Proopiomelanocortin (POMC) is a polypeptide precursor with 241 amino acid residues which undergoes extensive post-translational modification to yield a range of smaller, biological active peptides including £\-, £] -, £^-melanocyte-stimulating hormone (£\-MSH, £]-MSH, £^-MSH )¡A£]-endorphin (£]-EP) and adrenocorticotrophic hormone (ACTH). POMC-derived peptides play important roles in appetite and energy homeostasis. Recently, the peripheral POMC system is under active investigation to delineate their pathogenic roles in metabolic diseases such as Cushing¡¦s syndrome and obesity. In the present study, we utilized adenovirus gene delivery system to achieve systemic POMC overexpression in adult C57/BL6 mice for at least 30 days. Subsequently, the plasma and abdominal adipose tissue of mice were collected and analyzed by biochemical assays and weight determination respectively. POMC overexpression did not increase in the food uptake and body weight. These results imply that local POMC gene delivery induced the visceral fat accumulation and altered the metabolism in mice. It was observed that systemic POMC overexpression significantly elevated the triglyceride and the cholesterol levels in mice. However, POMC gene delivery also induced elevated plasma glucose concentration at weeks 1-4 and evoked glucose tolerance in mice at week 4. Interestingly, insulin resistance was readily detected in POMC-transduced in mice at as early as week 1. Besides, Micro-CT scanning and histological studies demonstrated that the visceral fat was significantly increased in POMC over-expressing mice compared with control animals. These data indicate that hepatic POMC gene delivery causes systemic ACTH rise and insulin resistance, which recapitulates the clinical features of Cushing¡¦s syndrome. In summary, POMC gene delivery induces systemic POMC overexpression and results in visceral fat accumulation and insulin resistance, which may facilitates a mice model for Cushing¡¦s-like metabolic syndrome.

PANcreatic-DERived Factor (PANDER), or FAM3B, is a 235-amino acid protein strongly expressed within and secreted from the endocrine pancreas. Research surrounding PANDER has revealed a large role for the protein in maintaining glucose homeostasis, as evidenced by several Ad-PANDER overexpressing murine models, our lab's pancreas-specific PANDER transgenic overexpressor, and most recently our mixed genetic C57/129J PANDER knockout (PANKO) mouse. However, PANDER's overall role in glycemic regulation and glucose homeostasis has yet to be studied in a purebred C57BL/6J PANDER knockout model. Here we present the first phenotypic characterization of our global PANDER knockout mouse on a C57BL/6J background (PANKO-C57) where we examined metabolics through glucose/insulin tolerance testing, fasting glycemia, and body weights, the concentrations of hormonal analytes along with lipids and corticosterones, and full elucidation of hepatic insulin signaling through the insulin signaling cascade. Overall, the PANKO-C57 mice exhibited increased body weights with enhanced glucose tolerance and lower fasting glycemia, similar peripheral insulin sensitivities, increased hepatic lipidemia, and enhanced hepatic insulin signaling at critical insulin signaling molecules. Taken together, the PANKO-C57 demonstrates that the disruption of PANDER results in selectively enhanced hepatic insulin signaling yet with increased lipidemia and overall body weight. These findings reveal a novel role for PANDER in differentially controlling lipogenesis and hepatic glucose production that may selectively impact overall glycemic control and potentially facilitate the onset and/or progression of type 2 diabetes.

No abstract available. / Thesis (M.D.)-University of Natal, 1990.

