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This experiment, a 3 x 3 factorial, was designed to determine whether the effects of type of dietary fat could be modified by hormonal status. Ovariectomized and shamoperated retired breeders were fed, for 56 days, diets containing 23% coconut oil, safflower oil or cocoa butter. All diets contained 0.5% cholesterol and 0.5% sodium glycotaurocholate. During the last 28 days of feeding, half the ovariectomized rats received, orally, 30 μg of Premarin per day while other rats received the vehicle only. Premarin, a conjugated equine estrogen, is commonly used to alleviate vasomotor discomforts associated with menopause. Over the period of oral dosing, food consumption and weight gain of ovariectomized rats that received the vehicle only did not differ from that of intact rats. However, both food consumption and body weight gain decreased as a result of Premarin administration. Weight gain and liver weights were greatest for rats fed safflower oil, intermediate for rats fed coconut oil and lowest for those fed cocoa butter. Normalizing for body weight did not alter this ranking of liver weights. Plasma total cholesterol levels of rats fed cocoa butter were higher than those of other rats, and the cocoa butter diet and intact hormonal status were synergistic with respect to plasma cholesterol levels. Plasma triglycerides were not influenced by hormonal status but were elevated by feeding coconut oil. Chemical composition of very low density lipoproteins (VLDL) isolated by gel filtration chromatography revealed high levels of cholesterol and protein when rats were fed cocoa butter, and the elevation of cholesterol and protein was especially prominent in VLDL of intact rats. A concomitant rise in VLDL triglyceride was not found with cocoa butter feeding. This suggests the presence of a modified lipoprotein within the VLDL fractions. It is speculated that intermediate density lipoproteins and p-migrating VLDL, which are cholesterol-rich with respect to VLDL, were induced by feeding cocoa butter. Rats fed coconut oil had the highest ratios of high density lipoproteins (HDL) to VLDL as determined from protein content of isolated lipoproteins. Similarly, as determined by electrophoresis of lipoproteins, ratios of HDL to VLDL plus low density lipoproteins (LDL) were greatest for rats fed coconut oil. In contrast to rats of other hormonal status, intact rats had the lowest ratios of HDL to VLDL plus LDL. This study emphasizes the difference in response of plasma lipoproteins to various dietary fats, including two saturated fats, and demonstrates that response of plasma total cholesterol and VLDL to type of dietary fat can be altered by hormonal status of rats. / Ph. D.

A depleção de tecido adiposo é um marcador da caquexia. Neste contexto, o aumento na lipólise decorrente do aumento na expressão da lipase hormônio-sensível (LHS) parece ser o fator-chave. Entretanto, a contribuição das novas proteínas relacionadas à lipólise [adipose triglyceride lipase (ATGL), comparative gene identification 58 (CGI-58) e perilipina] ainda é controversa. Caracterizamos a expressão destas proteínas e de adipocinas na caquexia. Pacientes com câncer caquéticos foram investigados. Um modelo experimental foi também estudado utilizando animais portadores de tumor sacrificados no 7º (TB7) e no 14º dia (TB14) após a inoculação tumoral e controles. Foram analisados no tecido adiposo os aspectos morfológicos, morfométricos e moleculares. Verificamos nos pacientes um aumento na expressão de LHS e ATGL, concomitantemente à redução da perilipina. Nos animais TB7 verificou-se um desequilíbrio na secreção de fatores anti e pró-inflamatórios e no grupo TB14 houve redução na expressão das proteínas analisadas sugerindo comprometimento da função celular. / Loss of fat mass is a hallmark of cachexia. It seems that an increase in lipolysis due to increased expression of hormone-sensitive lipase (HSL) is the key factor behind this effect. However, the contribution of novel proteins related to lipolysis [adipose triglyceride lipase (ATGL), comparative gene identification - 58 (CGI-58) and perilipin 1] is still controversial. We characterized the expression of those proteins and adipokines in cachexia. Subcutaneous adipose tissue from cachetic cancer patients and epidydimal pad from tumour-bearing rats was analysed. Morphological, morphometric and molecular aspects were examined. We found an increased HSL and ATGL expression and reduction in perilipin 1 content in cachectic patients. In rats, at the intermediate stage of the syndrome, there was an imbalance in the secretion of pro and anti-inflammatory factors. In terminal cachexia the expression of almost all proteins analysed was reduced in the animals, suggesting impairment of cellular function.

