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Die 11beta-HSD1 reguliert intrazellulär die Cortisolkonzentration durch Regeneration von Cortison z.B. aus dem Blutkreislauf, zu Cortisol. Daher stellt diese ein wichtiges Element in der Glucocorticoid-vermittelten Genregulation dar. Die 11beta-HSD1 wird ubiquitär exprimiert, auf hohem Niveau besonders in Leber, Fettgewebe und glatten Muskelzellen. Insbesondere die Bedeutung der 11beta-HSD1 in Leber und Fettgewebe konnte mehrfach nachgewiesen werden. In der Leber führte eine erhöhte Aktivität aufgrund einer Überexpression in Mäusen zu einer verstärkten Gluconeogeneserate. Des Weiteren konnte gezeigt werden, dass eine erhöhte Expression und erhöhte Enzymaktivität der 11beta-HSD1 im subkutanen und viszeralen Fettgewebe assoziiert ist mit Fettleibigkeit, Insulinresistenz und Dyslipidämie. Über die Regulation ist jedoch noch wenig bekannt. Zur Untersuchung der Promotoraktivität wurde der Promotorbereich von -3034 bis +188, vor und nach dem Translations- und Transkriptionsstart, der 11beta-HSD1 kloniert. 8 Promotorfragmente wurden mittels Dual-Luciferase-Assay in humanen HepG2-Zellen sowie undifferenzierten und differenzierten murinen 3T3-L1-Zellen untersucht. Anschließend wurde mittels nicht-radioaktiven EMSA die Bindung des TATA-Binding Proteins (TBP) sowie von CCAAT/Enhancer-Binding-Proteinen (C/EBP) an ausgewählte Promotorregionen analysiert. Nach der Charakterisierung des Promotors wurden spezifische endogene und exogene Regulatoren untersucht. Fettsäuren modifizieren die Entstehung von Adipositas und Insulinresistenz. Ihre Wirkung wird u.a. PPARgamma-abhängig vermittelt und kann durch das Inkretin (Glucose-dependent insulinotropic Peptide) GIP modifiziert werden. So wurden die Effekte von unterschiedlichen Fettsäuren, vom PPARgamma Agonisten Rosiglitazon sowie dem Inkretin GIP auf die Expression und Enzymaktivität der 11beta-HSD1 untersucht. Dies wurde in-vitro-, tierexperimentell und in humanen in-vivo-Studien realisiert. Zuletzt wurden 2 Single Nucleotide Polymorphismen (SNP) im Promotorbereich der 11beta-HSD1 in der Zellkultur im Hinblick auf potentielle Funktionalität analysiert sowie die Assoziation mit Diabetes mellitus Typ 2 und Körpergewicht in der MeSyBePo-Kohorte bei rund 1.800 Personen untersucht. Die Luciferase-Assays zeigten basal eine zell-spezifische Regulation der 11beta-HSD1, wobei in allen 3 untersuchten Zelltypen die Bindung eines Repressors nachgewiesen werden konnte. Zudem konnte eine mögliche Bindung des TBPs sowie von C/EBP-Proteinen an verschiedene Positionen gezeigt werden. Die Transaktivierungsassays mit den C/EBP-Proteinen -alpha, -beta und -delta zeigten eben-falls eine zellspezifische Regulation des 11beta-HSD1-Promotors. Die Aktivität und Expression der 11beta-HSD1 wurde durch die hier untersuchten endogenen und exogenen Faktoren spezifisch modifiziert, was sowohl in-vitro als auch in-vivo in unterschiedlichen Modellsystemen dargestellt werden konnte. Die Charakterisierung der MeSyBePo-Kohorte ergab keine direkten Assoziationen zwischen Polymorphismus und klinischem Phänotyp, jedoch Tendenzen für eine erhöhtes Körper-gewicht und Typ 2 Diabetes mellitus in Abhängigkeit des Genotyps. Der Promotor der 11beta-HSD1 konnte aufgrund der Daten aus den Luciferaseassays sowie den Daten aus den EMSA-Analysen näher charakterisiert werden. Dieser zeigt eine variable und zell-spezifische Regulation. Ein wichtiger Regulator stellen insbesondere in den HepG2-Zellen die C/EBP-Proteine -alpha, -beta und -delta dar. Aus den in-vivo-Studien ergab sich eine Regulation der 11beta-HSD1 durch endogene, exogene und pharmakologische Substanzen, die durch die Zellkulturversuche bestätigt und näher charakterisiert werden konnten.
