Atherosclerotic cardiovascular disease is a leading cause of death worldwide. Dysregulation of vascular redox state plays a crucial role in the atherosclerotic process. Increased production of vascular superoxide (O2·-) and other reactive oxygen species (ROS) leads to endothelial dysfunction, a key early step in atherogenesis. Adipose tissue is a source of vasoactive, hormone-like molecules which are termed adipokines. One of the most important adipokines is adiponectin. Adiponectin has been shown to have antioxidant, anti-atherosclerotic effects in cell culture studies and animal models. However, its role in human cardiovascular disease has not been extensively investigated. More specifically, its effects on the human vascular wall and the mechanisms regulating its synthesis in adipose tissue have not been studied before in humans. The aim of my thesis is to explore the role of adiponectin in human atherosclerosis. This was achieved through use of the Oxford CABG Bioresource: a well-phenotyped cohort and tissue bank of patients undergoing cardiac surgery. By employing a range of in vivo and ex vivo techniques, I demonstrate for the first time in humans that adiponectin has direct antioxidant effects in the vascular wall, by directly suppressing pro-oxidant vascular enzymes and restoring redox balance. These effects persist in type 2 diabetes, presence of which is linked to reduced circulating adiponectin levels. Indeed, a variety of stimuli affect adiponectin synthesis in human adipose tissue, with brain natriuretic peptide being a major driver of adiponectin synthesis. However, different adipose tissue depots demonstrate diverse responses to stimuli affecting adiponectin synthesis, owing to their functional and morphological differences. Of particular interest is the fact that synthesis of adiponectin in perivascular adipose tissue is driven by the oxidative stress status of the underlying vessel. This observation led me to document for the first time in humans the existence of a reciprocal, two-way interaction between perivascular adipose tissue and the vascular wall: high vascular oxidative stress leads to release of factors with the ability to up-regulate adiponectin expression in perivascular adipose tissue, acting as a local paracrine defence mechanism attempting to restore vascular redox state. My thesis provides proof-of-concept for this novel cross-talk between adipose tissue and the vascular wall. This can have significant impact in designing new therapeutic strategies against atherosclerosis.

Orientador: Joni Augusto Cirelli / Resumo: Citocinas e adipocinas são moléculas que se encontram em concentrações elevadas em tecidos e no soro de pacientes obesos e pacientes que apresentam condições ou doenças inflamatórias. A movimentação ortodôntica desencadeia uma sequência de eventos celulares e moleculares nos tecidos periodontais, onde há a liberação local de diversos mediadores inflamatórios. Assim, o objetivo do presente estudo foi avaliar in vivo o efeito da obesidade na remodelação dos tecidos periodontais de ratos induzida pela força mecânica ortodôntica. Um total de 32 animais foram randomicamente distribuídos em 4 grupos experimentais: C (controle), O (indução de obesidade), M (movimentação ortodôntica) e OM (indução de obesidade seguido de movimentação ortodôntica). Os animais submetidos à O receberam dieta hiperlipídica por 90 dias. A massa corporal dos animais foi registrada semanalmente. Após 15 dias de movimento ortodôntico (grupos M e OM), os animais de todos os grupos foram sacrificados e os tecidos adiposos (retroperitoneal, epididimal e mesentérico) foram removidos e pesados em balança de precisão. Além disso, foi feito análise sorológica para observar o perfil lipídico (triglicerídeos, colesterol total, HDL e LDL) e os níveis de glicemia. Análise microtomográfica realizada nas hemimaxilas para medir o percentual de volume ósseo alveolar (BVF), densidade óssea alveolar (BMD), análise linear de perda óssea e movimento dentário (nos grupos M e OM). Foi realizada também histometria para medir a pe... