Susann Blüher

Leptin in humans: lessons from translational research

Leptin has emerged over the past decade as a key hormone in not only the regulation of food intake and energy expenditure but also in the regulation of neuroendocrine and immune function as well as the modulation of glucose and fat metabolism as shown by numerous observational and interventional studies in humans with (complete) congenital or relative leptin deficiency. These results have led to proof-of-concept studies that have investigated the effect of leptin administration in subjects with complete (congenital) leptin deficiency caused by mutations in the leptin gene as well as in humans with relative leptin deficiency, including states of lipoatrophy or negative energy balance and neuroendocrine dysfunction, as for instance seen with hypothalamic amenorrhea in states of exercise-induced weight loss. In those conditions, most neuroendocrine, metabolic, or immune disturbances can be restored by leptin administration. Leptin replacement therapy is thus a promising approach in several disease states, including congenital complete leptin deficiency, states of energy deprivation, including anorexia nervosa or milder forms of hypothalamic amenorrhea, as well as syndromes of insulin resistance seen in conditions such as congenital or acquired lipodystrophy. In contrast, states of energy excess such as garden-variety obesity are associated with hyperleptinemia that reflects either leptin tolerance or leptin resistance. For those conditions, development of leptin sensitizers is currently a focus of pharmaceutical research. This article summarizes our current understanding of leptins role in human physiology and its potential role as a novel therapeutic option in human disease states associated with a new hormone deficiency, ie, leptin deficiency.

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.

Leptin in reproduction.

Purpose of reviewLeptin, a key hormone in energy homeostasis and neuroendocrine function, has a permissive role in initiating puberty and is crucial in the pathogenesis of reproductive dysfunction in several disease states of energy imbalance. KiSS1 neurons have recently been suggested to mediate leptins effect on the reproductive system. New insights from recent animal studies and clinical trials are discussed. Recent findingsAlterations in the expression profile of the KiSS1 gene and the kisspeptin receptor have been linked to reproductive dysfunction in leptin-deficient states. Neuroendocrine, including reproductive, dysfunction can be restored in humans and animals by leptin-replacement therapy. These insights have significantly advanced our understanding of hormonal systems needed to maintain normal reproduction. These data, if confirmed, also suggest a role for leptin as a novel therapeutic approach in several disease states. SummaryRecent proof-of-concept studies involving leptin administration to humans underline the critical role of leptin not only in regulating energy homeostasis, but also in maintaining normal reproductive function. Leptin-replacement therapy is currently under intensive investigation as a potential novel therapeutic option for several conditions associated with reproductive dysfunction due to hypoleptinemia.

Age-specific stabilization in obesity prevalence in German children: A cross-sectional study from 1999 to 2008

OBJECTIVE Trends of overweight (ov)/obesity (ob) prevalence among German children aged 4-16 years were studied between 1999 and 2008. SUBJECTS Body mass index (BMI) data (>P90 [ov] and >P97 [ob]) from the national CrescNet database were analysed in three age groups: 4-7.99, 8-11.99, and 12-16 years. RESULTS Trend analyses. Data from 272 826 children were analyzed. a) Whole study population aged 4-16 years old. A significant upward trend for ov/ob prevalence was found between 1999 and 2003, and a significant downward trend between 2004 and 2008. b) Subgroup analyses. Ov/Ob prevalence increased in most subgroups studied until 2004. Between 2004 and 2008, a downward trend for ov/ob prevalence was found in children, aged 4-7.99 years, whereas it stabilized in most other subgroups studied. Cross-sectional analyses. Data from 93 028 children were analyzed. Ov/ob prevalence was significantly higher in 2004 compared with 2000 in girls aged 12-16 years and in boys aged 8-16 years. Ov/ob obesity prevalence was significantly lower in 2008 compared with 2004 in children aged 4-7.99 years. CONCLUSION Ov/ob prevalence increased between 1999 and 2003 in German children. Since 2004, this trend has been stabilizing or turning into a downward trend. Our data confirm the global trend of stabilizing prevalence rates of childhood obesity at a high level and add important information for individual age groups. Intervention programs targeted to prevent childhood obesity may have had beneficial effects, and a new balance between factors favouring obesity and those favouring leanness may have been reached recently. Age- and gender-specific differences found in trends of ov/ob prevalence may help optimise preventive and therapeutic measures.