A depleção de tecido adiposo é um marcador da caquexia. Neste contexto, o aumento na lipólise decorrente do aumento na expressão da lipase hormônio-sensível (LHS) parece ser o fator-chave. Entretanto, a contribuição das novas proteínas relacionadas à lipólise [adipose triglyceride lipase (ATGL), comparative gene identification 58 (CGI-58) e perilipina] ainda é controversa. Caracterizamos a expressão destas proteínas e de adipocinas na caquexia. Pacientes com câncer caquéticos foram investigados. Um modelo experimental foi também estudado utilizando animais portadores de tumor sacrificados no 7º (TB7) e no 14º dia (TB14) após a inoculação tumoral e controles. Foram analisados no tecido adiposo os aspectos morfológicos, morfométricos e moleculares. Verificamos nos pacientes um aumento na expressão de LHS e ATGL, concomitantemente à redução da perilipina. Nos animais TB7 verificou-se um desequilíbrio na secreção de fatores anti e pró-inflamatórios e no grupo TB14 houve redução na expressão das proteínas analisadas sugerindo comprometimento da função celular. / Loss of fat mass is a hallmark of cachexia. It seems that an increase in lipolysis due to increased expression of hormone-sensitive lipase (HSL) is the key factor behind this effect. However, the contribution of novel proteins related to lipolysis [adipose triglyceride lipase (ATGL), comparative gene identification - 58 (CGI-58) and perilipin 1] is still controversial. We characterized the expression of those proteins and adipokines in cachexia. Subcutaneous adipose tissue from cachetic cancer patients and epidydimal pad from tumour-bearing rats was analysed. Morphological, morphometric and molecular aspects were examined. We found an increased HSL and ATGL expression and reduction in perilipin 1 content in cachectic patients. In rats, at the intermediate stage of the syndrome, there was an imbalance in the secretion of pro and anti-inflammatory factors. In terminal cachexia the expression of almost all proteins analysed was reduced in the animals, suggesting impairment of cellular function.

Pregnancy toxaemia (ketosis) is a metabolic disease of ewes which occurs during the late gestation as a result of the inability of the pregnant ewe to maintain an adequate energy balance for the fast growing maternal fetal unit. As a result of energy defi-ciency mobilization of lipid reserves results in a doubling of the plasma free fatty acid (FFA) giving rise to fatty liver and increased ketone bodies β-hydroxybutyrate (BHB) in blood and urine. It is associated with a higher rate of mortality and causes severe economic losses. The objective of this study was directed at investigating the relationship between metabolic parameters and cytokine TNFα, to check the interaction between the TNFα and fat metabolism in late pregnant ewes of different breeds, and whether TNFα play a role in the pathogenesis of pregnancy toxaemia, which may serve as marker to early diagnosis of the disease. In this study, 29 pregnant and clinically healthy ewes (16 Merino, 13 Blackhead) were selected out of a flock of sheep. Blood samples were collected at 5, 3, and 1 week be-fore parturition (b.p.) and also 4 weeks after parturition (a.p.). The average numbers of lambs were 2.18 and 1.58 /ewe for Merino and Blackhead breeds respectively. The blood samples were analyzed for the following:  Concentration of metabolic parameters: glucose, insulin, free fatty acids (FFA), β-hydroxybutyrate (BHB), albumin, total protein (TP), iron (Fe), glutamat-dehydro-genase (GLDH), creatin kinase (CK), gamma-glutamyl-transferase (GGT), choles-terol, haptoglobin.  Haematological parameters: Haematocrite (HK), haemoglobin concentration (HB), erythrocyte count (EC), leukocyte count (LC), mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), mean corpuscular haemoglobin concentration (MCHC).  