Madlen Neef

Leucocytes are a major source of circulating nicotinamide phosphoribosyltransferase (NAMPT)/pre-B cell colony (PBEF)/visfatin linking obesity and inflammation in humans.

Aims/hypothesisNicotinamide phosphoribosyltransferase (NAMPT) is a multifunctional protein potentially involved in obesity and glucose metabolism. We systematically studied the association between circulating NAMPT, obesity, interventions and glucose metabolism and investigated potential underlying inflammatory mechanisms.MethodsFasting morning NAMPT serum levels were measured in cohorts of lean vs obese children, cohorts of intervention by lifestyle, exercise and bariatric surgery, and during an OGTT. In addition, mRNA expression, protein production and enzymatic activity of NAMPT were assessed from isolated leucocytes and subpopulations.ResultsCirculating NAMPT was significantly elevated in obese compared with lean children and declined after obesity interventions concomitantly with the decline in BMI, high-sensitivity C-reactive protein (hsCrP) and leucocyte counts. Circulating NAMPT significantly correlated with glucose metabolism and cardiovascular variables in univariate analyses, but only the association with glucose response during an OGTT was independent from BMI. We therefore assessed the NAMPT dynamic following an oral glucose load and found a significant decline of NAMPT levels to 77.0 ± 0.1% as a function of time, and insulin-to-glucose ratio during an OGTT in obese insulin-resistant adolescents. Circulating NAMPT was, however, most strongly associated with leucocyte counts (r = 0.46, p < 0.001). The leucocyte count itself determined significantly and independently from BMI insulin resistance in multiple regression analyses. We systematically evaluated NAMPT expression among several tissues and found that NAMPT was predominantly expressed in leucocytes. In subsequent analyses of leucocyte subpopulations, we identified higher NAMPT protein concentrations in lysates of granulocytes and monocytes compared with lymphocytes, whereas granulocytes secreted highest amounts of NAMPT protein into cell culture supernatant fractions. We confirmed nicotinamide mononucleotide enzymatic activity of NAMPT in all lysates and supernatant fractions. In monocytes, NAMPT release was significantly stimulated by lipopolysaccharide (LPS) exposure.ConclusionsLeucocytes are a major source of enzymatically active NAMPT, which may serve as a biomarker or even mediator linking obesity, inflammation and insulin resistance.

Vaspin is related to gender, puberty and deteriorating insulin sensitivity in children

Background:Visceral adipose tissue-derived serine protease inhibitor (vaspin) has been suggested as a novel adipocytokine related to obesity and insulin sensitivity in adults.Design:We quantified vaspin serum concentrations in 65 lean and 67 obese children and aimed to evaluate the relationship of vaspin with physical development, obesity, and metabolic and cardiovascular phenotypes in children. We further assessed the acute vaspin response to glucose provocation in 20 obese adolescents and evaluated tissue expression patterns of vaspin in humans.Results:Vaspin levels were significantly higher in girls than in boys. In girls, vaspin increased with age and pubertal stage, whereas there was no change with development in boys. Obese girls had lower vaspin serum levels than those of lean controls, but there was no significant correlation with body mass index (BMI). Independent of sex, age and BMI, lower vaspin was associated with better insulin sensitivity, with higher systolic blood pressure and impaired endothelial function. In response to glucose provocation during an oral glucose tolerance test, vaspin serum levels declined by approximately 25% in adolescents with hyperinsulinemia, whereas there was no significant decline in normoinsulinemic patients. In support of our clinical data, we not only confirmed vaspin mRNA expression in adipose tissue but also found consistent expression of vaspin in the liver and indications for expression in the pancreas and the skin.Conclusion:We showed that gender differences in circulating vaspin levels develop during pubertal progression in girls. Although vaspins association with obesity remains controversial, vaspin was increased with worsening insulin resistance already in children and was acutely down-regulated following glucose provocation in insulin-resistant adolescents independent of obesity. Besides adipose tissue, vaspin expression in the liver and the pancreas may potentially contribute to circulating vaspin levels and their regulation.

Retinol binding protein 4 (RBP4) is primarily associated with adipose tissue mass in children

OBJECTIVE Retinol binding protein 4 (RBP4) is a novel adipocytokine that may link obesity and insulin resistance. We aimed to discriminate between primary and secondary associations of RBP4 with obesity and related disease. DESIGN We applied clinical and experimental approaches to investigate the association of RBP4 levels with normal development, obesity, metabolic and cardiovascular parameters in 68 lean and 61 obese children. RESULTS RBP4 significantly increased with age and pubertal development in healthy lean children. Obese children had significantly higher RBP4 levels compared with lean controls (30.5±1.4 vs. 26.3±1.1 mg/L, P<0.05) and there was a clear association with BMI independent of age (r=0.33, P<0.0001). RBP4 levels correlated significantly with parameters of lipid and glucose metabolism, as well as cardiovascular parameters in univariate analyses. Multiple regression analyses confirmed the strong association of RBP4 with BMI z-score and age, while the association with most metabolic and cardiovascular parameters was abolished. To assess whether the association of RBP4 with obesity may be attributable to adipogenesis, we evaluated RBP4 expression and secretion during adipocyte differentiation using the human SGBS cell line. In preadipocytes, RBP4 mRNA expression was nearly undetectable but increased during differentiation up to approximately 1600-fold (P<0.05). Likewise, RBP4 secretion was restricted to mature adipocytes, further indicating that RBP4 is strongly related to differentiation of adipocytes. CONCLUSION RBP4 is a marker of adipose tissue mass and obesity already evident in children. The association of RBP4 with metabolic and cardiovascular sequelae of obesity appears to be secondary to the underlying relationship wtih body fat.

