Diurnal rythm of Nampt is gender and weight dependent.

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.

Epigenetic inheritance of diet-induced and sperm-borne mitochondrial RNAs.

Spermatozoa harbour a complex and environment-sensitive pool of small non-coding RNAs (sncRNAs)1, which influences offspring development and adult phenotypes1-7. Whether spermatozoa in the epididymis are directly susceptible to environmental cues is not fully understood8. Here we used two distinct paradigms of preconception acute high-fat diet to dissect epididymal versus testicular contributions to the sperm sncRNA pool and offspring health. We show that epididymal spermatozoa, but not developing germ cells, are sensitive to the environment and identify mitochondrial tRNAs (mt-tRNAs) and their fragments (mt-tsRNAs) as sperm-borne factors. In humans, mt-tsRNAs in spermatozoa correlate with body mass index, and paternal overweight at conception doubles offspring obesity risk and compromises metabolic health. Sperm sncRNA sequencing of mice mutant for genes involved in mitochondrial function, and metabolic phenotyping of their wild-type offspring, suggest that the upregulation of mt-tsRNAs is downstream of mitochondrial dysfunction. Single-embryo transcriptomics of genetically hybrid two-cell embryos demonstrated sperm-to-oocyte transfer of mt-tRNAs at fertilization and suggested their involvement in the control of early-embryo transcription. Our study supports the importance of paternal health at conception for offspring metabolism, shows that mt-tRNAs are diet-induced and sperm-borne and demonstrates, in a physiological setting, father-to-offspring transfer of sperm mitochondrial RNAs at fertilization.

Prevalence of prediabetes and type 2 diabetes in children with obesity and increased transaminases in European German-speaking countries. Analysis of the APV initiative.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD), prediabetes and type 2 diabetes mellitus are known to be closely linked with obesity as early as during childhood. OBJECTIVES: The study aimed to determine the prevalence of prediabetes and T2DM in children with obesity with or without increased transaminases. METHODS: Data from the observational multicentre (n = 51), cross-sectional Adipositas Patienten Verlaufsbeobachtung registry were analyzed. Mild increase (mild group) was defined by alanine transaminase (ALT) >24 to ≤50 U/L and moderate to severe increase (advanced group) by ALT > 50 U/L. Prediabetes and T2DM were defined according to recent IDF/ISPAD guidelines. RESULTS: The prevalence of prediabetes and T2DM was 11.9% (95% CI: 11.0-12.8) and 1.4% (95% CI: 1.1-1.7) among all participants (n = 4932; male = 2481; mean age 12.9 ± 2.7 years; BMI-SDS 2.1 ± 0.5; Tanner stage 3.2 ± 1.5). The prevalence of impaired glucose metabolism (prediabetes and T2DM) was 13.8% (95% CI: 12.1-15.4) in the mild, 21.9% (95% CI: 18.8-25.1) in the advanced group, 10.7% (95% CI: 9.4-11.9) in the control group. Mild and advanced groups had greater odds ratios for prediabetes [1.42; 95% CI: 1.17-1.72, 2.26-fold; (1.78-2.86), respectively], the advanced group also for T2DM [2.39 (1.36-4.21)] compared to controls. While an increase in transaminases predominantly affected boys, girls within the advanced group had a higher T2DM prevalence than males (5.4 vs. male 2.1%). CONCLUSIONS: Children with obesity and increased liver transaminases as surrogates of NAFLD should be screened for T2DM.

Children and adolescents with obesity have reduced serum bone turnover markers and 25-hydroxyvitamin D but increased parathyroid hormone concentrations - Results derived from new pediatric reference ranges.

