京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20615号 / 医博第4264号 / 新制||医||1023(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 横出 正之, 教授 浅野 雅秀, 教授 妹尾 浩 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Vitamins are readily available in the modern diet due to liberalized fortification and supplementation policies. This research tested the hypothesis that high multi-vitamin intake by Wistar rats during pregnancy leads to the development of obesity and characteristics of the metabolic syndrome in the offspring. Pregnant Wistar rats were fed the AIN-93G diet containing either the recommended (RV) or 10-fold increase (HV) in vitamin content. Pups were weaned to the RV diet (Study 1), an obesogenic liquid diet (Ob, Study 2), low vitamin diets (1/3RV or 1/6RV, Study 3), or a nutrient selection paradigm (NSP) with 10% and 60% casein diets (Study 4). Body weight (BW), food intake (FI), glucose and insulin responses, appetite hormones, abdominal fat pad mass (FPM) and systolic blood pressure (SBP) was measured. Expressions of mRNA for hypothalamic serotonin (5-HT) receptors and proopiomelanocortin (POMC) were measured in Study 4. Males, but not females, born to HV dams had higher post-weaning BW and FI when weaned to the RV or 1/3RV diet, and exhibited components of metabolic syndrome, including higher FPM, hyperglycemia, insulin resistance and elevated SBP compared with those born to RV dams. The Ob diet led to exaggerated weight gain and expressions of components of metabolic syndrome in both sexes born to dams fed the HV diet. Female pups on the 1/6RV diet from HV dams had two-fold higher glucose response and lower insulin response, but no difference in post-weaning BW and daily FI compared to those from RV dams. In contrast to the pups born to HV dams and fed a single diet, those from the HV dams and on the NSP gained less weight and ate less, and had lower hypothalamic mRNA expressions of 5-HT receptors and POMC. In conclusion, high multi-vitamin intake during pregnancy may lead to obesity, and result in a higher risk of developing characteristics of metabolic syndrome in the offspring. However, sex, weaning diet composition, and the presence of diet choice alter the outcomes.

Vitamins are readily available in the modern diet due to liberalized fortification and supplementation policies. This research tested the hypothesis that high multi-vitamin intake by Wistar rats during pregnancy leads to the development of obesity and characteristics of the metabolic syndrome in the offspring. Pregnant Wistar rats were fed the AIN-93G diet containing either the recommended (RV) or 10-fold increase (HV) in vitamin content. Pups were weaned to the RV diet (Study 1), an obesogenic liquid diet (Ob, Study 2), low vitamin diets (1/3RV or 1/6RV, Study 3), or a nutrient selection paradigm (NSP) with 10% and 60% casein diets (Study 4). Body weight (BW), food intake (FI), glucose and insulin responses, appetite hormones, abdominal fat pad mass (FPM) and systolic blood pressure (SBP) was measured. Expressions of mRNA for hypothalamic serotonin (5-HT) receptors and proopiomelanocortin (POMC) were measured in Study 4. Males, but not females, born to HV dams had higher post-weaning BW and FI when weaned to the RV or 1/3RV diet, and exhibited components of metabolic syndrome, including higher FPM, hyperglycemia, insulin resistance and elevated SBP compared with those born to RV dams. The Ob diet led to exaggerated weight gain and expressions of components of metabolic syndrome in both sexes born to dams fed the HV diet. Female pups on the 1/6RV diet from HV dams had two-fold higher glucose response and lower insulin response, but no difference in post-weaning BW and daily FI compared to those from RV dams. In contrast to the pups born to HV dams and fed a single diet, those from the HV dams and on the NSP gained less weight and ate less, and had lower hypothalamic mRNA expressions of 5-HT receptors and POMC. In conclusion, high multi-vitamin intake during pregnancy may lead to obesity, and result in a higher risk of developing characteristics of metabolic syndrome in the offspring. However, sex, weaning diet composition, and the presence of diet choice alter the outcomes.

Thesis (Ph. D.)--University of Missouri-Columbia, 2009. / The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Vita. "May 2009" Includes bibliographical references.

