampt) is an adipocytokine that is elevated in obesity, type 2 diabetes and increased levels are associated with inflammatory processes. Nampt serum concentrations have been suggested to follow a diurnal rhythm peaking in the afternoon in lean males. However, no data exists regarding the effects of gender and body weight. MATERIAL AND METHODS:We measured Nampt serum levels over 24 h in a cohort of healthy individuals living with either normal weight or obesity. Furthermore, effects of meals, oral glucose tolerance test and physical exercise on Nampt concentrations were evaluated. Correlation analyses to other hormonal- and lab parameters and anthropometric measurements were performed. RESULTS:Nampt showed a diurnal rhythm with increased levels at daytime and a peak in the early afternoon. This diurnal rhythm was significant for all groups but obese males. The Nampt amplitude, measured both relatively and absolutely, was significantly higher in females than in males. Meals did not influence Nampt serum levels, whereas physical exercise and an OGTT did significantly influence Nampt serum levels. CONCLUSION:In conclusion, we found gender specific differences in Nampt amplitude and coefficient variation with both being higher in females. The circadian rhythm of Nampt was independent of gender in healthy lean individuals, whereas it was disturbed in men with obesity.

Abstract Background Accumulating evidence suggests a relationship between sleep alterations and overweight/obesity in children. Our aim was to investigate the association of sleep measures other than obstructive sleep apnea or sleep duration with overweight/obesity and metabolic function in children. Methods We conducted a prospective cohort study in school- aged children (aged 5 to 8 years, prepubertal, and 12 to 15 years, pubertal) with overweight/obesity and normal-weight children. All children underwent a standardized in-laboratory polysomnography followed by a fasting blood assessment for glucose and metabolic testing. Subjective sleep measures were investigated by a 7-day sleep diary and questionnaire. We analyzed prepubertal and pubertal groups separately using logistic regression and partial correlation analyses. Results A total of 151 participants were analyzed. Overweight/obese children had significantly higher odds for arousal index (prepubertal children: 1.28, Confidence interval (CI): 1.06, 1.67; pubertal children: 1.65, CI: 1.19, 2.29) than normal-weight children, independent of age and gender. In prepubertal children, arousal-index was positively associated with C-peptide (r=0.30, p=0.01), whereas Minimum O2 saturation was negatively associated with triglycerides (r=−0.34, p=0.005), adjusting for age and sex. However, associations were attenuated by further adjustment for body mass index standard deviation scores (BMI-SDS). In pubertal children, higher level of apnea-hypopnea-index and pCO2 predicted increased lipoprotein (a) levels (r=0.35, p=0.03 and r=0.40, p=0.01, respectively), independent of age, sex, and BMI-SDS. A negative association was found between pCO2 and high-density lipoprotein (HDL)-cholesterol (r=−0.40, p=0.01). Conclusions Overall, we report that sleep quality as measured by arousal index may be compromised by overweight and obesity in children and warrants attention in future intervention programs.

Nicotinamide phosphoribosyl transferase (NAMPT) is an inflammatory adipocytokine shown to interact in immune modulation in chronic inflammatory diseases, acute respiratory distress syndrome, sepsis, cancer and obesity in adulthood. It is, however, not clear whether this association reflects a chronic elevation or acute inflammatory response. We analyzed NAMPT concentrations in distinct states of inflammation in 102 children and found consistently significantly increased NAMPT levels in subjects with acute infections. NAMPT concentrations in children with stable chronic inflammatory diseases were not significantly different, whereas in patients with acute relapse of chronic disease NAMPT was significantly higher than in children in remission or healthy controls. In states of low-grade inflammation (children with atopic disease or obesity) we did not detect alterations in NAMPT serum levels. NAMPT correlated positively with inflammatory markers such as CRP. The most predictive factor for NAMPT serum concentrations was leucocyte count and therein the neutrophil count. Furthermore, systemic circulating NAMPT levels were closely associated with NAMPT release from corresponding cultured PBMCs. In conclusion, NAMPT is selectively increased in states of acute but not chronic inflammation in children. The close relationship between systemic circulating NAMPT with leucocyte counts and release indicate that leucocytes most probably are the source of inflammation related NAMPT levels.