Health impact in children and adolescents

Obesity in children and adolescents is associated with multiple comorbidities, including metabolic, cardiovascular, gastrointestinal, pulmonary, orthopedic and psychological disorders. In fact, cardiovascular and metabolic impairments in childhood and adolescence constitute major risk factors for developing cardiovascular disease in adulthood. Thus, obesity in childhood and adolescence leads to a higher morbidity and mortality in adulthood. Therefore, strong emphasis must be laid on the prevention and therapy of childhood obesity. Treatment requires a multidisciplinary and multiphase approach including dietary management, physical activity, pharmacotherapy and bariatric surgery. This paper reviews the different comorbidities of childhood obesity supporting the notion of a multidisciplinary therapy concept.

Perception of Body Weight Status: A Case Control Study of Obese and Lean Children and Adolescents and Their Parents

Background: The objective of this study was to investigate differences in weight perception and self-concept of obese and lean children, and to examine parents’ awareness of overweight in themselves and their children. A total of 59 obese patients aged 7–17 years and 49 of their parents from a pediatric obesity out-patient clinic participated and were compared with 96 normalweight patients and 81 of their parents from a pediatric pulmonary disease out-patient clinic. Methods: Children’s and parents’ self-perception of weight, desire for weight change and weight concerns, children’s belief that their desired weight can be achieved, and parents’ perception of their child’s weight status were assessed using single questionnaire items. Children’s self-concept was measured by the Self-Perception Profile for Children. In addition, children drew pictures about themselves and their favorite activity. Results: Obese patients wished to change their weight more frequently (p < 0.001) and had more weight concerns (p < 0.001). Their self-concept was significantly more negative. Physical activities were more common in their drawings than in those of normal-weight peers. Parents of obese children were more frequently overweight or obese themselves (p < 0.001). 35 of them and 73 parents of normal-weight children perceived their own weight realistically. Of the parents with overweight or obese children, 69.4% perceived their own child as overweight and 28.6% as very overweight, whereas 83% of them were obese. Conclusion: Children and adolescents as well as their parents recognize overweight as a health problem. In the majority, weight perception matches real body weight. Most parents at least recognize overweight in their children.

Childhood obesity at the crossroads

Overweight and obesity is frequently seen in children and adolescents across most developed, and developing, countries with a 20–35% prevalence. Although the prevalence of obesity at a young age seems to stabilise or even slightly decline in some countries, the number of adolescents with obesity is still increasing (1). This is a major concern, considering the well-described association of overweight and obesity with long-term health problems, such as cardiovascular disease, type 2 diabetes and cancer. In the majority of individuals, weight gain is the result of exposure to an ‘obesogenic’ environment, superimposed on a background of genetic susceptibility brought about through evolutionary adaptation (2). Approximately 40–70% of inter-individual differences in body weight and fat content is thought to be due to genetic variation (3). A large number of genes have been identified by genome wide association studies (GWAS) and candidate gene approaches that are associated with the regulation of body weight. According to the thrifty gene hypothesis, evolutionary selection pressure has selected genes which allow individuals to survive periods of food deprivation. Within our modern obesogenic environment, however, these same genetic susceptibility traits now appear to be detrimental by promoting obesity and its associated metabolic diseases (2). In this issue of our journal, three review papers, one on behavioural aspects of obesity (4), one on hypothalamic forms of obesity (5) and lastly and importantly one on the role of obesigenic environments address the important public health issue of childhood obesity. These reviews are followed by a series of papers that have been submitted recently to the journal and which cover a wide range of childhood obesity related topics mainly dealing with cardiovascular and metabolic sequelae of obesity. Scientific dilemma

Reciprocal Associations between Electronic Media Use and Behavioral Difficulties in Preschoolers

The use of electronic media has increased substantially and is already observable in young children. The present study explored associations of preschoolers’ use of electronic media with age, gender, and socio-economic status, investigated time trends, and examined reciprocal longitudinal relations between children’s use of electronic media and their behavioral difficulties. The study participants included 527 German two- to six-year-old children whose parents had provided information on their use of electronic media and their behavioral difficulties at two time points, with approximately 12 months between baseline and follow-up. The analyses revealed that older vs. younger children, as well as children from families with a lower vs. higher socio-economic status, were more often reported to use electronic media. Furthermore, the usage of mobile phones increased significantly between 2011 and 2016. Most interestingly, baseline usage of computer/Internet predicted more emotional and conduct problems at follow-up, and baseline usage of mobile phones was associated with more conduct problems and hyperactivity or inattention at follow-up. Peer relationship problems at baseline, on the other hand, increased the likelihood of using computer/Internet and mobile phones at follow-up. The findings indicate that preschoolers’ use of electronic media, especially newer media such as computer/Internet and mobile phones, and their behavioral difficulties are mutually related over time.