Submitted by RAQUEL LUNEDO (bln.raquel@yahoo.com.br) on 2016-03-01T19:55:22Z No. of bitstreams: 1 TESE_Raquel_Lunedo_repositorio.pdf: 2945618 bytes, checksum: a9cae139d1f67fb1f8ba4fa91aef40eb (MD5) / Approved for entry into archive by Juliano Benedito Ferreira (julianoferreira@reitoria.unesp.br) on 2016-03-03T19:46:23Z (GMT) No. of bitstreams: 1 lunedo_r_dr_jabo.pdf: 2945618 bytes, checksum: a9cae139d1f67fb1f8ba4fa91aef40eb (MD5) / Made available in DSpace on 2016-03-03T19:46:23Z (GMT). No. of bitstreams: 1 lunedo_r_dr_jabo.pdf: 2945618 bytes, checksum: a9cae139d1f67fb1f8ba4fa91aef40eb (MD5) Previous issue date: 2016-02-16 / Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / A hipótese testada neste projeto é que a restrição alimentar altera a composição da microbiota intestinal e a expressão gênica hepática em frangos de corte, e estas alterações podem influenciar a deposição tecidual das aves. Outra hipótese, é que a genética do frango influencia estas variáveis, e pode alterar a sua resposta frente a restrição alimentar. Os objetivos específicos foram analisar a resposta de duas linhagens de frangos de corte (crescimento rápido – Cobb – ou lento – Label Rouge) a dois programas de restrição alimentar (quantitativa ou energética) sobre: 1) o desempenho zootécnico; 2) a deposição tecidual; 3) a microbiota de íleo e ceco; 4) a expressão de genes relacionados ao metabolismo hepático. Para tal, dois experimentos foram conduzidos, sendo que no experimento I foram utilizados 480 frangos de corte, machos, da linhagem comercial Cobb500TM e no experimento II foram utilizados 480 frangos de corte, machos, da linhagem Label Rouge. Até os 21 dias as aves receberam mesma dieta e foram criadas em temperatura termoneutra. Aos 22 dias, oito grupos de 20 aves foram distribuídos dentro de cada um dos três tratamentos experimentais: 1. Controle (ad libitum – 3,176 Mcal/kg de EM e 19% PB); 2. Restrição energética (2,224 Mcal/kg EM e 19% PB) até os 43 dias de idade, com consumo equiparado ao controle; 3. Restrição quantitativa (restrição de 70%, ou seja, as aves restritas ingeriram apenas 30% da quantidade de ração consumida pelo grupo controle – 3,176 Mcal/kg EM e 19% PB) durante 7 dias, seguido de realimentação ad libitum até os 43 dias de idade. A restrição alimentar energética diminuiu o ganho de peso e o peso da carcaça e piorou a conversão alimentar em ambas as linhagens; diminuiu as contagens do grupo Lactobacillus e aumentou as contagens de Enterococcus e Enterobacteriaceae nas aves de crescimento rápido; favoreceu a proliferação de Lactobacillus, e diminuiu as populações de Enterococcus e Enterobacteriaceae nos cecos dos frangos de crescimento lento; induziu a expressão gênica das enzimas ACACA e FASN nas aves de crescimento lento e da enzima CPT1-A nas aves de crescimento rápido; e reduziu a massa de gordura corporal nas aves de crescimento rápido. Durante a semana de restrição alimentar quantitativa, não foi verificado ganho de peso em ambas as linhagens. A restrição levou a: diminuição das contagens do grupo Lactobacillus e aumento de Enterococcus e Enterobacteriaceae nas aves de crescimento rápido; indução da expressão gênica de ACACA, FASN e SREBP- 1 e repressão da expressão de CPT1-A nas duas linhagens. No período de realimentação, foi observado comportamento hiperfágico, melhor ganho de peso e melhor conversão alimentar nas aves restritas. O ganho compensatório não foi suficiente para alcançar o mesmo peso vivo. Nos frangos de crescimento rápido, a deposição tecidual foi semelhante ao controle, porém nas aves de crescimento lento ocorreu maior deposição de gordura e menor deposição de proteína corporal nas aves restritas. Em conclusão, apesar da resposta das variáveis ganho de peso e conversão alimentar aos programas de restrição alimentar ter sido semelhante nos dois grupos genéticos, a composição e a estabilidade da microbiota intestinal de frangos de corte foram dependentes da linhagem. Adicionalmente, encontramos evidências sobre a relação entre expressão de genes lipogênicos hepáticos e a deposição de lipídeos na carcaça de frangos de corte, além de demonstrar modificações no padrão de deposição tecidual em função da velocidade de crescimento da linhagem. / The hypothesis of this project is that feed restriction alters the composition of gut