A manutenção da saúde, depende, dentre outros aspectos, do controle da massa corporal, uma vez que a obesidade está associada ao desenvolvimento de doenças crônicas. Sendo assim, o exercício pode ser considerado uma ferramenta eficaz nesse controle. Contudo, está evidenciado que o exercício realizado em alta intensidade pode ocasionar maior redução da gordura corporal. Dentre as hipóteses sugeridas para explicar tal fenômeno, a supressão do apetite pós-exercício foi levantada, no entanto, o efeito da intensidade sobre o apetite ainda é incipiente. Além disso, mulheres podem ter maior resposta compensatória que homens. Portanto, o objetivo do estudo foi comparar o efeito da intensidade no controle agudo do apetite, energia ingerida absoluta e relativa (energia ingerida menos o gasto calórico do exercício), percepção de fome e das concentrações sanguíneas de grelina acilada, peptídeo YY3-36, insulina, cortisol, glicose, ácidos graxos, colesterol e triacilglicerol em homens e mulheres. Para isso, 11 homens e 9 mulheres eutróficos, foram submetidos a 6 sessões, sendo a primeira destinada à determinação da potência aeróbia máxima (PAM) em cicloergômetro, e a segunda para realização do exercício intermitente de alta intensidade realizado na máxima intensidade (all out), composto por 60 x 8s:12s (EIAI-A), para determinação do trabalho total, o qual foi utilizado para equalização das demais sessões: a) EIAI-A; b) exercício intermitente de alta intensidade (EIAI) - 60s:60s a 100% da PAM; c) exercício contínuo de intensidade moderada (ECMI) a 60% da PAM; d) sessão controle (sem exercício). Cada visita teve duração de 4h, sendo que os participantes chegaram em jejum e receberam um café da manhã padrão. O exercício foi realizado 1,5h pós-café da manhã, e uma alimentação ad libitum foi servida 4h pós-café da manhã. Coletas de sangue e da percepção de fome (escala analógica visual) foram realizadas em jejum e em 2, 2,5, 3,25 e 4h de experimento e calculada a área sob a curva (ASC) para cada uma dessas variáveis. A comparação das variáveis sanguíneas e da percepção de fome foi feita através de análise de variância a três fatores (condição, sexo e momento), e das variáveis envolvendo a ASC e a energia ingerida foi conduzida através de análise a dois fatores (condição e sexo), seguida do pós-teste de Bonferroni se observada diferença significativa (P<0,05). Não houve diferença para a energia ingerida absoluta, porém, a energia ingerida relativa foi maior no controle quando comparada ao EIAI-A, EIAI, e ao ECMI, sem diferenças entre os tipos de exercício e sexos. A ASC da percepção de fome foi menor somente nos exercícios realizados em alta intensidade comparado com o controle, independentemente do sexo. O PYY3-36 foi inferior nas mulheres em relação aos homens ao passo que o cortisol foi inferior nos homens comparado com as mulheres. Houve interação entre situação e momento de coleta para o cortisol e insulina sendo os valores mais elevados no EIAI-A que no controle às 2,5 horas de experimento para o cortisol e às 3,25h para insulina. Portanto, embora não tenha havido diferença na energia ingerida relativa entre os tipos de exercícios, àqueles realizados em maior intensidade foram capazes de promover efeitos mais pronunciados na supressão do apetite, independentemente do sexo / Maintaining one\'s health depends, among other things, on controlling body weight, since obesity is associated with the development of chronic diseases. Accordingly, exercise is an effective tool in this control. It has been demonstrated that exercise performed at a high intensity can cause greater reduction in body fat. Among the hypotheses put forward of this phenomenon is the suppression of appetite. However, the understanding of the effect of the intensity on appetite is still incipient. In addition, women may have a greater compensatory response than men. Therefore, the aim of the study was to compare the effect of intensity on absolute and relative (energy intake less caloric expenditure of the exercise) energy intake, hunger and blood concentrations of acylated ghrelin, PYY3-36, insulin, cortisol, glucose, fatty acids, cholesterol and triacylglycerol in men and women. Accordingly, 11 men and 9 women, all eutrophic, underwent six sessions. The first was designed to determine their maximum aerobic power (MAP) on a cycle ergometer, and the second involved performing high-intensity intermittent exercise at maximum intensity (all out) for 60 x 8s: 12s (HIIE-A) in order to determine the total work, which was used for the equalization of the other sessions: a) HIIE-A; b) high intensity intermittent exercise (HIIE) - 60s: 60s at 100% of MAP; c) steady-state exercise (SSE) at 60% of the MAP; d) a control session. Each session lasted a total of 4 hours. The participants arrived in fasting and received a standard breakfast upon arrival. The exercise session was performed 1.5 h after breakfast, and an ad libitum meal was served 4 hours post-breakfast. Blood sample collection and perception of hunger were collected when fasting and at 2, 2.5, 3.25 and 4 hours into the experiment and the area under the curve (AUC) for each of these variables was calculated. A comparison of the blood sample variables and rating of hunger was performed by analyzing the variance of three factors (condition, sex, and time) and the analysis of the variables involving the AUC and energy intake was conducted through examination of two factors (sex and condition) followed by a Bonferroni post-test if significant differences (P<0.05) were observed. There was no difference for the absolute energy intake, however, relative energy intake was higher in the control compared to HIIE-A, HIIE, and SSE, with no differences between the types of exercise and sex. The AUC of hunger was lower in exercises performed at high intensity when compared to the control, regardless of sex. There was interaction between condition and time for cortisol and insulin, with higher levels in the HIIE-A than in the control at 2.5 hours for cortisol and 3.25 hours for insulin. Therefore, although there were no differences in energy intake relative to the types of exercises, those performed at a higher intensity promoted more pronounced effects on appetite suppression, regardless of sex

Durante a endotoxemia, observa-se alteração no eixo hormônio do crescimento(GH)/fator de crescimento semelhante à insulina (IGF)-1. Acredita-se que o aumento de citocinas pró-inflamatórias seja responsável por essa alteração, apesar do mecanismo para essa alteração ainda não estar completamente elucidado. A ghrelina é um hormônio peptídico que apresenta propriedades anti-inflamatórias, e, portanto, pode contribuir para a manutenção da integridade do eixo GH/IGF-1. O objetivo do presente estudo foi avaliar o efeito do tratamento sistêmico de ghrelina sobre o eixo GH/IGF-1 em ratos Wistar submetidos à endotoxemia. Para a indução da endotoxemia, foi administrado lipopolissacarídeo (LPS; 5mg/kg intraperitoneal) sistemicamente. Os animais foram tratados com ghrelina (15nmol/kg; endovenoso) concomitantemente à administração de LPS e tiveram o sangue e o fígado coletados após 2h,6h ou 12h. Foram quantificadas a concentração sanguínea do fator de necrose tumoral alfa (TNF-?), interleucina (IL)-1?, IL-6, nitrato, corticosterona, GH, IGF-1 e ghrelina endógena, assim como a concentração hepática de TNF-?, IL-1? e IL-6. O TNF-?, IL-1?, IL-6, GH, IGF-1 e ghrelina endógena foram quantificados pela técnica de ELISA. A corticosterona foi quantificada pela técnica de radioimunoensaio. O Nitrato foi quantificado pela técnica de quimioluminescência. Também foram quantificadas a expressão proteica hepática do receptor do hormônio secretador do GH (GHSR-1a) e do receptor do GH (GHR) pela técnica de Western Blott, bem como a expressão gênica hepática de IGF-1 e GHR pela técnica de PCR-RT. Os ratos submetidos à endotoxemia apresentaram redução sérica de IGF-1 e de GH, caracterizando a alteração do eixo GH/IGF-1. Os animais endotoxêmicos e tratados com ghrelina apresentaram menor redução dos níveis circulantes de IGF-1, além de apresentarem menores níveis de TNF-?, IL-1?, IL-6 e nitrato após administração de LPS. A menor redução de IGF-1 circulante após o tratamento com ghrelina não foi relacionada a alterações na expressão proteica de GHSR-1a ou GHR, nem relacionada a alterações na expressão gênica de IGF-1 ou GHR nos intervalos de tempo analisados. Portanto, a propriedade anti-inflamatória da ghrelina levou à redução do aumento dos mediadores pró-inflamatórios e contribuiu para a manutenção da integridade do eixo GH/IGF-1 ao atenuar a queda na concentração sanguínea