Cytokine TNFα by using ovine TNFα ELISA assay. The results of glucose concentration of pregnant ewes showed significant increase (3.8 mmol/l) in five weeks b.p. and declined with advancing gestation (2.6 mmol/l) one week b.p. Insulin concentration remained constant with an average of 0.11 nmol/l b.p., and then significantly increased to 0.22 nmol/l four weeks a.p. Maximal FFA concentrations were found at five weeks b.p. (976 µmol/l). The levels of FFA showed high levels b.p. compared with reference range (R.R. < 600 µmol/l), and the FFA levels significantly decreased postpartum (four weeks b.p.). while there was significant increasing (p<0.05) in the level of FFA in Merino sheep than in Black-head sheep b.p. On the other hand there was no significant difference a.p. The mean values of BHB in all periods of sampling, period 1(5 w.b.p.), period 2 (3 w.b.p.), period 3 (1 w.b.p.), and period 4 (4 w.a.p.) were 0.37 mmol/l, 0.23 mmol/l, 0.17 mmol/l and 0.3 mmol/l respectively. The mean of BHB indicated normal levels of BHB before and after parturition compared to subclinical ketosis (BHB > 1 mmol/l) and clinical ketoses (BHB > 1.6 mmol/l), and there was a significant difference (p<0.05) in the values of BHB between Blackhead and Merino breeds before parturi-tion while there was no significant difference after parturition. The concentration of TNFα showed elevated levels in all period of sampling before parturition. The TNFα values were 30.4 (17.2, 785.0) ng/ml (median, first, and third quartiles), 35.6 (13.6, 54.3), and 26.6 (13.0, 39.9) ng/ml in period 1(5 w.b.p.), period 2 (3 w.b.p.), and period 3 (1 w.b.p.) respectively. These values decreased to 19.1 (9.9, 33.8) ng/ml at 4 weeks after parturition. Statistical analysis showed that there was a positive correlation between free fatty ac-ids and TNFα. This correlation means that adipose tissue produces TNFα causing insu-lin resistance, which stimulates the lipolysis and leads to an increase of circulatory free fatty acids levels. It is concluded that fat mobilization occurs in the prepartum clinically healthy ewes with a significant increase in the levels of FFA, and also there is an increase in the proinflammatory cytokine TNFα at late gestation which predisposes ewes to pregnancy toxaemia and can aid in the diagnosis of the disease.

Orientadores: Francesco Langone, Licio Augusto Velloso / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Biologia / Made available in DSpace on 2018-08-09T03:39:03Z (GMT). No. of bitstreams: 1 Vieira_AndreSchwambach_M.pdf: 3969141 bytes, checksum: 53eff5b5bbec953a73e9ddc63cd3ea39 (MD5) Previous issue date: 2007 / Resumo: O Fator Neurotrófico Ciliar (CNTF) é uma neurocitocina com múltiplas atividades biológicas, sendo notável sua habilidade de proteger motoneurônios. Entretanto, a administração de CNTF leva à redução de peso corporal. Por outro lado, a administração do CNTF fusionado a um Domínio de Transdução de Proteínas (PTD), denominado TAT-CNTF, é capaz de proteger motoneurônios da medula espinhal axotomizados sem causar este efeito. O presente trabalho investigou se a administração intracerebroventricular (i.c.v.) de TAT-CNTF produz os conhecidos efeitos catabólicos do CNTF. Para isso, ratos Wistar machos, com uma cânula crônicamente implantada no ventrículo lateral, foram distribuídos em quatro grupos: TAT-CNTF (2,5µg/8µl), CNTF (2,5µg/8µl), Leptina (LEP) (5µg/8µl) e PBS, que receberam uma infusão i.c.v. a cada 12h por 4 dias. O grupo tratado com TAT-CNTF apresentou menor perda de peso quando comparado aos grupos CNTF e LEP. As infusões i.c.v. de TAT-CNTF não reduziram o peso das gorduras retroperitonial (RP), epididimal (EP) e marrom interescapular (GM). O grupo CNTF apresentou redução do peso destas gorduras. Os grupos CNTF e LEP apresentaram aumento da fragmentação do DNA nas gorduras RP e EP. Por outro lado, o grupo TAT-CNTF não apresentou aumento da fragmentação do DNA nas amostras de RP, EP e GM. Um padrão de degradação internucleossomal do DNA e a presença de células TUNEL positivas foram detectados apenas nas gorduras dos animais dos grupos CNTF e LEP. Estes grupos também apresentaram aumento da expressão da UCP1 na GM, ao passo que o grupo TAT-CNTF não apresentou tal resultado. A análise da fosforilação da STAT3 no hipotálamo após uma única infusão i.c.v. de TAT-CNTF demonstrou, após 20 minutos, um efeito menor que o observado após infusão de CNTF. Em conclusão, nossos dados sugerem que o TAT-CNTF possui ação diferente do CNTF nas áreas hipotalâmicas envolvidas no controle da ingesta e do metabolismo / Abstract: The Ciliary Neurotrophic Factor (CNTF) is a neurocitokine with multiple biological activities, being notable its ability to protect lesioned motoneurons. However, administration of CNTF leads to reduction of body mass, while administration of CNTF fusioned with a Protein Transduction Domain (PTD), named TAT-CNTF, protects lesioned spinal motoneurons with no effects on body weight. In the present work, we investigated whether