BACKGROUND: We aimed to establish age- and gender-specific reference ranges for concentrations of the bone markers osteocalcin (OC), procollagen type 1 N-propeptides (PINP) and carboxy-terminal cross-linking telopeptide of type 1 collagen (CTX-I) as well as for the calciotropic hormones 25-hydroxyvitamin D [25(OH)D] and parathyroid hormone (PTH) in healthy infants, children and adolescents. In addition, the effect of age, gender, puberty and body mass index (BMI) on bone markers was investigated. METHODS: 2416 healthy subjects (5714 blood withdrawals), aged 3 months to 17 years, were included to estimate the age- and gender-dependence of reference ranges. Subsequently, measured values of the biomarkers were transformed to standard deviation scores (SDS) and their associations with age, gender and puberty were analyzed. Bone marker-SDS values of the reference cohort were compared with an obese cohort (n = 317 and 489 blood withdrawals) to analyze the effect of BMI. RESULTS: OC, PINP and CTX-I showed a distinct age- and gender-dependence with peak levels at 10 to 11 years (girls, Tanner 3) and 13 years (boys, Tanner 3-4). Children with obesity had significantly lower SDS levels for OC (-0.44), PINP (-0.27), CTX-I (-0.33), 25(OH)D (-0.43) and higher SDS levels for PTH (+0.44) than the reference cohort. CONCLUSIONS: OC, PINP and CTX-I vary with age, gender and pubertal stage. The body weight status has to be considered in the interpretation of pediatric OC, PINP, CTX-I, 25(OH)D and PTH levels. Consequences of childhood obesity on bone health should be carefully investigated in long-term studies.

The BDNF Val66Met polymorphism is associated with lower BMI, lower postprandial glucose levels and elevated carbohydrate intake in children and adolescents.

BACKGROUND: The amino acid-changing exonic variant rs6265 (Val66Met polymorphism) in the brain-derived neurotrophic factor (BDNF) has been linked to obesity in several genotype-phenotype association studies. OBJECTIVE: To identify metabolic factors by which this effect might be conveyed, we aimed to investigate its correlation with (i) obesity, (ii) metabolic parameters, (iii) serum levels of BDNF and (iv) measures of energy intake in children and adolescents. METHODS: We genotyped the variant in 2131 subjects (age 6-18 years) and checked for an association with obesity. Secondly, we correlated the genotype with parameters of glucose and lipid metabolism (fasting/postprandial glucose and insulin levels, HbA1c, homeostasis model assessment, Matsuda, high-density lipoprotein, low-density lipoprotein, total cholesterol and triglycerides) in a smaller subset of 845 subjects. We determined BDNF serum levels in 177 individuals by enzyme-linked immunosorbent assay and assessed the association with genotype and metabolic parameters. Finally, we investigated the association between genotype and macronutrient intake from self-reported food diaries (n = 146). RESULTS: The minor Met allele was associated with lower BMI standard deviation score (p = 0.002). Post-pubertal Met allele carriers showed lower postprandial glucose levels and a lower HbA1c (ß = 0.15, p = 0.046 and ß = 0.27, p = 0.012, respectively). Neither the genotype nor any of the metabolic parameters correlated with BDNF serum levels. We observed an increased total calorie intake (ß = -0.21, p = 0.007) with increased carbohydrate and protein intake (ß = -0.22, p = 0.005 and ß = -0.14, p = 0.028, respectively) in Met allele carriers. CONCLUSIONS: We confirmed the association of the minor Met allele with lower BMI in children and provide new data that it is associated with lower postprandial glucose in post-pubertal subjects. Moreover, Met allele carriers reported to consume more carbohydrates and proteins.

Hindwings of insects as concept generator for hingeless foldable shading systems.

Hingeless shading systems inspired by nature are increasingly the focus of architectural research. In contrast to traditional systems, these compliant mechanisms can reduce the amount of maintenance-intensive parts and can easily be adapted to irregular, doubly curved, facade geometries. Previous mechanisms rely merely on the reversible material deformation of composite structures with almost homogeneous material properties. This leads to large actuation forces and an inherent conflict between the requirements of movement and the capacity to carry external loads. To enhance the performance of such systems, current research is directed at natural mechanisms with concentrated compliance and distinct hinge zones with high load-bearing capacity. Here, we provide insights into our biological findings and the development of a deployable structure inspired by the Flexagon model of hindwings of insects in general and the hierarchical structure of the wing cuticle of the shield bug (Graphosoma lineatum). By using technical fibre-reinforced plastics in combination with an elastomer foil, natural principles have been partially transferred into a multi-layered structure with locally adapted stiffness. Initial small prototypes have been produced in a vacuum-assisted hot press and sustain this functionality. Initial theoretical studies on test surfaces outline the advantages of these bio-inspired structures as deployable external shading systems for doubly curved facades.