Adipocytes and adipose tissue

An epidemic of obesity is taking place in most societies around the world. Overall obesity substantially increases the risk of subsequent morbidity. In children and adolescents the degree of body fat mass depends upon ethnic background, gender, developmental stage and age. Obesity is characterized by increases in the number or size of fat cells, or a combination of both. It is generally believed that the number of fat cells depends on age of onset and degree of obesity. This chapter provides information on intrauterine growth of fetal adipose tissue, the earliest period of onset of proliferation, and some of the factors that interact to enhance or suppress development. Fetal adipose tissue development is regulated by the complex interaction of transcription factors, nutrients and adipocytokines. Maternal, endocrine, and paracrine factors also influence specific changes in angiogenesis, adipogenesis, and metabolism. During embryogenesis and in fetal life, leptin and adiponectin, two important adipocytokines, are present at high concentrations in the circulation and in tissues. Developmental stages and metabolic processes influenced by specific hormones and paracrine factors have been identified through examination of the offspring of obese and diabetic pregnancies, hormonal manipulation during late pregnancy in animal models, and the use of cell cultures. Collectively, the results of the studies cited herein delineate the basis for imprinting or conditioning of fetal pre-adipocytes at the paracrine/autocrine level, and of fetal adipose tissue development and metabolism.

Body Mass Index, Waist Circumference, and Waist-to- Height Ratio as Predictors of Cardiometabolic Risk in Childhood Obesity Depending on Pubertal Development

CONTEXT The predictive value of body mass index (BMI), waist circumference (WC), and waist-to-height ratio (WtHR) to define cardiometabolic risk is unclear in childhood obesity. OBJECTIVE [corrected] The associations between BMI, WtHR, or WC and cardiometabolic risk markers were analyzed in a multicenter data collection of obese youth. DESIGN AND SUBJECTS BMI, WtHR, and WC were retrospectively evaluated in 1278 patients (11-18 years, 53% boys) from the German/Austrian/Swiss Adiposity Patients Registry. MAIN OUTCOME MEASURES Parameters were correlated with homeostasis model assessment for insulin resistance, fasting insulin, blood pressure, transaminases, lipids and uric acid, applying adjusted regression models, with age group, pubertal stage and gender as covariates. RESULTS Homeostasis model assessment for insulin resistance and fasting insulin were most strongly correlated with BMI, independent of age group or gender. Lipids, transaminases, and uric acid were most strongly correlated with WC with stronger associations for boys. Correlations between BMI and WC as well as metabolic markers and systolic blood pressure showed only minor differences. The pattern of relationship changed during the course of pubertal development with the strongest associations for pubertal children. None of the parameters showed a dependency on WtHR that was superior to BMI or WC. CONCLUSIONS There is only small additional benefit in using WC measurements for routine pediatric care in addition to BMI for predicting metabolic risk. For all parameters, the relationship is strongest during midpuberty, emphasizing that among obese pubertal adolescents, anthropometric measures (BMI and WC) best predict cardiometabolic comorbidities. WtHR does not seem to be superior to BMI or WC in predicting metabolic or cardiovascular risk related to childhood obesity.

Secular trends in body mass index in German children and adolescents: a cross-sectional data analysis via CrescNet between 1999 and 2006

To assess secular trends in alterations in body mass index (BMI) in German children and adolescents between 1999 and 2006, we performed an analysis using data from a computerized database (CrescNet) and focusing on the data ranges above the 97th percentile (P97) and below the median (P50). This cross-sectional assessment of BMI data used a total of 143 495 single values (73 290 males and 70 205 females aged 0.5-17.5 years) from screening and/or consulting visits at 1 of the 294 participating German pediatricians. Body mass index data were calculated from standardized measurements of body weight and height entered into the CrescNet database. Individual percentiles were estimated according to German reference data sets. Across all age groups, the respective mean value of children with BMI above P97 increased from 5.32% to 7.02% in boys and from 5.70% to 7.18% in girls between 1999 and 2006, whereas those below P50 decreased from 48.52% to 43.71% in boys and from 47.48% to 42.57% in girls. The proportions of obese children (above the 97th percentile) were significantly higher than estimated by German reference values throughout the study period. The significant increase in childhood obesity between 1999 and 2006 was more pronounced in boys compared to girls. In conclusion, the cross-sectional study performed at a large cohort of German children and adolescents reveals an alarming increase in the number of obese children and adolescents and an accompanied shift toward higher BMI values. As the number of children below the 50th centile decreases accordingly, the shift in the distribution panel of the German reference percentile curves affecting the whole population can be observed.