Objective: We analyse temporal trends and regional variation among the most recent available anthropometric data from German conscription in the years 2008-2010 and their historical contextualization since 1956. Design/setting/subjects: The overall sample included German conscripts (N 13 857 313) from 1956 to 2010. Results: German conscripts changed from growing in height to growing in breadth. Over the analysed 54 years, average height of 19-year-old conscripts increased by 6.5 cm from 173.5 cm in 1956 (birth year 1937) to 180.0 cm in 2010 (birth year 1991). This increase plateaued since the 1990s (1970s birth years). The increase in average weight, however, did not lessen during the last two decades but increased in two steps: at the end of the 1980s and after 1999. The weight and BMI distributions became increasingly right-skewed, the prevalence of overweight and obesity increased from 11.6 % and 2.1 % in 1984 to 19.9 % and 8.5 % in 2010, respectively. The north-south gradient in height (north = taller) persisted during our observations. Height and weight of conscripts from East Germany matched the German average between the early 1990s and 2009. Between the 1980s and the early 1990s, the average chest circumference increased, the average difference between chest circumference when inhaling and exhaling decreased, as did leg length relative to trunk length. Conclusions: Measuring anthropometric data for military conscripts yielded year-by-year monitoring of the health status of young men at a proscribed age. Such findings contribute to a more precise identification of groups at risk and thus help with further studies and to target interventions.
Background: Obesity is not only a highly prevalent disease but also poses a considerable burden on children and their families. Evidence is increasing that a lack of self-regulation skills may play a role in the etiology and maintenance of obesity. Our goal with this currently ongoing trial is to examine whether training that focuses on the enhancement of self-regulation skills may increase the sustainability of a complex lifestyle intervention.
Methods/Design: In a multicenter, prospective, parallel group, randomized controlled superiority trial, 226 obese children and adolescents aged 8 to 16 years will be allocated either to a newly developed computer-training program to improve their self-regulation abilities or to a placebo control group. Randomization occurs centrally and blockwise at a 1:1 allocation ratio for each center. This study is performed in pediatric inpatient rehabilitation facilities specialized in the treatment of obesity. Observer-blind assessments of outcome variables take place at four times: at the beginning of the rehabilitation (pre), at the end of the training in the rehabilitation (post), and 6 and 12 months post-rehabilitation intervention. The primary outcome is the course of BMI-SDS over 1 year after the end of the inpatient rehabilitation. Secondary endpoints are the self-regulation skills. In addition, health-related quality of life, and snack intake will be analyzed.
Discussion: The computer-based training programs might be a feasible and attractive tool to increase the sustainability of the weight loss reached during inpatient rehabilitation.
The hepatokine FGF21 and the adipokine chemerin have been implicated as metabolic regulators and mediators of inter-tissue crosstalk. While FGF21 is associated with beneficial metabolic effects and is currently being tested as an emerging therapeutic for obesity and diabetes, chemerin is linked to inflammation-mediated insulin resistance. However, dietary regulation of both organokines and their role in tissue interaction needs further investigation.
The LEMBAS nutritional intervention study investigated the effects of two diets differing in their protein content in obese human subjects with non-alcoholic fatty liver disease (NAFLD). The study participants consumed hypocaloric diets containing either low (LP: 10 EN%, n = 10) or high (HP: 30 EN%, n = 9) dietary protein 3 weeks prior to bariatric surgery. Before and after the intervention the participants were anthropometrically assessed, blood samples were drawn, and hepatic fat content was determined by MRS. During bariatric surgery, paired subcutaneous and visceral adipose tissue biopsies as well as liver biopsies were collected. The aim of this thesis was to investigate circulating levels and tissue-specific regulation of (1) FGF21 and (2) chemerin in the LEMBAS cohort. The results were compared to data obtained in 92 metabolically healthy subjects with normal glucose tolerance and normal liver fat content.