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Ciyokines and adipokines are molecules presented in high levels in tissues and serum of patients with obesity or inflammatory diseases. Orthodontic movement triggers a sequence of cellular and molecular events, resulting in local liberation of inflammatory mediators. Therefore, the aim of this study was to evaluate the effect of obesity on rat periodontal tissues remodeling induced by mechanical orthodontic force. A total of 32 rats were randomly distributed into 4 experimental groups: C (control), O (obesity induction), M (orthodontic movement induction), and OM (obesity induction followed by orthodontic movement). Animals from O group received a high-fat diet for 90 days. The body weight was recorded weekly. After 15 days of orthodontic movement (groups M and OM), the animals from all the groups were euthanized and the adipose tissues (retroperitoneal, epididymal and mesenteric) were removed and weighed in a precision scale. In addition, serological analysis was performed to evaluate lipid profile (triglycerides, total cholesterol, HDL and LDL) and blood glucose levels. Microcomputerized tomography was performed to measure alveolar bone volume percentage (BVF), alveolar bone density (BMD), linear alveolar bone loss and tooth movement (on M and OM groups). Histological analysis was performed to evaluate linear alveolar bone loss and the proportion of tissue structures: collagens fibers, fibroblasts, inflammatory cells and blood vessels. In addition, gene expression on gingiv... (Complete abstract click electronic access below) / Mestre

Made available in DSpace on 2014-06-11T19:30:53Z (GMT). No. of bitstreams: 0 Previous issue date: 2010-10-02Bitstream added on 2014-06-13T19:00:56Z : No. of bitstreams: 1 queiroga_mr_dr_rcla.pdf: 2000308 bytes, checksum: 50e869bf9200e48db5cc5fe6f2f5f876 (MD5) / Estudos experimentais revelam que uma baixa aptidão cardiorrespiratória (VO2máx) está associada a distúrbios moleculares e bioquímicas que influenciam a sensibilidade e a secreção de insulina. Contudo, não está bem definido se esta associação é confundida por fatores genéticos. Utilizando o modelo de controle de casos (gêmeos monozigóticos (MZ) discordantes) este estudo, de caráter transversal, avaliou 38 pares de gêmeos MZ com idade entre 11 a 18 anos, dos quais nove pares demonstraram diferença média intra-par para o VO2máx de 13,5±3,7 ml.kg-1.min-1 (30,6±9,5%). O objetivo foi investigar o impacto da discordância no VO2máx nas concentrações bioquímicas de glicose, insulina, lipídios, leptina, interleucina 6 e na expressão do mRNA dos genes SUR1, KIR6.2, IL6, LEPTINA e PPARg, independente de efeitos genéticos. Foram obtidas as medidas antropométricas de massa corporal, estatura, circunferência da cintura (CC) e espessuras de dobras cutâneas (EDC). Um teste de esforço máximo em esteira rolante com análise direta dos gases foi utilizado para a determinação do VO2máx e uma colheita de sangue em jejum e pós-carga de glicose (TOTG) para a realização de exames laboratoriais, extração dos genes e estimativa do índice HOMA-RI e HOMA-β. A expressão do mRNA dos genes foi quantificada e avaliada por RT-PCR enquanto as variáveis laboratoriais foram determinadas por kits específicos. Os resultados revelaram maior adiposidade corporal (soma de 6 EDC), índice HOMA (RI e β), concentração sanguínea de leptina, insulina em jejum e pós-carga (2 h) favorecendo as meninas, enquanto os meninos demonstraram maior VO2máx. Correlação negativa foi observada entre o VO2máx e os indicadores de obesidade (IMC, CC e adiposidade), índice HOMA (RI e β) e concentração sanguínea de leptina, insulina em jejum e pós-carga (2 h)... / Experimental studies have shown that low cardiorespiratory fitness (VO2max) is associated with molecular and biochemical disturbances that influence insulin