microbiota and hepatic gene expression in broilers, and these changes can influence the tissue deposition of birds. The second hypothesis is that the broiler genetics influence on these variables, and can change the response in front of feed restriction. The specific objectives were investigated the response of broilers (fast – Cobb – or slow-growing – Label Rouge – strains), in front of two feed restriction programs (energetic or quantitative), on: 1) growth performance; 2) tissue deposition; 3) ileal and cecal microbiota; 4) expression of genes related to hepatic metabolism. For this, two experiments were conducted. In the experiment I, were used 480 male Cobb500TM broilers, and in the experiment II, were used 480 male Label Rouge broilers. Up to 21 days of age, the birds received the same diet and were created in thermoneutral temperature. At 22 days of age, birds were divided into 3 experimental treatments (8 replicates of 20 birds): T1. Control (ad libitum – 3.176 Mcal/kg ME and 19% CP); T2. Energetic restriction (2.224 Mcal/kg ME and 19% CP) up to 42 days with consumption equivalent to control; T3. Quantitative restriction (70% restriction, i. e., restricted broilers ingested only 30% of the quantity consumed by the control group – 3.176 Mcal/kg ME and 19% CP) for 7 days, followed by refeeding ad libitum until 42 days. Energetic restriction reduces body weight gain and carcass weight and increased feed conversion ratio in both strains; reduced the Lactobacillus and increased the Enterococcus and Enterobacteriaceae copies in fast-growing broilers; promoted the Lactobacillus proliferation and reduced Enterococcus and Enterobacteriaceae populations in ceca of slow-growing broilers; induced the gene expression of ACACA and FASN in slow-growing, and CPT1-A in fast-growing broilers; and reduced the fat mass in fast-growing broilers. During the quantitative feed restriction period, was not verified body weight gain, independently of strain. The restriction leads to: reduction in Lactobacillus and increase in Enterococcus and Enterobacteriaceae copies in fast-growing broilers; induction of ACACA, FASN and SREBP-1 and reduction in CPT1-A gene expression in both strains. During the refeeding period, was observed hyperphagic behavior, better body weight gain and lower feed conversion ratio in restricted birds. The compensatory growth was not sufficient to achieve the same 42d body weight than the control treatment. For slowgrowing broilers, there was greater fat deposition and lower protein deposition after refeeding, whereas for fast-growing broilers, no difference between control and restricted birds were found. In conclusion, although the body weight gain and feed conversion ratio response of two genetic groups in front of feed restriction programs is similar, the composition and stability of the intestinal microbiota are strongly dependent on host. Additionally, the present data provide evidence on the relationship between hepatic lipogenic gene expression and lipids deposition in broilers carcass, and demonstrated that changes in the tissue deposition is directly related to growth rate in broilers. / CNPq: 141453/2012-5 / FAPESP: 2013/05924-6

Submitted by Irene Nascimento (irene.kessia@ufpe.br) on 2017-03-29T19:31:11Z No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) TESE_MADGE FARIAS FECHINE_.pdf: 4788089 bytes, checksum: 648782ee88724431e5d44996b0235367 (MD5) / Made available in DSpace on 2017-03-29T19:31:11Z (GMT). No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) TESE_MADGE FARIAS FECHINE_.pdf: 4788089 bytes, checksum: 648782ee88724431e5d44996b0235367 (MD5) Previous issue date: 2016-05-31 / CAPES / Objetivo: Investigar os efeitos da desnutrição proteica perinatal ou manipulação do sistema serotoninérgico durante a lactação sob o comportamento alimentar compulsivo após ciclos de Restrição/Realimentação (R/R). Materiais e métodos: Foram formados quatro grupos conforme os tratamentos dietéticos e farmacológicos: Controle (17% caseína na vida perinatal) e Desnutrido (8% caseína na vida perinatal); Salina (10mg/Kg) e Fluoxetina (10mg/Kg) foram submetidos a três consecutivos ciclos de Restrição/Realimentação (ciclos R/R). Cada ciclo R/R é composto por uma fase de restrição (4 dias com 40% do consumo individual médio de dieta padrão