Metabolic syndrome in childhood and adolescence.

62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 U N C O R R E C The prevalence of obesity in childhood and adolescence is still increasing in many countries around the world or has reached stable albeit very high levels in others. Whether or not the term ‘metabolic syndrome’ adds to our understanding of the causes and consequences of obesity is uncertain and open for debate. There is also a vivid discussion about the criteria for the definition of themetabolic syndrome and their putative predictive power for co-morbidities. In order to establish a uniform working diagnostic tool for the metabolic syndrome that can be conveniently used in clinical practice world-wide and enable a comparison of data from different countries, a consensus was reached and a respective report has been issued by an international working group that included experts in the fields of diabetes, public health, epidemiology, lipidology, genetics, metabolism, nutrition and cardiology. According to this report, obesity, high blood pressure and disturbed lipid and glucose metabolism are among the diagnostic criteria of metabolic syndrome. Inclusion of sleep-disordered breathing and sleep apnoea into a definition of metabolic syndrome is controversial once children and/or adolescents are affected. Nevertheless, childhood obesity is associated with sleepdisordered breathing in many obese children and adolescents. Alongwith the high prevalence of childhoodobesity, theprevalence of themetabolic syndrome in obese children is reported to be approximately 30%, irrespective of the definition applied. Recent research on potential factors that may contribute to the emerging of co-morbidities of childhood obesity has yielded new and exciting findings. The adipocytokines, hormones synthesized and secreted from adipocytes, appear to be important in this respect. Leptin, a hormone secreted from the adipose tissue and signalling to specific receptors not only in the central nervous system but also in peripheral organs, was initially suggested as a promising “anti-obesity” compound. However, new concepts indicate that, in humans, leptin and its soluble receptor may be more important in states of energy deficiency rather than serving as predictors of the metabolic syndrome. Another adipocytokine, termed adiponectin, on the other hand, is not only related to obesity and insulin resistance, but appears to be the strongest predictor for metabolic syndrome, even in children. In newborns and infants, both adipocytokines occur in high concentrations, even though this cannot completely explain the increased risk for ensuing metabolic disease later in life. In recent years, a number of additional signalling molecules secreted by adipose tissue such as resistin,

Do adolescents with extreme obesity differ according to previous treatment seeking behavior? The Youth with Extreme obesity Study (YES) cohort

ObjectivesAdolescent extreme obesity is associated with somatic and psychiatric comorbidity, low quality of life, and social dysfunction. Nevertheless, few adolescents seek obesity treatment, thus many may elope appropriate care. We examine whether previous treatment seeking relates to disease burden, and whether previously non-treatment seeking adolescents accept diagnostic and therapeutic offers. This information is important to inform intervention strategies.MethodsThe Youth with Extreme obesity Study (YES) is a prospective, multicenter cohort study. We developed a novel recruitment strategy to span medical and vocational ascertainment settings and directly compare previously treatment seeking and non-treatment seeking youth. Participants aged 14–24 years; BMI ≥ 30 kg/m2 were enrolled at four medical- and one job centers. We present comorbidity and psycho-social baseline data by sex, obesity WHO grade I-III, and treatment-seeking status, defined as self-reported previous participation in a weight-loss program.ResultsOf 431 participants, 47% were male; mean age 16.6 (standard deviation 2.3) years, BMI 39.2 (7.5) kg/m2. Somatic comorbidity increased with obesity grade, p < 0.05: hypertension (42, 55, 64%), dyslipidemia (28, 24, 37%,), dysglycemia (9, 19, 20%,), elevated transaminases (15, 26, 30%). Quality of life (EQ5 D) decreased (74, 71, 70). Rates of psychiatric disorders were stable: depression 11%, attention deficit disorder 6%, substance use disorder 2%, self-injurious behavior 5%, suicide attempt 3%. Only 63% (56, 64, 69%) reported previous treatment seeking. Acceptance of the diagnostic (89%) or therapeutic (28%) program, medical or psychosocial situation did not differ by treatment seeking status. Acceptance of the therapeutic program was generally low, but high at the job center (92%).ConclusionIrrespective of previous treatment seeking, adolescent extreme obesity was associated with high comorbidity and psychosocial burden. Acceptance of the diagnostic program overall and the therapeutic program at the job center were high. This underscores the need of innovative, accessible programs beyond the currently offered care.