sensitivity and secretion. However, it is not defined whether this association is confounded by genetic factors. Using the monozygotic co-twin case-control, this cross-sectional study evaluated 38 MZ twins pairs from 11 to 18 years of age, of which nine pairs presented a mean intrapair difference in VO2max of 13.5 ± 3.7 ml.kg-1.min-1 (30.6 ± 9.5%). The objective was to investigate the impact of the discordances of VO2max on biochemical concentrations of glucose, insulin, lipids, leptin, and interleukin 6, as well as in genes SUR1, Kir6.2, IL6, leptin and PPARgamma mRNA expression, independent of genetic effects. We obtained the anthropometric measures of body weight, height, waist circumference (WC) and skinfold thickness (ST). The maximal treadmill test with direct analysis of inhaled and exhaled gases was used for determination of VO2max, as well as fasting and oral glucose tolerance tests (OGTT) blood sample collections for laboratory analysis, gene extraction and estimation of HOMA-IR and HOMA-β indexes. mRNA genes expression was quantified and evaluated by RT-PCR, while laboratory variables were determined using specific kits. The results showed greater body adiposity (sum of 6 STs), HOMA (IR and β) indexes, blood leptin concentration and fasting and post load (2 h) insulin levels in girls, while boys showed greater VO2max. Negative correlation was found between VO2max and indicators of obesity (BMI, WC and fatness), HOMA (IR and β) indexes and blood leptin concentration and fasting and post load (2 h) insulin levels and positive correlation with PPARgamma gene expression. Regarding the discordant pairs, we observed that the co-twins with the highest VO2max values (45.9 ± 10.0 ml.kg-1.min-1) had significanty... (Complete abstract click electronic access below)

CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / O diabetes mellitus tipo 2 (DM2), doenÃa multifatorial, heterogÃnica, resulta de suscetibilidade genÃtica associada a fatores ambientais, especialmente sedentarismo e dieta rica em gorduras saturadas, e a obesidade. Caracteriza-se por resistÃncia à insulina (RI) e pela diminuiÃÃo da secreÃÃo desse hormÃnio. InflamaÃÃo moderada e crÃnica no tecido adiposo branco disfuncional, denominada âmeta-inflamaÃÃoâ, parece ser o elo entre obesidade, RI e DM2. Papel de adipocinas produzidas pelo tecido adiposo nessas afecÃÃes vem sendo investigado. Objetiva-se neste estudo verificar se suplementaÃÃo oral (SO) de mistura de Ãleos (MXO) com relaÃÃo de Ãmega 9 / Ãmega 6 (ω9/ω6) elevada e de Ãmega 6 / Ãmega 3 (ω6/ω3) baixa, de diferentes fontes de ω3, interfere em adipocinas plasmÃticas de camundongos com DM2. Depois de alimentados ad libitum com dieta da AIN-93G atà ficarem adultos, camundongos Swiss (CSW) machos receberam, por onze semanas, dieta AIN-93HA, hiperlipÃdica adaptada, para induÃÃo de DM2, confirmado em 90% deles. Mantida a dieta AIN-93HA, os CSW com DM2 receberam, em grupos, por sete dias, SO com MXO: GA: H₂O (controle nulo); GB: MXO [ω9:ω3 0,4:1;ω6:ω3 8:1 (controle neutro)]; GC: MXO [ω9:ω3 3,7:1; ω6:ω3-ALA 1,4:1]; GD: MXO [ω9:ω3 3,7:1;ω6:ω3-EPA+DHA de peixe 1,4:1]; GE: MXO [ω9:ω3 3,7:1; ω6:ω3-DHA de algas 1,4:1]. Por imunoensaios, realizou-se dosagem plasmÃtica de insulina e de adipocinas, fator de necrose tumoralâalfa (TNF-α); interleucina-6 (IL-6); interleucina-1 beta (IL-1β); fator ativador de monÃcitos (MCP-1); resistina (RES); leptina (LEP); inibidor do fator ativador de plasminogÃnio 1 (PAI-1) e adiponectina (AdipoQ). Constatou-se diferenÃa estatÃstica significante de adipocinas do grupo GE (ω3-DHA de algas), em relaÃÃo aos outros grupos, com aumento de IL-6 em relaÃÃo ao GC e GD; diminuiÃÃo de LEP em relaÃÃo ao GA; aumento de TNF-α em relaÃÃo aos grupos GB, GC e GD; e diminuiÃÃo de AdipoQ em relaÃÃo ao GB; assim como de RES entre os grupos GC (ω3-ALA) e GD (ω3-EPA+DHA). NÃo houve diferenÃa estatÃstica significante em nenhuma das variÃveis entre grupos controles. Continuidade de dieta rica em