nos 7 dias antes de iniciar os ciclos R/R) seguida por uma fase realimentação (4 dias com dieta padrão ad libitum). Assim, os quatro grupos anteriormente descritos foram subdivididos ou não de acordo com a fase de restrição dos ciclos R/R para formar oito grupos: Grupos não restritos [Controle Naïve (CN) n=6 e 10 ou Desnutrido Naïve (DN) n=7 e 11 e Salina Naïve (SN) n=13/15 ou Fluoxetina Naïve (FN) n=12/13] e Grupos restritos [Controle Restrito (CR) n=6 e 11 ou Desnutrido Restrito (DR) n=7 e 10 e Salina Restrito (SR) n=11/13 ou Fluoxetina Restrito (FR) n=13/14]. Após os três ciclos R/R, todos os animais foram submetidos ao teste alimentar (dieta padrão e palatável por 24hs). Após uma semana, os animais dos grupos [Controle Naïve (CN) n=10 ou Controle Restrito (CR) n=11 e Desnutridos Naïve (DN) n=11 ou Desnutrido Restrito (DR) n=10] foram submetidos a um teste de privação alimentar (24hs sem dieta padrão) e em seguida receberam dieta palatável (2hs) e dieta padrão (22hs). Já todos os animais dos grupos Salina e Fluoxetina, aos 120 dias de vida foram submetidos a outro teste alimentar semelhante ao primeiro teste alimentar (após os ciclos R/R). Resultados: Após ciclos R/R os animais Desnutrido Restrito demonstraram hiperfagia por dieta palatável comparados com os animais do grupo Controle Naïve, como também aumentaram o peso corporal sugerindo o desenvolvimento de obesidade. Contudo, estes animais perderam a capacidade para aumentar o consumo de dieta palatável quando estavam com fome, após a privação alimentar. Em relação aos grupos Salina e Fluoxetina não houve diferenças significativas no consumo alimentar (dieta palatável e padrão) nos dois testes alimentares. Conclusão: Desnutrição proteica perinatal ou tratamento de fluoxetina no aleitamento não contribuem para o desenvolvimento de compulsão alimentar após três ciclos R/R. / Objective: To investigate the effects of the perinatal protein undernourishment or manipulation of the serotonergic system in breastfeeding on the binge eating behavior after Restriction/Refeeding cycles (R/R cycles). Materials and methods: Four groups were formed as dietary and pharmacological treatments: Control (17% casein in perinatal life) and Undernourished (8% casein in perinatal life); Saline (10mg/kg) and Fluoxetine (10mg/kg) were submitted to three consecutive cycles of Restriction/Refeeding cycles (R/R cycles). Each R/R cycle was composed of a restriction phase (4 days with 40% of the mean individual consumption standard diet 7 days before starting cycles R/R) followed by a feedback phase (4 days with a standard diet ad libitum). Thus, the four groups described above were subdivided or not according to the restriction phase of R/R cycles to form eight groups: not restricted Groups [Control Naïve (CN) n=6 and 10 or Undernourished Naïve (UN) n=7 and 11 and Saline Naïve (SN) n=13/15 or Fluoxetine Naïve (FN) n=12/13] and Restricted Groups [Restricted Control (CR) n=6 and 11 or Undernourished Restricted (DR) n=7 and 10 and Saline Restricted (SR) n=11/13 or Fluoxetine Restricted (FR) n=13/14]. After three R/R cycles, all animals were subjected to the feeding test (standard diet and palatable food for 24hrs). After one week, the animals of the groups [Control Naïve (CN) n=10 or Restricted Control (CR) n=11 and Undernourished Naïve (DN) n=11 or Undernourished Restricted (UR) n=10] were subjected to a test food deprivation (24hrs without standard diet) and then received palatable food (2hrs) and standard diet (22hrs). Already all the animals of Saline and Fluoxetine groups at 120 days of age were subjected to a similar feeding test the first test (after R/R cycles). Results: After R/R cycles the Restricted Undernourished animals showed hyperphagia by palatable food compared to animals Naïve control group, as well as increased body weight suggesting the development of obesity. However, these animals have lost the ability to increase the intake of palatable food when they were hungry after food deprivation. Regarding Saline and Fluoxetine groups there was not significant differences in food intake (standard diet and palatable food) in both feeding tests. Conclusion: Perinatal protein undernourishment or treatment of fluoxetine in breastfeeding do not contribute to the development of binge eating after three R/R cycles.