Eine gezielte bewegungstherapeutische Intervention verbessert den Glukosestoffwechsel, reduziert den Grad der Adipositas und belegt einen antiinflammatorischen Effekt. Ungeklärt ist dabei, in welchem Zeitintervall sich die jeweiligen Risikoparameter Adipositas, Glukosestoffwechsel und chronische Entzündungsreaktionen, in einer 12-monatigen Kontroll-Interventionsstudie bei Patienten mit gestörter Glukosetoleranz (IGT) im Vergleich zu einer Rosiglitazontherapie und einer unbehandelten Kontrollgruppe adaptieren. In der vorliegenden Untersuchung wurden 60 Patienten aus einer Population von 500 Probanden mittels 2-Stunden oralem Glukose Toleranztest (2h-oGTT) als Patienten mit gestörter Glukosetoleranz identifiziert und randomisiert den zwei Therapiearmen, Rosiglitazon- und Bewegungstherapie, sowie einer Kontrollgruppe zugeführt. Es werden dabei die Effekte einer 3-mal wöchentlichen Bewegungstherapie auf den Body Mass Index (BMI), Waist Hip Ratio (WHR), Fasting Plasma Insulin (FPI), Fasting Plasma Glukose (FPG), HbA1c, 2h-oGTT, maximale Sauerstoffaufnahme (VO2max) sowie Interleukin 6 (IL6) und C-reaktives Protein (CrP) nach 1, 6 und 12 Monaten untersucht. Die Bewegungstherapie erzielt nach 1 Monat eine signifikante Verbesserung der Adipositas und des Glukosestoffwechsels. Eine Reduzierung der chronischen Entzündungsreaktion via IL6 konnte nach 12 Monaten erreicht werden. Im vergleichbaren Zeitraum zeigt die Kontrollgruppe keine statistischen Änderungen des BMI, des WHR und der inflammatorischen Parameter. Die Insulinsensitivität verminderte sich in der Kontrollgruppe signifikant innerhalb von 12 Monaten. Unter Applikation von täglich 4 mg Rosiglitazon verbessert sich der Glukosestoffwechsel nach 6 Monaten. Änderungen des Grades der Adipositas und der chronischen Entzündungsreaktion konnten nicht erzielt werden. Die Untersuchungen belegen den hohen Stellenwert der Bewegungstherapie in der Behandlung von IGT-Patienten als Standardtherapieoption. Die Bewegungstherapie sollte mindestens 3-mal wöchentlich als kombiniertes Kraft- und Ausdauertraining bei einer Intensität von 70 - 85 % VO2max und 70 - 85 % 1RM erfolgen.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2005. / Härtill 4 uppsatser.

Diss. (sammanfattning) Uppsala : Univ., 2003. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 5 uppsatser.

Thesis (Ph. D.)--University of Washington, 1997. / Vita. Includes bibliographical references (leaves [102]-118).