CONTEXT:Leptin secreted from adipose tissue signals peripheral energy status to the brain. Monogenic leptin deficiency results in severe early onset obesity with hyperphagia. Recently, a similar phenotype of inactivating leptin mutations but with preserved immunoreactivity and hence normal circulating immunoreactive leptin has been reported.OBJECTIVE:We aimed to evaluate the proportion of bioactive leptin serum levels (compared to immunoreactive leptin) as a biomarker for the screening of leptin gene mutations causing monogenic obesity. Furthermore, we aimed to compare the immunoreactive and bioactive leptin levels associations with parameters of insulin resistance and insulin secretion in obese children and adolescents.PATIENTS AND METHODS:We measured bioactive and immunoreactive leptin levels by enzyme-linked immunosorbent assays in fasting serum samples of 70 children with severe (BMI SDS >3) non-syndromic obesity with onset <3 years of life from our Leipzig childhood obesity cohort (n = 1204). Sanger sequencing of the leptin gene was performed in probands with proportion of bioactive/immunoreactive leptin <90%.RESULTS:The mean levels of bioactive and immunoreactive leptin were almost identical (41.1±25.2 vs. 41.1±25.4ng/mL). In three probands with the lowest bioactive leptin proportion (<90%) we did not identify mutations in the leptin gene. Compared to immunoreactive leptin, bioactive leptin showed similar and slightly better statistical associations with indices of insulin resistance in correlation and multivariate analyses.CONCLUSION:In our sample selected for severe early onset childhood obesity, we did not identify leptin gene mutations leading to decreased proportion of bioactive leptin. Nevertheless, the bioactive leptin levels were stronger associated with selected insulin secretion/resistance indices than the immunoreactive leptin levels.

BACKGROUND:Adipokines have been implicated in obesity, insulin resistance and sleep regulation. However, the role of chemerin and progranulin, two recently described adipokines, in the context of sleep remains unclear. The aim of this study was to compare nocturnal serum chemerin and progranulin levels between overweight/obese and normal-weight adolescents and to assess variations by sex, across different sleep stages and in relation to glucose metabolism.METHODS:The study sample included 34 overweight/obese and 32 normal-weight adolescents from secondary schools and the Leipzig Research Center for Civilization Diseases (LIFE) Child study cohort. We obtained longitudinal serum adipokine levels during in-laboratory polysomnography followed by an oral glucose tolerance test.RESULTS:Overweight/obese adolescents had significantly higher mean nocturnal serum chemerin area under the curve (AUC) levels (348.2±133.3 vs. 241.7±67.7 vs. ng/mL×h, p<0.001) compared to normal-weight controls. In detail, higher chemerin AUC levels in obese/overweight subjects were exclusively due to increased levels in females. No overall difference for serum progranulin AUC was found between the groups. However, when assessing sex-specific levels, serum progranulin AUC levels were ~30% higher in overweight/obese males compared to overweight/obese females. Of note, nocturnal serum chemerin and progranulin AUC did not exhibit a correlation with markers of glucose metabolism or sleep stages.CONCLUSIONS:Collectively, we report a sexual dimorphism in nocturnal progranulin and chemerin levels, which may help explain underlying differences in energy balance and body composition between males and females in the context of obesity.