No description available.

Background Obesity is currently one of the major causes of ill health and it is clear that overeatingis the cause of obesity. However, the actions of many endogenous factors that contribute to overeating are still not well understood. Gamma-aminobutyric acid (GABA)-ergic transmission has been shown to be of great importance for food intake regulation. The progesterone metabolite allopregnanolone is a potent positive GABAA receptor modulating steroid (GAMS) and in humans, elevated allopregnanolone levels have been suggested to be involved in increased food intake, and also with overweight and obesity. GABAA receptors that express the α2 and α3 subunits are proposed to be the main subtypes involved in food intake regulation. Therefore, the aims of the work in this thesis were to further investigate the effect of allopregnanolone on food intake, feeding behaviour, possible effects on weight gain and also to characterize a possible antagonist at α2β3γ2and α3β3γ2 GABAA receptors. Methods Allopregnanolone effects on food intake of different food items were recorded in male Wistar rats. Feeding patterns were analyzed. Food preference tests were also conducted and rats were repeatedly exposed to allopregnanolone under different feeding conditions to elucidate possible effects on body weight gain. To deeper investigate GABAA receptor subtypes suggested to be involved in food intake regulation, electrophysiological whole-cell patch-clamp recordings were performed to identify the specificity of the GAMS antagonist UC1020, at human α2β3γ2 and α3β3γ2 GABAA receptors expressed in HEK293-cells. Results Allopregnanolone increased the intake of standard chow, cookies and a high fat diet in male Wistar rats. Preferentially, allopregnanolone increased the rats´intake of the more calorie dense food type. Allopregnanolone reduced feeding latency and prolonged feeding duration. The increased chow intake induced by allopregnanolone was more pronounced at the beginning of the rats´ active period compared to the inactive. Repeated allopregnanolone administration during 5 consecutive days led to an increased body weight gain, more evident in schedule fed rats on a high fat diet. Both obesity prone and obesity resistant rats gained significantly more weight with repeated allopregnanolone exposure and the increased body weight gain correlated with increased food intake. The compound UC1020 was a potent antagonist of GAMS-enhanced GABA evoked currents at human α3β3γ2 GABAA receptors, whereas it had no effect at α2β3γ2 GABAA receptors. Conclusions Our findings indicate that allopregnanolone induced hyperphagia may be one of the endogenous factors involved in weight gain, especially when the diet is energy-rich. The compound UC1020 may prove useful for investigating the involvement of the α2 and α3 GABAA receptor subtypes in GAMS-induced hyperphagia.

Thesis (Ph. D.) -- University of Texas Southwestern Medical Center at Dallas, 2005. / Vita. Bibliography: 123-135.