intracerebroventricular (i.c.v.) administration of TAT-CNTF would produce CNTF known catabolic effects. Male Wistar rats with a canula chronically implanted in the lateral ventricle were randomly assigned to four treatment groups: TAT-CNTF (2,5µg/8µl), CNTF (2,5µg/8µl), Leptin (LEP) (5µg/8µl) and PBS, that received an i.c.v. infusion every 12h for 4 days. TAT-CNTF treated group had a reduced weight loss when compared with CNTF and LEP groups. TAT-CNTF i.c.v. infusions did not reduce the weights of retroperitoneal (RP) and epididimal (EP) white adipose tissue, as well as interescapular brown adipose tissue (BAT) while CNTF i.c.v. administration reduced the weight of all these tissues. CNTF and LEP groups showed an increase of DNA fragmentation in RP and EP. On the other hand, TAT-CNTF group had no increase in DNA fragmentation in RP, EP and GM. A DNA ladder pattern and TUNEL positive cells could only be detected in adipose tissues from CNTF and LEP groups. CNTF and LEP treated groups had an increase in the expression of UCP1 in BAT, while TAT-CNTF treatment had no effects on UCP1 expression. An acute i.c.v. administration demonstrated that after 20 minutes TAT-CNTF induced less intense STAT3 phosphorilation in the hypothalamus when compared with CNTF acute infusions. In conclusion these data suggest that TAT-CNTF has a different action on hypothalamic areas involved in the control of food intake and energy metabolism / Mestrado / Fisiologia / Mestre em Biologia Funcional e Molecular

京都大学 / 0048 / 新制・課程博士 / 博士(農学) / 甲第19042号 / 農博第2120号 / 新制||農||1032(附属図書館) / 学位論文||H27||N4924(農学部図書室) / 31993 / 京都大学大学院農学研究科食品生物科学専攻 / (主査)教授 伏木 亨, 教授 保川 清, 教授 金本 龍平 / 学位規則第4条第1項該当 / Doctor of Agricultural Science / Kyoto University / DGAM

Plasticizers are synthetic organic chemicals that are used in different products to make them flexible, elastic, and durable. Plasticizers are not attached to the products by covalent bonds, as a result, they leach out from the products leading to environmental contamination. The most widely used plasticizer, Di-(2-ethyl hexyl) phthalate (DEHP), have been restricted from general use in the EU, Canada, and the USA due to their reported toxicity. The alternative plasticizer, Di-(isononyl) cyclohexane-1,2-dicarboxylate (DINCH), was introduced to the European market as a safer alternative for endocrine-disrupting phthalates such as DEHP, and diisononyl phthalate (DINP).  According to the current toxicological data, DINCH is neither an endocrine disruptor and nor a reproductive toxicant. Thus, DINCH was approved for use in food contact containers, and in children’s toys.  The increase in global demand for alternative plasticizers led to their buildup in the environment and an increase in DINCH exposure. The lack of toxicity data and safety assessment of DINCH has raised the concern to human and animal health. Due to the similar structure of DEHP, DINP, and DINCH, we suggest that DINCH can be classified as a metabolic disruptor that alters fat metabolism and induces adipogenesis. In this study, we investigated the negatives effects of DINCH (at concentrations ranging from 0.01 to 10 μM) compared it to phthalates DINP, DEHP, Dibutyl phthalate (DBP), and Diethyl phthalate (DEP) at the early developmental stages of zebrafish. We further analyzed DINCH and DINP using the mouse preadipocyte cells  3T3L1. We found that DINCH and DEHP caused hatching delay in a dose-dependent manner. Behavioral analysis of larvae demonstrated that DEHP, DBP, DEP, and DINCH impair motor activity. The Oil Red O lipid staining showed a slight lipid accumulation in larval zebrafish at different DINP and DINCH concentrations. To further confirm the findings, qPCR was performed to analyze lipid metabolism genes. DINCH and DINP altered lipid metabolism genes including, fasn, srebp, pparg etc.  The oxidative stress state imposed by DINCH exposure was shown by a slight increase in superoxide dismutase enzymatic activity and the alteration on stress-related genes. In 3T3L1 cells, 10 and 100 μM of DINCH and DINP exposure induced lipid droplets formation like that induced by 100 nM rosiglitazone. Genes associated with lipid metabolism and lipid transport were altered by DINCH and DINP. These results indicate that DINCH exposure could induce physiological and metabolic toxicity. The data presented in this thesis could provide crucial information for further toxicological assessment.