Childhood obesity is associated with changes in myocardial geometry and function indicating early onset of unfavorable alterations of the myocardium [(1,2)][1]. The value of those studies is limited by a cross-sectional study design. We aimed to assess the impact of weight reduction on temporal

Insulin-like peptide 5 (INSL5) is a gut hormone produced by L-cells in the colorectal epithelium and may play a role in the regulation of metabolic processes. The biological role of INSL5 is poorly investigated and nothing is known about the role of this hormone in obese and lean humans. Two cohorts were analyzed in the study. In the first cohort (n=76) the relationship between serum levels of INSL5 and different metabolic and hormonal parameters in obese and lean men and women were investigated. In the second cohort 14 male subjects underwent bariatric surgery. Circulating levels of INSL5 were then measured before and after interventions.We report for the first time that circulating INSL5 interacts with multiple metabolic and hormonal variables in lean and obese men and women and is affected by bariatric surgery. Serum levels of INSL5 negatively correlated with testosterone and blood lipids but positively with cortisol in obese men. In contrast to males, obese women had a strong negative correlation of plasma levels of INSL5 with C-reactive protein (CRP). We observed that adipose tissue loss after bariatric surgery significantly reduced serum levels of INSL5 in obese men with and without Type 2 Diabetes Mellitus (T2DM) that was associated with the restoration of circulating levels of testosterone. All together, our data demonstrated that INSL5 may interact with some metabolic parameters in obese humans and this process is dependent of gender and obesity state.

CONTEXT Osteopontin (OPN) has been proposed to predict adverse cardiac events in patients with adult type 2 diabetes. OBJECTIVE We investigated potential associations of circulating OPN and OPN expression in adipose tissue (AT) with obesity and early metabolic and cardiovascular dysfunction in children. Furthermore, we assessed the functional relevance of OPN on primary human endothelial cells. DESIGN Serum OPN was determined in healthy lean (n = 65) and obese (n = 100) children by ELISA. Expression levels were assessed in sc AT samples from healthy lean (n = 33) and overweight and obese (n = 31) children by qRT-PCR. Direct effects of recombinant (rh) OPN on adhesion molecule and ENOS expression were assessed in human coronary arterial endothelial cells. RESULTS OPN serum concentrations decreased with pubertal development in lean children. The degree of obesity was negatively associated with OPN serum levels. Multiple regression analysis revealed that body mass index (BMI) standard deviation score (SDS), next to pubertal status, was the strongest independent predictor for OPN serum concentrations. Metabolically, the homeostasis model assessment index and circulating plasma insulin were negatively correlated with OPN serum levels secondary to obesity. In contrast, independent from BMI, OPN was positively related to VCAM-1 levels, intima media thickening, and negatively associated with endothelial function. Functionally, full-length rhOPN did not affect adhesion molecule and ENOS mRNA expression in primary human coronary arterial endothelial cells. In addition, OPN expression levels in AT positively correlated with BMI SDS, AT inflammation, and markers of metabolic dysfunction but were not related to OPN serum levels. CONCLUSION Our findings suggest that OPN levels are BMI-independently related to markers of early endothelial dysfunction in children.

Qi, Qibin; Downer, Mary K; Oskari Kilpeläinen, Tuomas; Taal, H Rob; Barton, Sheila J; Ntalla, Ioanna; Standl, Marie; Boraska, Vesna; Huikari, Ville; Kiefte-de Jong, Jessica C; Körner, Antje; Lakka, Timo A; Liu, Gaifen; Magnusson, Jessica; Okuda, Masayuki; Raitakari, Olli; Richmond, Rebecca; Scott, Robert A; Bailey, Mark E S; Scheuermann, Kathrin; Holloway, John W; Inskip, Hazel; Isasi, Carmen R; Mossavar-Rahmani, Yasmin; Jaddoe, Vincent W V; Laitinen, Jaana; Lindi, Virpi; Melén, Erik; Pitsiladis, Yannis; Pitkänen, Niina; Snieder, Harold; Heinrich, Joachim; Timpson, Nicholas J; Wang, Tao; Yuji, Hinoda; Zeggini, Eleftheria; Dedoussis, George V; Kaplan, Robert C; Wylie-Rosett, Judith; Loos, Ruth J F; Hu, Frank B; Qi, Lu