gordura saturada pode ter comprometido a eficÃcia da suplementaÃÃo de MXO ricos em ω3 e ω9. O âestado da arteâ demanda outros estudos para esclarecer o papel do DHA na âmeta-inflamaÃÃoâ. / Diabetes mellitus type 2 (DM2), a multifactorial disease, heterogenic results of associated genetic susceptibility to environmental factors, especially sedentary lifestyle and a diet rich in saturated fats, and obesity. It is characterized by insulin resistance (IR) and by decreasing the secretion of this hormone. Moderate and chronic inflammation in white adipose tissue dysfunctional, called "meta-inflammation," seems to be the link between obesity, IR and DM2. Role of adipokines produced by adipose tissue in these diseases has been investigated. Objective of this study was to verify whether oral supplementation (SO) of oil blend (MXO) compared with omega 9 / omega 6 (ω9/ω6) and high omega 6 / omega 3 (ω6/ω3) low, from different sources of ω3 interferes with adipokines plasma of mice with T2DM. After fed ad libitum with AIN-93G diet until they become adult Swiss mice (CSW) males received by eleven weeks AIN-93HA, hyperlipidic adapted to induce DM2 confirmed in 90% of them. Maintained the AIN-93HA, the CSW with T2DM were in groups of seven days, with MXO SO: GA: H ₂ O (null control) GB: MXO [ω9: ω3 0.4:1; ω6: ω3 8: 1 (neutral control)]; GC: MXO [ω9: 3.7:1 ω3, ω6: ω3-ALA 1.4:1]; GD: MXO [ω9: 3.7:1 ω3, ω6: ω3-EPA + DHA from fish 1.4:1]; GE: MXO [ω9: ω3 3.7:1; ω6: ω3, DHA from algae 1.4:1]. Why immunoassays, held measurement of plasma insulin and adipokines, tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-1 beta (IL-1β), monocyte activating factor ( MCP-1), resistin (RES), leptin (LEP), an inhibitor of plasminogen activator 1 (PAI-1) and adiponectin (ADIPOQ). It found a statistically significant difference of adipokines group GE (ω3-DHA from algae), compared to the other groups, with increased IL-6 compared to GC and GD, fewer LEP compared to GA; increase of TNF- α in relation to groups GB, GC and GD, and ADIPOQ decrease compared to GB, as well as RES between GC (ω3-ALA) and GD (ω3-EPA + DHA). There was no statistically significant difference in any of the variables between control groups. Continuity diet high in saturated fat may have compromised the effectiveness of supplementation MXO rich in ω3 and ω9. The "state of the art" demand further studies to clarify the role of DHA in the "meta-inflamaÃÃoDM2, Adipokines, saturated fatty acids, omega fatty acids 3, 6 and 9 and" meta-inflammation

Introdução: A prevalência de Síndrome Metabólica (SM) tende a ser alta em pacientes com doenças reumáticas, sendo as doenças cardiovasculares a principal causa de óbito nestas condições. Objetivos: Determinar a prevalência de SM em pacientes com Arterite de Takayasu (AT) e sua associação com fatores de risco, níveis de adipocinas e de citocinas. Métodos: Foi realizado um estudo transversal incluindo 45 mulheres com AT e 47 controles saudáveis pareados por idade e índice de massa corporal (IMC). Resultados: A prevalência de SM (critérios da IDF/AHA) foi maior em pacientes com AT comparada aos controles (33,34 vs. 8,51%, p = 0,003). Pacientes com TA apresentaram maior frequência de hipertensão (p < 0,001) e dislipidemia (p = 0,001) e maiores níveis de insulina (p = 0,021), HOMA-IR (p = 0,024), apolipoproteína E (p = 0,029), resistina (p = 0,018) e PCR (p < 0,001) comparada aos controles saudáveis, com níveis comparáveis de adiponectina e PAI-1 (p > 0,05). Análise adicional de pacientes com AT com e sem SM revelou um maior frequência de sobrepeso/obesidade (66,66 vs. 26,66%, p = 0,022), escore de Framingham >-1 (p=0,032) e menores níveis de adiponectina (20,37+-21,16 vs. 38,64+-22,62ug/ml, p=0,022) no primeiro grupo. Não foram encontradas diferenças quanto à duração de doença, atividade, uso de glicorticóides, níveis de resistina e PAI-1 nos dois grupos de pacientes com AT (p > 0,05). Pacientes com e sem SM não demonstraram diferenças em