de IGF-1. Endotoxemia. Inflamação. Eixo GH/IGF-1 / During the endotoxemia it is possible to observe a change on the growth hormone (GH) /insulin-like growth factor (IGF)-1 axis. It is believed that the pro inflammatory cytokines increase is responsible for this change even not having the mechanism for this change completely elucidated. The ghrelin is a peptidic hormone which has antiinflammatory properties and, because of that, can contribute to the GH/IGF-1 axis integrity maintenance. This research goal is to evaluate the ghrelin systemic treatment effect on the GH/IGF-1 axis on Wistar rats submitted to endotoxemia. To induct the endotoxemia it was given systemically to the rats a lipopolysaccharide (LPS; 5mg/kg intraperitoneal). The animals were treated with ghrelin (15nmol/kg; intravenous) while receiving the LPS and they had their blood and liver collected after 2h, 6h or 12h. Blood concentration of alfa tumoral necrose (TNF-?), interleukin (IL)-1?, IL-6, nitrate, corticosterone, GH, IGF-1 and endogenous ghrelin were quantified as well as their TNF-?, IL-1? e IL-6 hepatic concentration. The TNF-?, IL-1?, IL-6, GH, IGF-1 and the endogenous ghrelin were quantified through the ELISA technique. The corticosterone was quantified through the radioimmunoassay technique. The nitrate was quantified through the chemiluminescence technique. The hepatic protein expression from the growth hormone secretagogue receptor (GHSR)-1a and the receptor of the GH (GHR) were quantified through the Western Blott technique and the IGF-1 and the GHR hepatic gene expression through the PCR-RT technique. The rats submitted to the endotoxemia presented an IGF-1 and a GH serum decrease characterizing a change on the GH/IGF-1 axis. The endotoxemic animals treated with ghrelin showed a smaller reduction of the IGF-1 circulating levels besides presenting a smaller TNF-?, IL-1?, IL- 6 and nitrate levels after receiving the LPS. The smallest IGF-1 circulating decrease, after the treatment with ghrelin, was related neither to the changes on the GHSR-1a or GHR protein expressions nor to the IGF-1 or GHR gene expressions during the analyzed time intervals. Therefore, the ghrelin anti-inflammatory property inflected a reduction of the pro-inflammatory mediators increase and contributed for the GH/IGF- 1 axis integrity maintenance while mitigating the IGF-1 blood concentration fall.

Recent years have witnessed significant research into the acute effects of exercise on appetite, energy intake and gut hormone responses. The experiments in this thesis have further investigated this topic by examining the appetite, acylated ghrelin, peptide YY and energy intake responses to energy deficits induced via different exercise protocols and food restriction. To achieve this, 48 young healthy males (mean (SD): age 23 (3) years, body mass index 23.7 (2.7) kg.m-2, maximum oxygen uptake 52.9 (9.8) mL.kg 1.min-1) were recruited into four studies. In study one, 60 min of treadmill running at 70% of VO2 max did not stimulate any increases in appetite or daily energy intake regardless of whether the exercise was performed after breakfast or in the fasted state. In study two, six 30 s Wingate tests stimulated increases in appetite during the subsequent hours compared with 60 min of cycling at 68% of VO2 max. Differences in appetite appeared to be unrelated to changes in plasma acylated ghrelin concentrations and did not influence ad libitum energy intake. Subsequently, endurance exercise resulted in a significantly greater negative daily energy balance than sprint exercise due to a larger exercise energy expenditure. Study three revealed that appetite and energy intake did not differ from a resting control trial after either ten, 4 min cycling bouts at 85 90% of VO2 max separated by 2 min of rest or 60 min of constant cycling at 60% of VO2 max. This occurred despite elevated PYY3-36 concentrations during the hours after exercise. Finally, study four showed that an energy deficit of ~1475 kJ stimulated increases in appetite when induced via food restriction but not when achieved by an acute bout of exercise. This was associated with differences in plasma PYY3-36 concentrations but did not appear to be related to changes in circulating levels of acylated ghrelin and did not influence energy intake. This thesis has shown that appetite perceptions do not differ from a resting control trial during the hours after continuous endurance exercise. Alternatively, supramaximal cycling exercise and subtle reductions in food intake stimulated increases in appetite during the subsequent hours. Such increases in appetite do not appear to be related to changes in acylated ghrelin but may be influenced by plasma PYY3-36 concentrations. Despite differences in appetite, daily energy intake was unaffected by all interventions.