(1) Serum FGF21 concentrations were elevated in the obese subjects, and strongly associated with intrahepatic lipids (IHL). In accordance, FGF21 serum concentrations increased with severity of NAFLD as determined histologically in the liver biopsies. Though both diets were successful in reducing IHL, the effect was more pronounced in the HP group. FGF21 serum concentrations and mRNA expression were bi-directionally regulated by dietary protein, independent from metabolic improvements. In accordance, in the healthy study subjects, serum FGF21 concentrations dropped by more than 60% in response to the HP diet. A short-term HP intervention confirmed the acute downregulation of FGF21 within 24 hours. Lastly, experiments in HepG2 cell cultures and primary murine hepatocytes identified nitrogen metabolites (NH4Cl and glutamine) to dose-dependently suppress FGF21 expression.
(2) Circulating chemerin concentrations were considerably elevated in the obese versus lean study participants and differently associated with markers of obesity and NAFLD in the two cohorts. The adipokine decreased in response to the hypocaloric interventions while an unhealthy high-fat diet induced a rise in chemerin serum levels. In the lean subjects, mRNA expression of RARRES2, encoding chemerin, was strongly and positively correlated with expression of several cytokines, including MCP1, TNFα, and IL6, as well as markers of macrophage infiltration in the subcutaneous fat depot. However, RARRES2 was not associated with any cytokine assessed in the obese subjects and the data indicated an involvement of chemerin not only in the onset but also resolution of inflammation. Analyses of the tissue biopsies and experiments in human primary adipocytes point towards a role of chemerin in adipogenesis while discrepancies between the in vivo and in vitro data were detected.
Taken together, the results of this thesis demonstrate that circulating FGF21 and chemerin levels are considerably elevated in obesity and responsive to dietary interventions. FGF21 was acutely and bi-directionally regulated by dietary protein in a hepatocyte-autonomous manner. Given that both, a lack in essential amino acids and excessive nitrogen intake, exert metabolic stress, FGF21 may serve as an endocrine signal for dietary protein balance. Lastly, the data revealed that chemerin is derailed in obesity and associated with obesity-related inflammation. However, future studies on chemerin should consider functional and regulatory differences between secreted and tissue-specific isoforms.
Nob1 (New Zealand obese 1) bezeichnet einen Adipositas-QTL auf Chr. 5 der Maus (LODBMI >3,3), der in einem Rückkreuzungsexperiment der Mausstämme NZO (adipös) und SJL (schlank) identifiziert wurde. Um Kandidatengene für Adipositas zu finden, wurden mehr als 300 Nob1-Transkripte mit Hilfe von Genexpressionsanalysen auf Unterschiede in stoffwechselrelevanten Geweben zwischen beiden Mausstämmen untersucht. Sieben Gene zeigten eine differentielle Expression: 2310045A20Rik, Tbc1d1, Ppp1cb, Mll5, Insig1, Abhd1 und Alox5ap. Die codierenden Bereiche dieser Gene wurden anschließend auf Sequenzunterschiede zwischen NZO und SJL untersucht. Nur im Gen Tbc1d1, das im Peak-Bereich des Nob1 lokalisiert ist, wurde eine SJL-spezifische Deletion von sieben Basen detektiert, die zu einer Leserasterverschiebung und einem vorzeitigen Abbruch des Proteins in der funktionellen Rab-GAP-Domäne führt (Loss-of-Function-Mutation). Interessanterweise wurde eine Variante von TBC1D1 (R125W) in Kopplungsanalysen mit Adipositas beim Menschen assoziiert (Stone et al., 2006). TBC1D1 zeigt eine hohe Homologie zu TBC1D4 (AS160), das im Insulinsignalweg eine wichtige Rolle spielt. In 17 weiteren Genen im Peak-Bereich des Nob1 wurde keine weitere SJL-spezifischen Mutation detektiert. Bei NZO-Tieren erfolgte die Tbc1d1-mRNA-Expression vorwiegend in glycolytischen Fasern des Skelettmuskels. Zudem wurden zwei gewebsspezifisch exprimierte Tbc1d1-Isoformen identifiziert, die sich durch alternatives Splicen der Exone 12 und 13 unterscheiden. Die im Rahmen dieser Arbeit gefundenen Ergebnisse machen Tbc1d1 zu einem plausiblen Kandidatengen für den Nob1-QTL. Welche Funktion Tbc1d1 im Glucose- und Fettstoffwechsel des Skelettmuskels hat, muss in weiteren Analysen untersucht werden.