Effects of a 1‐year exercise and lifestyle intervention on irisin, adipokines, and inflammatory markers in obese children

Exercise improves weight status and metabolism. Irisin, a novel myokine, may be involved in the regulation of metabolic function. The effect of an exercise and dietary lifestyle intervention for 1‐year on irisin, adipokines (leptin, adiponectin, resistin) and inflammatory markers (C‐reactive protein (CRP), soluble tumor necrosis factor receptor II (sTNFR‐II) was evaluated, and predictors of irisin levels were characterized in obese children.

Dysfunction of Autonomic Nervous System in Childhood Obesity: A Cross-Sectional Study

Objective To assess the distribution of autonomic nervous system (ANS) dysfunction in overweight and obese children. Methods Parasympathetic and sympathetic ANS function was assessed in children and adolescents with no evidence of impaired glucose metabolism by analysis of heart rate variability (low frequency power ln(LF), high frequency power, ln(HF); ln(LF/HF) ratio, ratio of longest RR interval during expiration to shortest interval during inspiration (E/I ratio), root mean square of successive differences (RMSSD); sympathetic skin response (SSR); and quantitative pupillography (pupil diameter in darkness, light reflex amplitude, latency, constriction velocity, re-dilation velocity). The relationship of each ANS variable to the standard deviation score of body mass index (BMI-SDS) was assessed in a linear model considering age, gender and pubertal stage as co-variates and employing an F-statistic to compare the fit of nested models. Group comparisons between normal weight and obese children as well as an analysis of dependence on insulin resistance (as indexed by the Homeostasis Model Assessment of Insulin Resistance, HOMA-IR) were performed for parameters shown to correlate with BMI-SDS. Statistical significance was set at 5%. Results Measurements were performed in 149 individuals (mean age 12.0 y; 90 obese 45 boys; 59 normal weight, 34 boys). E/I ratio (p = 0.003), ln(HF) (p = 0.03), pupil diameter in darkness (p = 0.01) were negatively correlated with BMI-SDS, whereas ln(LF/HF) was positively correlated (p = 0.05). Early re-dilation velocity was in trend negatively correlated to BMI-SDS (p = 0.08). None of the parameters that depended significantly on BMI-SDS was found to be significantly correlated with HOMA-IR. Conclusion These findings demonstrate extended ANS dysfunction in obese children and adolescents, affecting several organ systems. Both parasympathetic activity and sympathetic activity are reduced. The conspicuous pattern of ANS dysfunction raises the possibility that obesity may give rise to dysfunction of the peripheral autonomic nerves resembling that observed in normal-weight diabetic children and adolescents.

Bariatric surgery in severely obese adolescents improves major comorbidities including hyperuricemia.

OBJECTIVE Serum uric acid (sUA) is believed to contribute to the pathogenesis of metabolic comorbidities like hypertension, insulin-resistance (IR) and endothelial dysfunction (EDF) in obese children. The present pilot study investigated the association between sUA concentrations and loss of body weight following laparoscopic sleeve gastrectomy (LSG) or laparoscopic Roux-en-Y-gastric bypass (RYGB) in severely obese adolescents. MATERIALS/METHODS 10 severely obese adolescents underwent either LSG (n=5) or RYGB (n=5). 17 normal weight, healthy, age- and gender-matched adolescents served as a normal weight peer group (NWPG). Pre- and 12 months postoperatively, sUA and relevant metabolic parameters (glucose homeostasis, transaminases, lipids) were compared. RESULTS Preoperatively, sUA was significantly elevated in patients with severe obesity compared to NWPG. Twelve months after LSG and RYGB, a significant decrease in sUA, BMI, CVD risk factors, hepatic transaminases, and HOMA-IR was observed. Reduction in SDS-BMI significantly correlated with changes in sUA. CONCLUSIONS sUA levels and metabolic comorbidities improved following bariatric surgery in severely obese adolescents. The impact of changes in sUA on long-term clinical complications of childhood obesity deserves further study.