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Durante a temporada de nidação, fêmeas de tartarugas marinhas costumam reduzir ou cessar por completo a ingestão de alimentos. Este fato sugere que o armazenamento de energia e nutrientes para a reprodução ocorra durante o período que antecede a migração para os sítios reprodutivos, enquanto estes animais ainda se encontram nas áreas de alimentação. Do ponto de vista fisiológico, tartarugas em atividade reprodutiva são capazes de permanecer longos períodos em jejum. Fatores neuroendócrinos vêm sendo recentemente apontados como os mais relevantes para a manutenção da homeostase energética de todos os vertebrados; entre eles, a leptina (hormônio anorexígeno) e a grelina (peptídeo orexígeno). Com o objetivo de compreender o mecanismo de fome e saciedade nas tartarugas marinhas, investigamos os níveis séricos destes hormônios e de outros indicadores nutricionais em fêmeas de Eretmochelys imbricata desovando no litoral do Rio Grande do Norte, Brasil. Foram coletadas amostras de sangue de 41 tartarugas durante as temporadas reprodutivas de 2010/2011 e 2011/2012. Os níveis séricos de leptina diminuíram significativamente ao longo do período de nidação, de modo a explicar a busca por alimentos ao término da temporada. Ao mesmo tempo, registramos uma tendência crescente nos níveis séricos de grelina, fator este que também justifica a remigração para as áreas de alimentação no fim do período. Não foram observadas tendências lineares para alguns dos parâmetros avaliados, entre eles: hematócrito, alanina aminotransferase (ALT), aspartato aminotransferase (AST), fosfatase alcalina (FA), gama glutamil transferase (GGT), lipoproteínas de baixa densidade (LDL) e lipoproteínas de alta densidade (HDL). É possível que a maior parte dos indicadores nutricionais tenha apresentado redução gradativa devido ao estresse fisiológico decorrente da vitelogênese e de repetidas oviposições. No entanto, é valido ressaltar que o quadro de restrição calórica por tempo prolongado é o principal responsável pelas alterações em índice de massa corpórea e padrões bioquímicos nestes animais. / Reproductive female sea turtles rarely have been observed foraging during the nesting season. This suggests that prior to their reproductive migration to nesting beaches, the adult females must store sufficient energy and nutrients at their foraging grounds, and must be physiologically capable of undergoing months without feeding. Leptin (an appetite-suppressing protein) and ghrelin (a hunger-stimulating peptide) affect body weight by influencing energy intake in all vertebrates. We investigated the levels of these hormones and other physiological and nutritional parameters in nesting female hawksbill sea turtles in Rio Grande do Norte State, Brazil, by collecting consecutive blood samples from 41 turtles during the 2010/2011 and 2011/2012 reproductive seasons. We found that levels of serum leptin decreased over the nesting season, which potentially relaxed appetite suppression and led females to begin foraging either during or after the post-nesting migration. Concurrently, we recorded an increasing trend in ghrelin, which stimulated appetite towards the end of the nesting season. Both findings are consistent with the prediction that post-nesting females will begin to forage, either during or just after their post-nesting migration. We observed no seasonal trend for other physiological parameters: PCV values, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma glutamyl transferase (GGT) low-density lipoprotein (LDL) and high-density lipoprotein (HDL) serum levels. The observed downward trends in general serum biochemistry levels were likely due to the physiological stress of vitellogenesis and nesting in addition to limited energy resources and probable fasting.