The role of patient education and physician support in self-efficacy for skin self-examination among patients with melanoma.

OBJECTIVE: This project aims to elucidate the relationships between skin self-examination (SSE), perceived physician support of SSE, and self-efficacy for SSE among melanoma patients. METHODS: A longitudinal study of patients diagnosed with melanoma was conducted over the span of 18 months. Participants filled out questionnaires at four assessment points and participated in an SSE education about the early signs of melanoma. RESULTS: Among the 242 patients enrolled, the level of self-efficacy for SSE was 23% higher immediately after the educational intervention (p<.001) and the increase was retained three months (p<.001) and twelve months later (p<.001). Additionally, a one-way repeated measures ANOVA revealed that the perceived physician support of SSE positively corresponded to the level of patient self-efficacy with higher patient-reported physician support being related to higher self-efficacy (p=.001). CONCLUSION: Patient education and perceived physician support of SSE are positively associated with patients' level of self-efficacy. PRACTICE IMPLICATIONS: Physicians caring for melanoma survivors should be aware that, both SSE education and patients' perception of high physician support of SSE may be associated with higher self-efficacy for checking one's own skin for signs of cancer recurrence.

Self-efficacy and comfort with partner-assisted skin examination in patients receiving follow-up care for melanoma.

The objective of this study was to examine the role of interpersonal variables on melanoma survivors' self-efficacy for performing skin self-examinations (SSEs) during melanoma follow-up care. Specifically, the impact of comfort with partner assistance for SSE, SSE support received from one's partner, general partner support, relationship satisfaction, as well as partner attendance at a SSE education session, were examined. One hundred and thirty-seven patients with melanoma between the ages of 18 and 70 years, who also reported being involved in a romantic relationship, received a standardized education on SSE, and completed self-report questionnaires. Results indicate that SSE support and SSE comfort predicted patients' SSE self-efficacy. Partner attendance at the SSE education moderated the relationship between SSE comfort and SSE self-efficacy. In other words, SSE self-efficacy was found to be affected by partner attendance at the SSE education only in cases where the patient reported lower levels of comfort having his or her partner assist with SSE. Results highlight the importance of partner involvement in SSE education, as well as patient comfort with a partner's assistance during skin examinations. Findings inform potential modifications to the follow-up care provided to melanoma survivors by demonstrating the importance of partner involvement in SSE education.

Adipocyte C1QTNF5 expression is BMI-dependently related to early adipose tissue dysfunction and systemic CTRP5 serum levels in obese children.

BACKGROUND/OBJECTIVES: The recently identified adipocytokine C1QTNF5 (encodes for CTRP5) has been demonstrated to inhibit pro-metabolic insulin signaling in adipocytes. We hypothesized that adipocyte C1QTNF5 expression in subcutaneous (sc) adipose tissue (AT) would correlate with the degree of obesity, systemic CTRP5 serum levels, and early AT and metabolic dysfunction in children. SUBJECTS/METHODS: Sc AT samples were obtained from 33 healthy Caucasian lean children aged 10.06±4.84 years and 42 overweight and obese children aged 13.34±3.12 years. C1QTNF5 expression in sc AT as well as in investigated cell lines was assessed by quantitative real-time PCR. Systemic CTRP5 levels were assessed by ELISA. RESULTS: C1QTNF5 expression in sc adipocytes increased with body mass index (BMI) standard deviation score (SDS; R=0.48, P<0.001), body fat percentage (R=0.4, P=0.004), adipocyte number (R=0.69, P<0.001) and systemic CTRP5 serum levels (R=0.28, P=0.025) whereas expression in the stromal vascular fraction (SVF) was inversely correlated with BMI SDS (R=-0.24, P=0.04). Multiple regression analysis confirmed that BMI SDS was the strongest independent predictor for C1QTNF5 expression in sc adipocytes. SVF C1QTNF5 levels strongly correlated with SVF CD31 expression (R=0.54, P<0.001) indicating expression by endothelial cells. Primary human endothelial cells demonstrated stronger expression compared with human Simpson-Golahbi-Behmel syndrome pre-adipocytes and adipocytes. Adipocyte C1QTNF5 expression levels were BMI-dependently related to fasting insulin (R=0.3, P=0.03) and leptin serum levels (R=0.5, P<0.001). Sc AT samples containing crown-like structures (CLS) demonstrated increased adipocyte C1QTNF5 expression compared to CLS-negative samples (P=0.03). Functionally, tumor necrosis factor (TNF)α caused a fourfold induction of C1QTNF5 in human adipocytes (P<0.001) and a 50% reduction in primary human endothelial cells (P<0.001). CONCLUSIONS: In children adipocyte C1QTNF5 expression is already strongly related to the degree of obesity and is associated with obesity-related AT alterations, systemic CTRP5 serum levels as well as circulating markers of metabolic disease and is positively regulated by TNFα in vitro.