Cardiovascular complications are commonly associated with obesity. However, a subgroup of obese individuals may not be at an increased risk for cardiovascular complications; these individuals are said to have metabolically healthy obesity (MHO). In contrast, metabolically unhealthy individuals are at high risk of cardiovascular disease (CVD), irrespective of BMI; thus, this group can include individuals within the normal weight category (BMI 18.5-24.9kg/m(2)). This review provides a summary of prospective studies on MHO and metabolically unhealthy normal-weight (MUHNW) phenotypes. Notably, there is ongoing dispute surrounding the concept of MHO, including the lack of a uniform definition and the potentially transient nature of metabolic health status. This review highlights the relevance of alternative measures of body fatness, specifically measures of fat distribution, for determining MHO and MUHNW. It also highlights alternative approaches of risk stratification, which account for the continuum of risk in relation to CVD, which is observable for most risk factors. Moreover, studies evaluating the transition from metabolically healthy to unhealthy phenotypes and potential determinants for such conversions are discussed. Finally, the review proposes several strategies for the use of epidemiological research to further inform the current debate on metabolic health and its determination across different stages of body fatness.
Loss to follow-up in a randomized controlled trial study for pediatric weight management (EPOC)
(2016)
Background
Attrition is a serious problem in intervention studies. The current study analyzed the attrition rate during follow-up in a randomized controlled pediatric weight management program (EPOC study) within a tertiary care setting.
Methods
Five hundred twenty-three parents and their 7–13-year-old children with obesity participated in the randomized controlled intervention trial. Follow-up data were assessed 6 and 12 months after the end of treatment. Attrition was defined as providing no objective weight data. Demographic and psychological baseline characteristics were used to predict attrition at 6- and 12-month follow-up using multivariate logistic regression analyses.
Results
Objective weight data were available for 49.6 (67.0) % of the children 6 (12) months after the end of treatment. Completers and non-completers at the 6- and 12-month follow-up differed in the amount of weight loss during their inpatient stay, their initial BMI-SDS, educational level of the parents, and child’s quality of life and well-being. Additionally, completers supported their child more than non-completers, and at the 12-month follow-up, families with a more structured eating environment were less likely to drop out. On a multivariate level, only educational background and structure of the eating environment remained significant.
Conclusions
The minor differences between the completers and the non-completers suggest that our retention strategies were successful. Further research should focus on prevention of attrition in families with a lower educational background.
Loss to follow-up in a randomized controlled trial study for pediatric weight management (EPOC)
(2016)
Background
Attrition is a serious problem in intervention studies. The current study analyzed the attrition rate during follow-up in a randomized controlled pediatric weight management program (EPOC study) within a tertiary care setting.
Methods
Five hundred twenty-three parents and their 7–13-year-old children with obesity participated in the randomized controlled intervention trial. Follow-up data were assessed 6 and 12 months after the end of treatment. Attrition was defined as providing no objective weight data. Demographic and psychological baseline characteristics were used to predict attrition at 6- and 12-month follow-up using multivariate logistic regression analyses.
Results
Objective weight data were available for 49.6 (67.0) % of the children 6 (12) months after the end of treatment. Completers and non-completers at the 6- and 12-month follow-up differed in the amount of weight loss during their inpatient stay, their initial BMI-SDS, educational level of the parents, and child’s quality of life and well-being. Additionally, completers supported their child more than non-completers, and at the 12-month follow-up, families with a more structured eating environment were less likely to drop out. On a multivariate level, only educational background and structure of the eating environment remained significant.
Conclusions
The minor differences between the completers and the non-completers suggest that our retention strategies were successful. Further research should focus on prevention of attrition in families with a lower educational background.