Submitted by Simone Souza (simonecgsouza@hotmail.com) on 2017-09-20T13:55:03Z No. of bitstreams: 1 DISS_2014_Morenna Alana Giordani.pdf: 1859265 bytes, checksum: b5d9642bcb74a3b47527bc37b687bab3 (MD5) / Approved for entry into archive by Jordan (jordanbiblio@gmail.com) on 2017-09-26T12:41:05Z (GMT) No. of bitstreams: 1 DISS_2014_Morenna Alana Giordani.pdf: 1859265 bytes, checksum: b5d9642bcb74a3b47527bc37b687bab3 (MD5) / Made available in DSpace on 2017-09-26T12:41:05Z (GMT). No. of bitstreams: 1 DISS_2014_Morenna Alana Giordani.pdf: 1859265 bytes, checksum: b5d9642bcb74a3b47527bc37b687bab3 (MD5) Previous issue date: 2014-08-25 / CNPq / A Cedrela odorata L. (cedro-rosa) foi selecionada para a avaliação antidiabética in vivo, com base nos resultados obtidos em triagem in vitro, realizada com várias plantas citadas em levantamento etnofarmacológico na região do Vale do Juruena – Mato Grosso. Nesta triagem foram avaliadas a inibição da alfa-glicosidase e a capacidade antioxidante pelo sequestro do radical DPPH dos extratos hidroetanólicos. O extrato hidroetanólico da entrecasca de C. odorata L. (EHeCo) apresentou CI50 e CD50 na avaliação inibidora da alfa-glicosidase e antioxidante de 84,6 e 3,7 μg/mL respectivamente, muito abaixo do controles positivos acarbose e vitamina C (5115,5 e 7,9 μg/mL) respectivamente. O fingerprint do EHeCo mostrou a presença de ácido gálico, (-)-galocatequina e (+)-catequinas. Os testes de toxicidade aguda (10 a 5000 mg/kg) e de toxicidade subcrônica (500 mg/kg), mostraram que o extrato apresentou baixa toxicidade nas doses avaliadas. Nos testes de avaliação antidiabética subcrônica, foram utilizados animais diabéticos induzidos com estreptozotocina (40 mg/kg em tampão citrato 0,01 M pH 4,5 iv) e não diabéticos. Os animais diabéticos foram tratados com 250 e 500 mg/kg de EHeCo (DT250 e DT500) por 21 dias e os resultados comparados com o grupo diabético tratados com veículo – DMSO 2% (DC) e com o grupo controle positivo (metformina 500 mg/kg - DMet). Não foram observadas alterações no peso corporal, consumo de ração e água, volume urinário de 24h, glicemia, glicosúria e ureia urinária. O nível de triglicérides plasmáticos foi reduzido nas duas doses avaliadas (N = 132 ± 15; DC = 123 ± 15; DT250 = 73 ± 10#; DT500 = 78 ± 8#; DMet = 142 ± 10 mg/dL, #p<0,05). Após 21 dias de tratamento com EHeCo houve redução na concentração de malonaldeído no sangue (N = 1,9 ± 0,3; DC = 5,6 ± 0,5; DT250 = 3,3 ± 0,3; DT500 = 2,9 ± 0,5#; DMet = 3,9 ± 1,0 μmol/L, #p<0,05) e aumento da atividade das enzimas superóxido dismutase (N = 42,3 ± 0,3; DC = 40,9 ± 0,7; DT250 = 60,7 ± 1,8#; DT500 = 60,8 ± 1,1#; DMet = 42,0 ± 0,4 U/L, #p<0,05) e glutationa peroxidase (N = 16,2 ± 0,5; DC = 11,4 ± 0,7*; DT250 = 15,6 ± 0,5#; DT500 = 14,8 ± 0,3#; DMet = 12,2 ± 0,5 103 U/L, *p<0,05 vs N, #p<0,05 vs DC). O efeito do EHeCo sobre a tolerância à glicose, foi avaliada após uma sobrecarga de glicose, amido e sacarose, sendo o extrato administrado nas mesmas doses dos experimentos subcrônicos, 30 minutos antes da sobrecarga de carboidratos. Foram utilizadas floridzina (DF) como controle positivo para o teste em que a sobrecarga foi glicose, e a acarbose (DA), quando a sobrecarga foi de sacarose ou amido. O extrato, nas duas doses reduziu o pico glicêmico e também a área sobre a curva (glicemia x tempo de avaliação) quando a sobrecarga foi de glicose (N = 16253 ± 318; DC = 37666 ± 2347*; DT250 = 32353 ± 1467; DT500 = 27666 ± 1423#; DF = 25033 ± 1241# mg/dL x 120 minutos, *p<0,05 vs N, #p<0,05 vs DC). Quando a sobrecarga foi de sacarose, o extrato na dose de 500 mg/kg reduziu o pico glicêmico após 30 minutos (N = 138 ± 3; DC = 437 ± 39*; DT250 = 294 ± 38; DT500 = 243 ± 69#; DA = 253 ± 22# mg/dL, *p<0,05 vs N, #p<0,05 vs DC) sem redução da área sobre a curva. O EHeCo não teve efeito sobre a glicemia dos animais que receberam amido. O EHeCo apresentou efeitos anti-hiperglicemiante, hipolipidêmico e antioxidante, mostrando o potencial terapêutico da entrecasca de C. odorata no tratamento do diabetes e das complicações relacionadas à doença. / Cedrela odorata L. (cedro-rosa) was selected for the antidiabetic in vivo evaluation, based on the results obtained from an in vitro screening performed with various plants mentioned in an ethnopharmacological survey in the region of Vale do Juruena - Mato Grosso, Brazil. This screening aimed to evaluate the inhibition of alpha-glucosidase and the antioxidant capacity by DPPH radical sequestering of hydroethanolic extracts. The hydroethanolic extract of the inner stem bark of Cedrela odorata L. (HeECo) showed IC50 and DC50 in the evaluation of inhibition of alpha-glucosidase and an antioxidant capacity of 84.7 e 3.7 μg/mL, respectively, well below the positive control acarbose and vitamin C (5115.5 e 7.9 μg/mL), respectively. The fingerprint of EHeCo showed the presence of gallic acid, (-)- gallocatechin and (+)- catechins. Tests for acute and sub-chronic toxicity showed that the extract presented low toxicity at the evaluated doses. In the sub-chronic antidiabetic evaluation tests, streptozotocin-induced diabetic rats (40 mg/kg in 0.01 M citrate buffer pH 4.5 iv) and non-diabetic rats were used. Diabetic animals were treated with 250 and 500 mg/kg HeECo for 21 days and the results were compared with the vehicle-treated diabetic group - 2% DMSO (DC) and the positive control group (metformin - DMet). No changes were observed in body weight, food and water intake, urine volume, blood glucose, glucosuria and urinary urea. The triglyceride level was reduced at the two doses (N = 132 ± 15; DC = 123 ± 15; DT250 = 73 ± 10#; DT500 = 78 ± 8#; DMet = 142 ± 10 mg/dL, #p<0,05). After 21 days of treatment with HeECo, the concentration of malondialdehyde in the blood was reduced (N = 1.9 ± 0.3; DC = 5.6 ± 0.5; DT250 = 3.3 ± 0.3; DT500 = 2.9 ± 0.5#; DMet = 3.9 ± 1.0 μmol/L, #p<0.05) and the activity of superoxide dismutase (N = 42.3 ± 0.3; DC = 40.9 ± 0.7; DT250 = 60.7 ± 1.8#; DT500 = 60.8 ± 1.1#; DMet = 42.0 ± 0,4 U/L, #p<0.05) and glutathione peroxidase increased (N = 16.2 ± 0.5; DC = 11.4 ± 0.7*; DT250 = 15.6 ± 0.5#; DT500 = 14.8 ± 0.3#; DMet = 12.2 ± 0.5 103 U/L, *p<0.05 vs N, #p<0.05 vs DC). The HeECo effect on glucose tolerance was assessed after a glucose, starch and sucrose overload, the extract being administered at the same dose as in the sub-chronic experiment, 30 minutes before the carbohydrate overload. Phloridzin (DF) was used as positive control for the test in which the overload consisted of glucose, and acarbose (DA), when the overload was sucrose or starch. The extract, at both doses reduced the glycemic peak and also the area under the curve (N = 16253 ± 318; DC = 37666 ± 2347*; DT250 = 32353 ± 1467; DT500 = 27666 ± 1423#; DF = 25033 ± 1241# mg/dL x 120 minutes, *p<0.05 vs N, #p<0.05 vs DC) when the overload was glucose. When the loading was sucrose, the extract at a dose of 500 mg/kg, reduced the peak blood glucose after 30 minutes without reduction in the area under the curve (N = 138 ± 3; DC = 437 ± 39*; DT250 = 294 ± 38; DT500 = 243 ± 69#; DA = 253 ± 22# mg/dL, *p<0.05 vs N, #p<0.05 vs DC). The HeECo had no effect on blood glucose levels of the animals receiving starch. The HeECo showed antihyperglycaemic, hypolipidemic and antioxidant, showing the therapeutic potential of the inner stem bark of C. odorata in the treatment of diabetes and disease-related complications.