ZusammenfassungDie Pathogenese der hypothalamen Adipositas ist vielfältig und beinhaltet neben der Hyperphagie auch einen vermindertem Grundumsatz, autonome Fehlregulationen als auch Schlafstörungen und eine verminderte Mobilität. Resultierend daraus existieren verschiedene Therapiekonzepte. Bisher konnte jedoch weder für den konservativ-medikamentösen Ansatz als auch für den bariatrisch-chirurgischen Therapieansatz eine allgemeingültige Empfehlung gegeben werden. Am vorliegenden Fallbericht möchten wir noch einmal die Komplexität der Erkrankungen und die Schwierigkeit sinnvoller Therapieentscheidungen darstellen.

RATIONALE:The newly discovered myokine irisin has been proposed to affect obesity and metabolism by promoting browning of white adipose tissue. However, clinical and functional studies on the association of irisin with obesity, muscle mass, and metabolic status remain controversial. Here we assessed the effect of 4 distinct exercise regimens on serum irisin levels in children and young adults and systematically evaluated the influence of diurnal rhythm, anthropometric and metabolic parameters, and exercise on irisin.RESULTS:Serum irisin levels did not show diurnal variations, nor were they affected by meal intake or defined glucose load during oral glucose tolerance testing. Irisin levels decreased with age. In adults, irisin levels were higher in men than in women, and obese subjects had significantly higher levels than lean control subjects. Irisin levels were closely correlated with muscle-associated bioimpedance parameters such as fat-free mass and body cell mass. Of the 4 exercise regimens that differed in duration and intensity, we identified a clear and immediate increase in serum irisin levels after acute strenuous exercise (cycling ergometry) and a 30-minute bout of intensive exercise in children and young adults, whereas longer (6 weeks) or chronic (1 year) increases in physical activity did not affect irisin levels.SUMMARY:We show that irisin levels are affected by age, sex, obesity, and particularly muscle mass, whereas diurnal rhythm and meals do not contribute to the variation in irisin levels. Short bouts of intensive exercise but not long-term elevations in physical activity, acutely and transiently increase serum irisin levels in children and adults.

The FTO gene harbors variation with the strongest effect on adiposity and obesity risk. Previous data support a role for FTO variation in influencing food intake. We conducted a combined analysis of 16,094 boys and girls aged 1–18 years from 14 studies to examine the following: 1) the association between the FTO rs9939609 variant (or a proxy) and total energy and macronutrient intake; and 2) the interaction between the FTO variant and dietary intake, and the effect on BMI. We found that the BMI-increasing allele (minor allele) of the FTO variant was associated with increased total energy intake (effect per allele = 14.3 kcal/day [95% CI 5.9, 22.7 kcal/day], P = 6.5 × 10−4), but not with protein, carbohydrate, or fat intake. We also found that protein intake modified the association between the FTO variant and BMI (interactive effect per allele = 0.08 SD [0.03, 0.12 SD], P for interaction = 7.2 × 10−4): the association between FTO genotype and BMI was much stronger in individuals with high protein intake (effect per allele = 0.10 SD [0.07, 0.13 SD], P = 8.2 × 10−10) than in those with low intake (effect per allele = 0.04 SD [0.01, 0.07 SD], P = 0.02). Our results suggest that the FTO variant that confers a predisposition to higher BMI is associated with higher total energy intake, and that lower dietary protein intake attenuates the association between FTO genotype and adiposity in children and adolescents.