Submitted by Luciana Ferreira (lucgeral@gmail.com) on 2017-01-17T10:23:56Z No. of bitstreams: 2 Dissertação - Gabriel Camargo da Silva - 2016.pdf: 2237673 bytes, checksum: f750ddf2e821b6d6b8bc80eae327232d (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Approved for entry into archive by Luciana Ferreira (lucgeral@gmail.com) on 2017-01-17T10:24:17Z (GMT) No. of bitstreams: 2 Dissertação - Gabriel Camargo da Silva - 2016.pdf: 2237673 bytes, checksum: f750ddf2e821b6d6b8bc80eae327232d (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Made available in DSpace on 2017-01-17T10:24:17Z (GMT). No. of bitstreams: 2 Dissertação - Gabriel Camargo da Silva - 2016.pdf: 2237673 bytes, checksum: f750ddf2e821b6d6b8bc80eae327232d (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2016-10-28 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / Ghrelin is a 28 amino acid peptide described at 90’s. Within its multiple functions, production of growth hormone (GH), food intake, cell proliferation, regulation of cardiovascular system and behavior may be highlighted. Ghrelin actions are mediated by the growth hormone secretagogue receptor subtype 1a (GHS-R1a), which is distributed along several peripheral tissues and central areas involved in the control of cardiovascular responses to aversion. Since GHS-Rs1a is expressed in central areas that govern cardiovascular responses to aversion, our aim was to assess the role of Ghrelin in the cardiovascular reactivity to acute emotional stress. Adult male Wistar rats (250-350g) underwent acute emotional stress following i.v. injection of ghrelin (1 or 10 µg/kg), the antagonist of GHS-R1a (PF04628935) or vehicle (VHE). We further investigated the cardiac beta-adrenergic sensitivity in vivo by injecting isoproterenol (1 µg/kg) and ghrelin (10 µg/kg). Autonomic blockade was reached by subsequent injections of atenolol (4 mg/kg), methylatropine (3 mg/kg), ghrelin (10 µg/kg) e VHE. Finally, we evaluated in isolated hearts the effects of perfusion with ghrelin (0.2nMol/L) followed by crescent bolus concentrations of isoproterenol and acetylcholine. Current findings show that ghrelin potentiates the tachycardia evoked by restraint and by air jet stress. We demonstrated that administration of ghrelin improves beta-adrenergic sensitivity in vivo and ex vivo. Autonomic blockade experiments revealed that autonomic nervous system, through sympathetic branch, modulates the stress-evoked positive chronotropy. Furthermore, perfusion of isolated hearts with ghrelin resulted in positive inotropy and potentiated contractile responses caused beta-adrenergic agonism, without altering the amplitude of the responses evoked by acetylcholine. In conclusion, administration of ghrelin and the consequent activation of GHS-R1a increased the magnitude of the tachycardia evoked by acute emotional stress by modulating autonomic nervous system and through peripheral mechanisms, strongly dependent on activation of cardiac beta-adrenergic receptors. / A grelina é um peptídeo de 28 aminoácidos identificado no fim da década 90. Dentre suas várias funções, destacam-se a produção do hormônio de crescimento (GH), os efeitos sobre o apetite, proliferação celular, participação no sistema cardiovascular e regulação do comportamento. Sua ação se dá pela ligação ao receptor secretagogo do hormônio do crescimento subtipo 1a (GHS-R1a) distribuído em vários tecidos periféricos e em algumas regiões do sistema nervoso central (SNC) envolvidas na modulação cardiovascular durante eventos aversivos. Sabendo que os GHS-R1a são distribuídos em áreas centrais que modulam as respostas cardiovasculares durante eventos aversivos, o objetivo do nosso trabalho foi avaliar o papel da grelina nas respostas cardiovasculares evocadas por estresse emocional agudo. Ratos Wistar (250-350g) foram submetidos ao estresse emocional agudo após administração i.v. de grelina (1 ou 10 µg/kg), antagonista de GHS-R1a (PF04628935) ou veículo (VHE).Também avaliamos a sensibilidade beta adrenérgica cardíaca in vivo com administrações de isoproterenol na dose 1 µg/kg e grelina (10 µg/kg). O bloqueio autonômico cardíaco foi realizado com administrações de atenolol (4 mg/kg), metilatropina (3 mg/kg), grelina (10 µg/kg) e VHE. Por fim, avaliamos em corações isolados os efeitos da perfusão com grelina na concentração de 0,2 nMol, seguida de administrações in bolus de concentrações crescentes de isoproterenol e acetilcolina. Os achados demonstram que a grelina potencia a taquicardia evocada pelo estresse por contenção e por jato de ar. Demonstramos que a administração de grelina promove um aumento da sensibilidade beta adrenérgicai n vivo e ex vivo. Os experimentos de bloqueio autonômico revelaram que o sistema nervoso central, através do eixo simpático, modula a resposta taquicárdica pela administração de grelina. Além disso, a perfusão de corações isolados com grelina promoveu um aumento da contratilidade cardíaca e potenciação da resposta ao agonismo beta adrenérgico, sem alterar a resposta à acetilcolina. Em conclusão, a administração de grelina e subsequente ativação de GHS-R1a potencia a taquicardia evocada por estresse emocional agudo através da modulação do sistema nervoso central e de mecanismos periféricos, dependentes da ativação de receptores beta adrenérgicos cardíacos.