A inibição de mTOR com rapamicina exacerba a intolerância glicose associada a obesidade, um efeito que pode estar associado ao desenvolvimento de processo pró-inflamatório no tecido adiposo. O tratamento de camundongos com rapamicina exacerbou a intolerância a glicose e inflamação do tecido adiposo induzida por dieta hiperlipídica. In vitro, a inibição dos complexos 1 e 2 da mTOR com rapamicina e torina induziu polarização espontânea de macrófagos para o fenótipo M1 e aumentou a atividade fagocítica de macrófagos M0. Camundongos com ativação constitutiva de mTORC1 exclusivamente em células mielóides foram protegidos do ganho de peso, adiposidade, intolerância a glicose e a insulina induzidos pela ingestão de dieta hiperlipídica e apresentaram um aumento da polarização de macrófagos para o fenótipo M2. Em conjunto, nossos dados indicam que a atividade do complexo 1 da mTOR atenua o desenvolvimento da inflamação do tecido adiposo associada a obesidade por um mecanismo que envolve a polarização de macrófagos para o fenótipo M2. / Pharmacological mTOR inhibition with rapamycin exacerbates the glucose intolerance associated with obesity, such an effect that may be associated to the development of inflammatory process in adipose tissue. Rapamycin treatment exacerbates the glucose intolerance and adipose tissue inflammation induced by high fat diet feeding. In vitro, inhibition of mTOR complexes 1 and 2 with rapamycin and torin induced spontaneous macrophage polarization into a pro-inflammatory M1 phenotype and increased M0 macrophage phagocytosis. Mice with constitutive activation of mTOR complex 1 in myeloid cells were protected from body weight gain, fat accretion, glucose and insulin tolerance induced by the intake of high fat diet and displayed a significant increase in macrophage polarization to a M2 phenotype. Altogether, our findings indicate that the activity of mTOR complex 1 attenuates the development of adipose tissue inflammation induced by high fat feeding, through a mechanism that involves a higher polarization of macrophages to anti-inflammatory M2 phenotype.