relação aos níveis plasmáticos de citocinas (IL-12, IL-1a, IL-6 e TNFalfa). Foi evidenciada correlação de Pearson positive entre IL-6 e PCR somente nos pacientes com SM (r=0.57; p=0.050). Conclusão: Alta prevalência de SM foi observada em pacientes com AT, sendo que esta comorbidade parece identificar um subgrupo de pacientes com sobrepeso/obesidade com alto risco cardiovascular sem associação com o status de doença. Estudos longitudinais são necessários para observar o impacto do controle de fatores de risco modificáveis na qualidade de vida e sobrevida dos pacientes com AT / Introduction: The prevalence of Metabolic Syndrome (MetS) tends to be high among rheumatic patients, and cardiovascular disease is the leading cause of death in these conditions. Objective: To determine the prevalence of MetS in Takayasu Arteritis patients (TA) and its association with risk factors and adipokines and cytokines levels. Methods: A cross sectional study was conducted in 45 consecutive TA women with 47 age- and body mass index (BMI)-matched healthy controls. Results: The prevalence of MetS (IDF/AHA criteria) was higher in TA compared to controls (33.34 vs. 8.51%, p=0.003). TA patients had higher frequency hypertension (p < 0.001), dyslipidemia (p=0.001), insulin (p=0.021), HOMA-IR (p=0.024), apoliprotein E (p=0.029), resistin (p=0.018) and CRP (p < 0.001) compared to healthy subjects, with similar levels of adiponectin and PAI-1 (p > 0.05). Further analysis of TA patients with and without MetS revealed a higher frequency of overweightness/obesity (66.66 vs. 26.66%, p=0.022), Framingham score >-1 (p=0.032), and lower adiponectin levels (20.37+-21.16 vs. 38.64±22.62ug/ml, p=0.022) in the former group. No differences were found regarding disease duration, activity, glucocorticoid use, resistin and PAI-1 levels in these two groups of TA patients (p > 0.05). Patients with and without MetS showed no differences respect to cytokines levels (IL-12, IL-1a, IL-6 and TNFalfa). IL-6 had a positive Pearson correlation with CRP only in TA patients with MetS (r=0.57; p=0.050). Conclusion: A high prevalence of MetS was observed in TA patients and this comorbidity seems to identify a subgroup of overweight/obese patients with high cardiovascular risk without a significant association with disease status. Further longitudinal studies are necessary to observe the impact of controlling this modifiable risk factor in the quality of life and survival of TA patients

C1q TNF Related Protein 3 (CTRP3) is a novel adipose tissue derived secreted factor, or adipokine, which has been linked to a number of beneficial biological effects on metabolism, inflammation, and survival signaling in a variety of tissues. However, very little is known about CTRP3 in regards to human health. The purpose of this project was to examine circulating CTRP3 levels in a clinical population, patients with symptoms requiring heart catheterization in order to identify the presence of obstructive coronary artery disease (CAD). It was hypothesized that serum CTRP3 levels would be decreased in the presence of CAD. Methods Body mass index (BMI), diabetes status, and plasma samples were collected from 100 patients who were >30 years of age and presented at the East Tennessee State University Heart Clinic with symptoms requiring heart catheterization in order to identify the presence of cardiovascular blockages (n = 52 male, n = 48 female). Circulating CTRP3 levels were quantified using commercially available ELISA. Results Circulating CTRP3 levels had no relationship to the presence of CAD regardless of gender. However, circulating concentrations of CTRP3 were significantly higher in normal weight (BMI < 30) females (0.88 ± 0.12 µg/ml) compared with males (0.54 ± 0.06 µg/ml). Further, obesity (BMI > 30) resulted in an increase in circulating CTRP3 levels in male subjects (0.74 ± 0.08 µg/ml) but showed a significant decrease in female subjects (0.58 ± 0.07 µg/ml). Additionally, there