METRNL decreases during adipogenesis and inhibits adipocyte differentiation leading to adipocyte hypertrophy in humans.

BACKGROUND: Meteorin-like (METRNL) is a recently described circulating protein shown to be highly expressed in white adipose tissue and to beneficially affect energy metabolism in mice. OBJECTIVE: We systematically evaluated the role of METRNL for human adipogenesis and its association with obesity, browning and hyperinsulinemia in children. In addition, we assessed the functional relevance of METRNL for human adipogenesis. RESULTS: METRNL expression decreased during human adipocyte differentiation in vitro. Coherently, METRNL expression was lower in isolated adipocytes compared with stromal vascular fraction (SVF) cells in human samples. Withdrawal of the peroxisome proliferator-activated receptor-γ (PPARγ) agonist rosiglitazone from adipogenic media partially preserved the METRNL downregulation during adipogenesis. METRNL expression was higher in adipocytes of obese compared with lean children and correlated with adipocyte size, whereas in SVF METRNL expression correlated with proliferation capacity. Concordantly, overexpression of METRNL inhibited human adipocyte differentiation as shown by decreased lipogenesis and lower expression of PPARγ and markers of adipogenesis, whereas experimental downregulation promoted adipogenesis. Proliferation, in contrast, was advanced by METRNL overexpression. These interactions with adipose tissue dynamics may contribute to the clinically observed body mass index-independent association of METRNL expression with hyperinsulinemia and adipose tissue inflammation in human samples. METRNL was not associated with UCP1 expression or induction of browning in white adipocytes. CONCLUSIONS: Taken together, the downregulation of METRNL during adipogenesis and functional induction of increased proliferation in SVF cells with concomitant inhibition of adipocyte differentiation may result in hypertrophic AT accumulation. This may also explain our observations of increased METRNL expression in adipocytes but not SVF cells in obese children compared with lean children and the subsequent hyperinsulinemia.

Insulin-Like Peptide 5 Interacts with Sex Hormones and Metabolic Parameters in a Gender and Adiposity Dependent Manner in Humans.

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.

Morphological and compositional monitoring of a new cell-free cartilage repair hydrogel technology - GelrinC by MR using semi-quantitative MOCART scoring and quantitative T2 index and new zonal T2 index calculation.

OBJECTIVE: To evaluate cartilage repair tissue (RT) using MOCART scoring for morphological and T2 mapping for biochemical assessment following implantation of GelrinC, a biosynthetic, biodegradable hydrogel implant. DESIGN: MR imaging (1.5/3T) was performed on 21 patients at six sites. Standard protocols were used for MOCART evaluation at 1 week (baseline) 1, 3, 6, 12, 18 and 24 months. Multi-echo SE was used for T2 mapping. Global (T2 in RT divided by T2 in normal cartilage) and zonal T2 index (deep T2 divided by superficial T2) of RT were calculated. RESULTS: Average MOCART score was 71.8 (95% CI 62.2 to 81.3) at six, 75.2 (95% CI 62.8 to 87.5) at twelve, 71.8 (95% CI 55.4 to 88.2) at eighteen and 84.4 (95% CI 77.7 to 91.0) at twenty-four months. The global T2 index ranged between 0.8 and 1.2 (normal healthy cartilage) in 1/11 (9%) patients at baseline, 8/12 (67%) at 12 months, 11/13 (85%) at 18 months and 13/16 (81%) at 24 months. The zonal T2 index for RT was <20% difference to the zonal T2 index for normal cartilage in: 6/12 patients (50%) at 12 months, 7/13 (53.8%) at 18 months and 10/16 (63.5%) at 24 months. The standard deviation for T2 showed a significant decrease over the study. CONCLUSIONS: The increase of MOCART scores over follow-up indicates improving cartilage repair tissue. Global and zonal T2 repair values at 24 months reached normal cartilage in 81% and 63.5% of the patients respectively, reflecting collagen organization similar to hyaline cartilage.