Obesidade sindrômica é definida como a obesidade ocorrendo em conjunto com várias características clínicas distintas, associadas a retardo mental. A forma sindrômica mais freqüente é a síndrome de Prader-Willi (PWS) caracterizada por hipotonia, dificuldade de sucção no período neonatal, atraso do desenvolvimento neuropsicomotor (DNPM), hiperfagia, obesidade, baixa estatura na adolescência, mãos e pés pequenos, hipogonadismo, dificuldade de aprendizado e distúrbios de comportamento. Estudamos 141 pacientes com obesidade e/ou hiperfagia, atraso no desenvolvimento neuropsicomotor e/ou dificuldades de aprendizado e distúrbios de comportamento, pela técnica de MLPA (multiplex ligation-dependent probe amplification) assim como 19 pacientes que apresentavam além de atraso do DNPM e/ou dificuldade de aprendizado, distúrbios de comportamento, obesidade e/ou hiperfagia, outro sinal ao exame físico que sugerisse alteração cromossômica, pela técnica de SNP-array (The GeneChip 174; Mapping 100K Set, Affymetrix), com o objetivo de identificar genes e/ou segmentos cromossômicos envolvidos com obesidade sindrômica. Essas técnicas detectam deleções e/ ou duplicações do genoma, seja analisando regiões específicas, como a de MLPA, seja cobrindo praticamente o genoma inteiro (SNP-array). Dez pacientes apresentaram alterações cromossômicas: duas deleções 1p36, uma deleção 2p25.3, uma deleção 3p26.3 e duplicação 11q22.3, uma deleção 6(q16.1-q21), duas deleções 12(q15q21.1) (irmãs gêmeas), uma deleção X(p22.13p22.12), uma duplicação 14q11.2 e uma duplicação X(q26.3). Dentre as alterações encontradas estão duas síndromes relacionadas com obesidade já descritas, a monossomia 1p36 e a monossomia 6q16, que são diagnósticos diferencias da PWS. Nos segmentos alterados foram localizados vários genes relacionados a obesidade: DRD2, MCHR2, PLCH2, PRKCZ, RAB21, RAB2B, RAB39, TPO e SIM1. Onze genitores foram analisados por MLPA, SNP-Array e/ou cariótipo e rearranjos cromossômicos não foram identificados. Na presença dos cromossomos parentais normais o risco de recorrência é considerado desprezível. O diagnóstico de pacientes com obesidade sindrômica é um desafio, pois há sobreposição de fenótipos impossibilitando até agora o diagnóstico diferencial, a não ser o da síndrome de Prader-Willi clinicamente reconhecível, pelo menos, em sua segunda fase. O emprego de técnicas que detectam variações no número de cópias do genoma humano amplia a possibilidade de reconhecimento de novas síndromes e a descrição do espectro da variabilidade fenotípica de síndromes conhecidas. Estas síndromes são uma potencial fonte de esclarecimento das causas das formas comuns de obesidade. / Syndromic obesity is defined as obesity occurring in association with several distinct clinical features and mental retardation (MR). Prader-Willi syndrome (PWS) is the most frequent syndromic form of obesity and is characterized by hypotonia, poor sucking in the neonatal period, developmental delay, hyperphagia, obesity, short stature in adolescence, small hands and feet, hypogonadism, learning disabilities and behavior disturbances. Herein, we studied 141 patients with obesity and/or hyperphagia, psychomotor developmental delay and/or learning disabilities and behavior disturbances with the technique of MLPA (multiplex ligation-dependent probe amplification), and 19 patients by SNP-array technique (\"The GeneChip 174; Mapping 100K Set, Affymetrix) to identify copy number variations. By using both techniques we detected deletions or duplications of the genome in ten patients: two deletions at 1p36, two deletions at 12q15q21.1 (twins), a deletion of chromosomes 2p25.3, 6q16.1-q21, and Xp22.13p22.12, a duplication of chromosomes 14q11.2 and Xq26.3, and an unbalanced translocation between chromosomes 3p26.3 and 11q22.3. Monosomy 1p36 and monosomy 6q16 are well-known syndromes and had already been related with obesity. Both syndromes are considered as differential diagnosis of PWS. Several genes related to obesity are mapped in the altered chromosome segments: DRD2, MCHR2, PLCH2, PRKCZ, RAB21, RAB2B, RAB39, TPO and SIM1. Eleven parents were studied by MLPA, SNP array, and / or karyotype analyses, and chromosomal rearrangements were not identified. Therefore, we consider these rearrangements to be causative of the patients´ phenotype. The diagnosis of patients with syndromic obesity is a challenge due to the overlapping of the phenotypes, except for Prader-Willi syndrome that is a clinically recognizable syndrome, mainly in its second phase. The use of techniques that detect copy number variations of the human genome will increase the recognition of new syndromes and also the description of the spectrum of phenotypic variability of known syndromes. These syndromes are a potential source for the understanding of the etiology of the common forms of obesity.