was a significant reduction in circulating CTRP3 levels in female subjects who were diagnosed with Type 2 diabetes compared with patients without (0.79 ± 0.08 vs. 0.42 ± 0.10 µg/ml). There was no relationship between diabetes status and circulating CTRP3 levels in male subjects. Conclusion Circulating CTRP3 levels had a different relationship with diabetes and obesity status between male and female patients. It is possible that circulating CTRP3 levels are controlled by hormonal status, however more research is needed to explore this relationship. Nevertheless, future studies examining the relationship between CTRP3 levels and disease status should treat gender as an independent variable.

Ο λιπώδης ιστός δεν θεωρείται πλέον αποκλειστικά παθητικός αποταμιευτικός ιστός, αλλά εκκρίνει ποικίλα βιοδραστικά πεπτίδια, γνωστά ως λιποκίνες. Η εμπλοκή των τελευταίων στην παθογένεια του μεταβολικού συνδρόμου και των επιπλοκών του τις καθιστά μόρια-στόχους που δύνανται να συμβάλουν στη θεραπευτική προσέγγιση του μεταβολικού συνδρόμου. / Adipose tissue is no more considered a passive tissue with storage function, but it has proved to be a source of a variety of bioactive peptides, described as adipokines. The implication of adipokines in the pathogenesis of metabolic syndrome and its consequences renders many of them putative target molecules in a new therapeutic approach of this syndrome.

Adipose tissue represents an important endocrine organ that secretes a multitude of adipokines known to mediate inflammation, lipid metabolism, and insulin sensitivity in peripheral tissues such as skeletal muscle. Specifically, adiponectin stimulates skeletal muscle fatty acid oxidation and is associated with improvements in insulin response. Long-chain n-3 polyunsaturated fatty acids (PUFA) are well known for their anti-inflammatory and insulin-sensitizing properties, and their dietary consumption is associated with a more favourable circulating adipokine profile, including increased adiponectin. However, whether n-3 PUFA can directly stimulate adiponectin secretion from human adipocytes, as well as the underlying mechanisms involved, is unknown. In contrast to n-3 PUFA, diets high in saturated fatty acids (SFA) are thought to decrease adiponectin and increase pro-inflammatory adipokines, as well as blunt skeletal muscle response to both adiponectin and insulin, possibly via activation of inflammatory pathways. The role of n-3 PUFA in mediating the communication between adipose tissue and skeletal muscle, as well as preventing SFA-induced impairments in skeletal muscle function, has yet to be examined. In this thesis, it was found that long-chain n-3 PUFA increase adiponectin secretion from human adipocytes via a peroxisome proliferator-activated receptor gamma-dependent mechanism. The effects of n-3 PUFA on adiponectin secretion were additive when combined with the thiazolidinedione, rosiglitazone. Secondly, incorporation of n-3 PUFA into a high SFA diet prevented impairments in adiponectin response and both prevented and restored impairments in insulin response in rodent skeletal muscle. Interestingly, these findings were paralleled by prevention of SFA-induced increases in toll-like receptor 4 expression by n-3 PUFA, suggesting inflammatory changes may be involved. Finally, dietary n-3 PUFA and SFA modulated the secretion of adipose tissue-derived factors from visceral rodent adipose tissue and subsequent exposure of isolated skeletal muscle to such factors induced acute changes in inflammatory gene expression without affecting insulin sensitivity. Together, the findings in this thesis suggest that n-3 PUFA modulate adipokine secretion from adipose tissue and that adipose-derived factors mediate skeletal muscle inflammation and response to adiponectin and insulin. Ultimately, this work highlights the importance of considering n-3 PUFA as a therapeutic strategy in the prevention and treatment of obesity and related pathologies.