One-to-one peer support in cancer care: a review of scholarship published between 2007 and 2014.

The primary goal of this review was to determine whether one-to-one peer support programmes benefit cancer patients. The secondary goal was to assess the quality of the research methodology and of the peer programme description as reported in original research studies. MEDLINE and PsycINFO databases were systematically searched in order to identify relevant studies published between May 2007 and July 2014. Eligible articles were evaluated using pre-existing criteria based on the Consolidated Standards of Reporting Trials Statement Checklist. This review included 13 studies: four randomised controlled trials, one non-randomised comparative study and eight one-group descriptive studies. All studies reported high participant satisfaction with the peer support intervention, and the majority noted positive outcomes regarding psychological adjustment. The quality of the description of the peer support programmes as well as the research methodology of the studies was rated as fair. Methodological weaknesses included biased recruitment strategies and limited information regarding peer volunteers, non-users of peer support and those who withdrew from support programmes. One-to-one peer support programmes have the unique advantage of being a low-cost intervention approach, but also showing potential for relieving the health-care system by reallocating some aspects of the cancer care to community settings. Future research should address the methodological weaknesses in study design and reporting.

Patient participation in the medical decision-making process in haemato-oncology--a qualitative study.

Cancer patients are showing increased interest in shared decision-making. Patients with haematological illnesses, however, express considerably less desire for shared decision-making as compared with other oncological patient groups. The goal of the current project was to identify the reasons for the lower desire for shared decision-making among patients with haematological illness. We conducted qualitative, semi-structured interviews with 11 haematological patients (39-70 years old) after the beginning of therapy concerning the course and evaluation of medical shared decision-making. The patients were often overwhelmed by the complexity of the illness and the therapy and did not want to assume any responsibility in medical decision-making. They reported a great deal of distress and very traditional paternalistic role expectations with regards to their health care providers, which limited the patients' ability to partake in the decision-making process. In contrast to the socio-cultural support for many other oncological diseases, haematological diseases are not as well supported, e.g. there is a lack of self-help materials, systematic provision of information and support groups for patients, which may be related to a lower empowerment of this patient population. Results show the limits of patient participation in the context of highly complicated medical conditions. In addition to already researched preferences of the physicians and patients for shared decision-making, future research should pay greater attention to the process and other variables relevant to this aspect of the doctor-patient relationship.

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.

[High blood pressure in obese children and adolescents]. / Bluthochdruck bei Adipositas im Kindes- und Jugendalter.

Obesity is also an important risk factor in children and adolescents for "essential" arterial hypertension, and contrary to what was assumed earlier, high blood pressure does cause damage to the cardiovascular system. As known from adults, elevated blood pressure induces cardiac hypertrophy, calcifications and atherosclerosis at the coronary vessels and thickens the small blood vessels. These early vascular alterations are particularly pronounced, when increased blood pressure is accompanied by other risk factors, such as dyslipidemia, hyperinsulinemia or smoking. As in any child with elevated blood pressure, the diagnostic evaluation should focus on confirmation of hypertension, determine if an underlying cause can be identified and whether hypertensive target organ damage is present. New reference office blood pressure values were recently published by a large representative community-based study in Germany. Therapy should begin with lifestyle modifications; however, antihypertensive medications will often be needed. Hypertension in obese adolescents occurs frequently and must be diagnosed and treated adequately.

[Does childhood obesity affect sexual development?]. / Beeinflusst die kindliche Adipositas die Pubertätsentwicklung?

