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Adiponectin is an adipocytokine with profound antidiabetic and antiatherogenic effects that is decreased in obesity. With the increasing prevalence of obesity and the emergence of related disorders, including type 2 diabetes in children, the regulation of adiponectin and its relationship to childhood obesity is of great interest. In this study we aimed to elucidate the impact of gender, pubertal development, and obesity on adiponectin levels in children. We investigated two phenotypically characterized cohorts of 200 normal weight and 135 obese children and adolescents covering a wide range of age (3.4-17.9 yr) and body mass index (-2.1 to +4.8 sd score). In healthy lean boys, adiponectin levels significantly declined in parallel with physical and pubertal development, subsequently leading to significantly reduced adiponectin levels in adolescent boys compared with girls (5.6 +/- 0.5 vs. 7.1 +/- 0.5 mg/liter; P = 0.03). This decline was inversely related to testosterone (r = -0.42; P < 0.0001) and dehydroepiandrosterone sulfate (r = -0.20; P = 0.0068) serum concentrations and may account for the gender differences seen in adults. Using a stepwise forward multiple regression model, pubertal stage was the strongest independent predictor of adiponectin (r(2) = 0.206; P < 0.0001), with additional influences of body mass index sd score and testosterone. Adiponectin levels were decreased in obese children and adolescents compared with lean peers of corresponding age and pubertal stage (5.18 vs. 7.13 mg/liter; P = 0.015). In obese children, adiponectin levels were closely associated with parameters related to the metabolic syndrome, such as insulin resistance, hyperinsulinemia, blood pressure, and uric acid, in univariate and multivariate analyses, with the insulin sensitivity index being the strongest independent parameter identified by stepwise forward multiple regression (r(2) = 0.226; P < 0.0001). Hence, there is a strong association of adiponectin serum concentrations with obesity, pubertal development, and metabolic parameters in children indicating epidemiological and pathophysiological relevance already in childhood.

BackgroundThe LIFE-Adult-Study is a population-based cohort study, which has recently completed the baseline examination of 10,000 randomly selected participants from Leipzig, a major city with 550,000 inhabitants in the east of Germany. It is the first study of this kind and size in an urban population in the eastern part of Germany. The study is conducted by the Leipzig Research Centre for Civilization Diseases (LIFE). Our objective is to investigate prevalences, early onset markers, genetic predispositions, and the role of lifestyle factors of major civilization diseases, with primary focus on metabolic and vascular diseases, heart function, cognitive impairment, brain function, depression, sleep disorders and vigilance dysregulation, retinal and optic nerve degeneration, and allergies.Methods/designThe study covers a main age range from 40-79 years with particular deep phenotyping in elderly participants above the age of 60. The baseline examination was conducted from August 2011 to November 2014. All participants underwent an extensive core assessment programme (5-6 h) including structured interviews, questionnaires, physical examinations, and biospecimen collection. Participants over 60 underwent two additional assessment programmes (3-4 h each) on two separate visits including deeper cognitive testing, brain magnetic resonance imaging, diagnostic interviews for depression, and electroencephalography.DiscussionThe participation rate was 33 %. The assessment programme was accepted well and completely passed by almost all participants. Biomarker analyses have already been performed in all participants. Genotype, transcriptome and metabolome analyses have been conducted in subgroups. The first follow-up examination will commence in 2016.

Accumulation of fat mass in obesity may result from hypertrophy and/or hyperplasia and is frequently associated with adipose tissue (AT) dysfunction in adults. Here we assessed early alterations in AT biology and function by comprehensive experimental and clinical characterization of 171 AT samples from lean and obese children aged 0 to 18 years. We show an increase in adipocyte size and number in obese compared with lean children beginning in early childhood. These alterations in AT composition in obese children were accompanied by decreased basal lipolytic activity and significantly enhanced stromal vascular cell proliferation in vitro, potentially underlying the hypertrophy and hyperplasia seen in obese children, respectively. Furthermore, macrophage infiltration, including the formation of crownlike structures, was increased in AT of obese children from 6 years on and was associated with higher hs-CRP serum levels. Clinically, adipocyte hypertrophy was not only associated with leptin serum levels but was highly and independently correlated with HOMA-IR as a marker of insulin resistance in children. In summary, we show that adipocyte hypertrophy is linked to increased inflammation in AT in obese children, thereby providing evidence that obesity-associated AT dysfunction develops in early childhood and is related to insulin resistance.Obesity is characterized by the accumulation of fat mass and is often associated with adipose tissue (AT) dysfunction (1). Clinical data indicate that obesity already develops during early childhood between 2 and 6 years of age (2). Expansion of AT can be achieved by hyperplasia (increase in adipocyte number) or hypertrophy (increase in adipocyte size) or the combination of both (3). Early studies suggested that adipocyte number is determined in childhood and remains relatively constant during adulthood, implying that expansion of AT mass in (adult) obesity occurs via hypertrophy of adipocytes (4,5). On the other hand, the capability for cell renewal, achieved by differentiation of preadipocytes into mature adipocytes, persists throughout life (6). Whether AT expansion in the development of obesity occurs primarily by hyperplasia or hypertrophy and the time point when AT dysfunction emerges are still a matter of debate.In addition to the mere accumulation of fat mass, obesity is often associated with changes in AT biology and