Dysregulation of adipokines in obese adipose tissue contributes to inflammation and insulin resistance. Fatty acids and lipopolysaccharide (LPS) can modulate adipokine secretion, however, less is known about their effects in combination. Long-chain n-3 polyunsaturated fatty acids (PUFA) exert anti-inflammatory effects and less is known about other n-3 and n-6 PUFA, which are more prevalent in the typical diet. Co-incubation of 3T3-L1 adipocytes with LPS and long-chain n-3 PUFA decreased LPS-induced secreted MCP-1 protein. n-6 PUFA arachidonic acid and LPS synergistically increased MCP-1 and IL-6 secreted proteins. Plant-derived PUFA were relatively neutral stimuli. mRNA expression results suggest potential roles for G protein-coupled receptor 120 and toll-like receptor 2 in mediating the effects of long-chain n-3 PUFA and arachidonic acid, respectively. Overall, this thesis suggests that both n-3 and n-6 PUFA are important factors to consider in the development of nutritional strategies for improving adipose tissue inflammation associated with obesity. / NSERC CGS, Ontario Graduate Scholarship

Apelin ist ein Adipokin, das Einfluß auf die Glukosehomöostase hat und vermutlich eine wichtige Rolle in der Regulation von Adipositas und den damit assoziierten Erkrankungen einnimmt. Die Effekte von Apelin scheinen metabolisch günstig zu sein. In dieser Arbeit wurden zunächst Apelin-Serumkonzentrationen und metabolische Parameter bei 740 Studienteilnehmern bestimmt und in einer Querschnittsstudie (n=629) sowie in drei Interventionsstudien (n=111) dargestellt. In einer Subgruppe (n=161) wurde die mRNA-Expression von Apelin und dessen Rezeptor APJ im viszeralen und subkutanen Fettgewebe bei Patienten mit Typ-2-Diabetes genauer untersucht. Im Rahmen der Interventionsstuden wurde der Einfluß von 12 Wochen körperlichem Training (n=60), 6 Monaten hypokalorischer Mischkost (n=19) und bariatrischer Chirurgie (n=32) auf den Serum-Apelinspiegel sowie Zusammenhänge mit Gewichtsreduktion, verbesserter Insulinsensitivität und subklinischer Inflammation analysiert. Die höchsten Apelin-Serumkonzentrationen fanden sich beim adipösen Typ-2-Diabetiker. Die Apelin-Serumkonzentration korrelierte aber auch unabhängig vom Bodymassindex signifikant mit Parametern für Insulinresistenz und subklinischer Inflammation. Die Apelin-Expression war in den unterschiedlichen Fettgewebsdepots bei normal glukosetoleranten Patienten gleich, beim Typ-2-Diabetiker mit insgesamt höherer Expression überwog sie im viszeralen Fettgewebe. Nach allen Interventionsstudien kam es zur Abnahme der Apelin-Serumkonzentration und korrelierte auch dann signifikant mit einer verbesserten Insulinsensitivität, wenn es zu keiner Gewichtsreduktion kam. Die Apelinkonzentration im Serum sowie die Expression im Fettgewebe ist nicht nur vom Bodymassindex abhängig, sondern steht im direkten Zusammenhang mit Insulinsensitivität und inflammatorischen Prozessen. Die unterschiedliche fettdepotspezifische Regulation unterstreicht die pathogenetische Bedeutung eines „kranken“ viszeralen Fettgewebes in der Entwicklung von Typ-2-Diabetes, wobei Apelin als metabolisch günstiges Adipokin vermutlich eine kompensatorische Rolle einnimmt.