The aim of our study was to assess geometric and functional changes of the heart in obese compared with nonobese children and adolescents.Obesity in children and adolescents has increased over the past decades and is considered a strong risk factor for future cardiovascular morbidity and mortality. Obesity has been associated with myocardial structural alterations that may influence cardiac mechanics.We prospectively recruited 61 obese (13.5 ± 2.7 years of age, 46% male sex, SD score body mass index, 2.52 ± 0.60) and 40 nonobese (14.1 ± 2.8 years of age, 50% male sex, SD score body mass index, -0.33 ± 0.83) consecutive, nonselected Caucasian children and adolescents. A standardized 2-dimensional (2D) echocardiography and 2D speckle-tracking analysis was performed in all children. Furthermore, blood chemistry including lipid and glucose metabolism was assessed in all children.Compared with nonobese children, blood pressure, low-density lipoprotein cholesterol, and parameters of glucose metabolism were significantly increased in obese children, whereas high-density lipoprotein cholesterol was significantly lower. Compared with nonobese children, obese children were characterized by enlarged left- and right-sided cardiac chambers, thicker left ventricular walls, and, consequently, increased left ventricular mass. Despite a comparable left ventricular ejection fraction, decreased tissue Doppler-derived peak systolic velocity and regional basoseptal strain were found in obese children compared with nonobese children. Beyond that, 2D speckle tracking-derived longitudinal (-18.2 ± 2.0 vs. -20.5 ± 2.3, p < 0.001) and circumferential (-17.0 ± 2.7 vs. -19.5 ± 2.9, p < 0.001) strain of the left ventricle was reduced in obese children compared with nonobese children. Diastolic function was also impaired in obese compared with nonobese children. Both longitudinal strain and circumferential strain were independently associated with obesity.The results of this study demonstrate that childhood obesity is associated with significant changes in myocardial geometry and function, indicating an early onset of potentially unfavorable alterations in the myocardium.

OBJECTIVES The aim of our study was to assess geometric and functional changes of the heart in obese compared with nonobese children and adolescents.BACKGROUND Obesity in children and adolescents has increased over the past decades and is considered a strong risk factor for future cardiovascular morbidity and mortality. Obesity has been associated with myocardial structural alterations that may influence cardiac mechanics.METHODS We prospectively recruited 61 obese (13.5 +/- 2.7 years of age, 46% male sex, SD score body mass index, 2.52 +/- 0.60) and 40 nonobese 04.1 +/- 2.8 years of age, 50% male sex, SD score body mass index, -0.33 +/- 0.83) consecutive, nonselected Caucasian children and adolescents. A standardized 2-dimensional (2D) echocardiography and 2D speckle-tracking analysis was performed in all children. Furthermore, blood chemistry including lipid and glucose metabolism was assessed in all children.RESULTS Compared with nonobese children, blood pressure, low-density Lipoprotein cholesterol, and parameters of glucose metabolism were significantly increased in obese children, whereas high-density lipoprotein cholesterol was significantly Lower. Compared with nonobese children, obese children were characterized by enlarged Left- and right-sided cardiac chambers, thicker Left ventricular walls, and, consequently, increased Left ventricular mass. Despite a comparable Left ventricular ejection fraction, decreased tissue Doppler-derived peak systolic velocity and regional basoseptal strain were found in obese children compared with nonobese children. Beyond that, 2D speckle tracking-derived longitudinal (-18.2 +/- 2.0 vs. -20.5 +/- 2.3, p < 0.001) and circumferential (-17.0 +/- 2.7 vs. 19.5 +/- 2.9, p < 0.001) strain of the left ventricle was reduced in obese children compared with nonobese children. Diastolic function was also impaired in obese compared with nonobese children. Both Longitudinal strain and circumferential strain were independently associated with obesity.CONCLUSIONS The results of this study demonstrate that childhood obesity is associated with significant changes in myocardial geometry and function, indicating an early onset of potentially unfavorable alterations in the myocardium. (C) 2014 by the American College of Cardiology Foundation.

Background: The new myokine irisin has been proposed to be secreted upon exercise to promote the browning of white adipose tissue, suggesting irisin as a treatment option for obesity and associated diseases. The proposed induction of irisin by activity is still conflicting.