The process of pubertal development is only partly understood and is influenced by many different factors. During the twentieth century there was a general trend toward earlier pubertal development. Fat mass is thought to be a major inducer of puberty. Owing to the rising epidemic of childhood obesity, the relationship between body composition in children and the rate and timing of puberty needs to be investigated. Some studies suggest that central obesity is associated with an earlier onset of pubertal development. Rapid weight gain in early life is linked to advanced puberty in both sexes. A clear correlation exists between increasing body mass index (BMI) and earlier pubertal development in girls. In boys the data are controversial: The majority of studies propose that there is an earlier puberty and voice break in obese boys, but some studies show the opposite. There are several factors and mechanisms that seem to link obesity and puberty, for example, leptin, adipocytokines, and gut peptides. Important players include genetic variation and environmental factors (e.g., endocrine-disrupting chemicals). This article presents the latest studies and evidence on this topic, underlining the inconsistencies in the data and, therefore, the need for further research in this area.

[Carbohydrate metabolism disorders among obese children and adolescents. Diabetes mellitus type 2]. / Störungen des Kohlenhydratstoffwechsels bei Kindern und Jugendlichen mit Adipositas. Diabetes mellitus Typ 2.

As obesity has become more prevalent, the incidence of type 2 diabetes mellitus in children and adolescents has also increased. Obesity during adolescence leads to an increased risk for disease and premature death during adulthood, independent of obesity during adulthood. Obesity is the major risk factor impacting insulin sensitivity. Subjects with insulin resistance are at risk for progression to diabetes. Type 2 diabetes mellitus in obese children and adolescents is frequently asymptomatic. It is essential to identify children at high risk who need aggressive lifestyle modification focused on weight reduction and increased physical activity. Early detection and therapy of obese children and adolescents with type 2 diabetes may reduce the risk of cardiometabolic consequences and other long-term complications in adulthood.

Functional relevance of genes implicated by obesity genome-wide association study signals for human adipocyte biology.

AIMS/HYPOTHESIS: Genome-wide association studies (GWAS) have identified numerous single-nucleotide polymorphisms associated with obesity, consequently implying a role in adipocyte biology for many closely residing genes. We investigated the functional relevance of such genes in human adipocytes. METHODS: We selected eight genes (BDNF, MAF, MTCH2, NEGR1, NPC1, PTER, SH2B1 and TMEM18) from obesity GWAS and analysed their effect in human adipogenesis using small interfering (si)RNA-mediated knockdown, their regulation by metabolic agents in adipocytes and pre-adipocytes, and gene expression in paired samples of human fat biopsies (68 non-obese, 165 obese) by quantitative real-time PCR. RESULTS: We show a two- to threefold upregulation of MAF, MTCH2 and NEGR1 and a two- to fourfold downregulation of BDNF and PTER during adipogenesis. Knockdown of BDNF (mean ± SEM; 83.8 ± 4.7% of control; p = 0.0002), MTCH2 (72.7 ± 9.5%; p = 0.0006), NEGR1 (70.2 ± 5.7%; p < 0.0001) and TMEM18 (70.8 ± 6.1%; p < 0.0001) significantly inhibited adipocyte maturation, while knockdown of the other proteins had no effect. Insulin slightly induced MAF (1.65-fold; p = 0.0009) and MTCH2 (1.72-fold; p < 0.0001), while it suppressed BDNF (59.6%; p = 0.0009), NEGR1 (58.0%; p = 0.0085) and TMEM18 (69.3%; p = 0.0377) in adipocytes. The synthetic glucocorticoid dexamethasone suppressed MAF (45.7%; p = 0.0022), BDNF (66.6%; p = 0.0012) and TMEM18 (63.5%; p = 0.0181), but induced NEGR1 (3.2-fold; p = 0.0117) expression. Furthermore, MTCH2, NEGR1 and TMEM18 were differentially expressed in subcutaneous and visceral adipose tissue. TMEM18 expression was decreased in the adipose tissue of obese patients, and negatively correlated with anthropometric variables and adipocyte size. CONCLUSIONS/INTERPRETATION: Our results imply a regulatory role for TMEM18, BDNF, MTCH2 and NEGR1 in adipocyte differentiation and biology. In addition, we show a variation of MAF expression during adipogenesis, while NPC1, PTER and SH2B1 were not regulated.