Leptin is an adipocyte-secreted hormone important in energy homeostasis and diverse physiological processes. A circulating soluble form of the leptin receptor [soluble leptin receptor (sOB-R)] is the main leptinbinding protein and determinant of free leptin index (FLI), the presumed biologically active form of leptin. We performed observational and interventional studies to elucidate the regulation of sOB-R and FLI in humans. In a cross-sectional study (n ‫؍‬ 118), leptin, gender, and adiposity were significant determinants of sOB-R. By multivariate analysis, estradiol (E2) and testosterone predict sOB-R, whereas insulin predicts leptin and FLI. In a frequent-sampling study (n ‫؍‬ 6), sOB-R followed a significant circadian rhythm inverse to that of leptin, suggesting that leptin's biological activity may have an even more pronounced diurnal variation than originally thought. A 72-h fast in eight men decreased leptin levels by 80% and increased lymphocyte expression of leptin receptor mRNA and serum sOB-R levels by 100%. Physiological and pharmacological doses of recombinantmethionyl human leptin (rhLeptin) administered to fasted men prevented the fasting-induced increase of sOB-R levels, and pharmacological doses resulted in a decrease in sOB-R levels. These studies provide evidence that sOB-R is regulated by gender, adiposity, hormones, and rhLeptin administration. This may have important implications for the biological activity of leptin in disease states associated with abnormal leptin levels (e.g., obesity and anorexia nervosa). Diabetes 51: 2105-2112, 2002 L eptin, the protein product of the ob gene, is produced by adipose tissue and is secreted into circulation. It acts mainly in the hypothalamus but also in other tissues by binding to specific leptin receptors, which belong to the cytokine receptor family (1,2). Multiple isoforms of the leptin receptor are generated through alternative splicing of the leptin receptor gene, including a long isoform expressed primarily in the hypothalamus and several short isoforms with a much wider tissue distribution (3). A soluble form of the leptin receptor [soluble leptin receptor (sOB-R)], consisting of only the extracellular region (4), binds leptin with an affinity similar to that of membrane-bound receptors (5) and represents the main leptin binding activity in serum (6).Recent work in rodent models has demonstrated that the sOB-R modulates serum leptin levels by delaying its clearance and determines the amount of free versus bound leptin in serum (7). It has also been proposed that free leptin, the form present in cerebrospinal fluid (CSF), is the biologically active form of leptin (8). These data suggest that sOB-R plays an important role in the pathophysiology of energy homeostasis in rodents (7) and humans (9). Thus, understanding the regulation of circulating sOB-R and free leptin in humans may have important physiological and therapeutic implications for human obesity and eating disorders.In obese subjects, a significantly higher percentage of leptin circulat...

Resistin appears to be not the main link between obesity and insulin resistance in children and adolescents but because of its association with Tanner stage, it may be related to the maturation of children during pubertal development. Additionally, we have demonstrated the presence of different molecular isoforms of resistin in human blood, and this may raise problems in comparing data from diverse assay systems.

Gender differences in the regulation of body-weight are well documented. Here, we assessed obesity-related influences of gender on brain structure as well as performance in the Iowa Gambling Task. This task requires evaluation of both immediate rewards and long-term outcomes and thus mirrors the trade-off between immediate reward from eating and the long-term effect of overeating on body-weight. In women, but not in men, we show that the preference for salient immediate rewards in the face of negative long-term consequences is higher in obese than in lean subjects. In addition, we report structural differences in the left dorsal striatum (i.e., putamen) and right dorsolateral prefrontal cortex for women only. Functionally, both regions are known to play complimentary roles in habitual and goal-directed control of behavior in motivational contexts. For women as well as men, gray matter volume correlates positively with measures of obesity in regions coding the value and saliency of food (i.e., nucleus accumbens, orbitofrontal cortex) as well as in the hypothalamus (i.e., the brain's central homeostatic center). These differences between lean and obese subjects in hedonic and homeostatic control systems may reflect a bias in eating behavior toward energy-intake exceeding the actual homeostatic demand. Although we cannot infer from our results the etiology of the observed structural differences, our results resemble neural and behavioral differences well known from other forms of addiction, however, with marked differences between women and men. These findings are important for designing gender-appropriate treatments of obesity and possibly its recognition as a form of addiction.

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