La ghréline est une hormone de 28 acides aminés, synthétisée principalement par l'estomac. D'abord identifiée comme un sécretagogue de l'hormone de croissance, elle joue également un rôle central dans la prise alimentaire, la glycémie ainsi que dans certains processus liés à l'addiction. Ces effets sont médiés par un récepteur couplé aux protéines G : le GHS-R1a (Growth Hormone Secretagogue Receptor). Ce récepteur possède une activité constitutive élevée et un réseau de signalisation intra-cellulaire relativement complexe via l'activation de β-arrestines et de différentes isoformes de protéines G (Gq, Gi/o, G12/13). Compte tenu de ces multiples effets, les ligands du GHS-R1a présentent un intérêt thérapeutique certain.Cette thèse est consacrée au développement d'antagonistes et d'agonistes inverses du hGHS-R1a, dont la structure est basée sur le motif 1,2,4-triazole 3,4,5-trisubstitué. Grâce à une étude successive des différents substituants de cette plateforme peptido-mimétique nous avons identifié des antagonistes d'affinités nanomolaires ainsi que des agonistes inverses possédant une efficacité significative. Ces composés paraissent donc être des candidats intéressants pour des études in vivo sur des modèles de prise alimentaire ou d'addiction. D'autre part, une étude pharmacologique sophistiquée, menée sur nos composés, a démontré qu'il est possible d'obtenir des ligands biaisés sur la base du motif triazole. Ces résultats fournissent de nouvelles informations sur la sélectivité fonctionnelle du GHS-R1a. Ainsi, associés à des études in vivo complémentaires, ces données pourraient être précieuses pour la conception de nouveaux médicaments possédant des effets secondaires limités. / Ghrelin is a hormone of 28 amino acids, mostly synthesized in the stomach. Firstly identified as a growth hormone secretagogue, this peptide is also involved in food intake, blood glucose and in some processes related to addiction. Ghrelin effects are mediated by a G protein-coupled receptor: GHS-R1a (Growth Hormone Secretagogue Receptor). This receptor has a high constitutive activity and a complex intra-cellular signaling network via the activation of β-arrestin and different isoforms of G protein (Gq, Gi / o, G12 / 13). Given these multiple effects, ligands of GHS-R1a have a therapeutic interest.This thesis is devoted to the development of antagonists and inverse agonists of hGHS-R1a whose structure is based on the 3,4,5-trisubstituted 1,2,4-triazole scaffold. Thanks to a successive study of the various substituents of the peptidomimetic platform we identified antagonists with nanomolar affinity and inverse agonists with a significant efficiency. These compounds appear to be attractive candidates for in vivo studies on food intake or addiction models. On the other hand, a sophisticated pharmacological study, conducted on our compounds, has demonstrated that it is possible to obtain biased ligands based on the triazole motif. These results provide new informations about the functional selectivity of GHS-R1a. Thus, these data, combined with additional in vivo studies, could be useful for the design of new drugs with limited side effects.

This thesis examines the effect of surgical weight loss on gut and adipose tissue peptides involved in appetite regulation and energy homeostasis in morbidly obese humans. Roux-en-Y gastric bypass (RYGBP) is the gold standard operation used for effective long-term weight loss and improved health. The exact mechanisms for this outcome are under investigation. We measured ghrelin, a recently discovered hunger hormone, insulin, adiponectin and leptin along with anthropometry measures in 66 morbidly obese patients prior to and 6 and 12 months after RYGBP. Impressive weight loss occurred postoperatively as did alterations in the peptides. Consistent correlations were found between weight, leptin, ghrelin and insulin. The main findings were low ghrelin concentrations in obesity and an increase after RYGBP. We explored inflammatory proteins C-reactive protein (CRP), serum amyloid A and interleukin-6 before and during massive weight loss 6 and 12 months after RYGBP in morbidly obese subjects. The studied proteins declined after surgery and a correlation between CRP and homeostatic model of assessment for insulin resistance, independent of BMI, strongly linked insulin resistance and inflammation. CRP declined most in insulin-sensitive subjects. We examined the excluded stomach mucosa and vagus nerve by measuring gastrin, pepsinogen I (PGI), pancreatic polypeptide (PP) and ghrelin levels during week 1 and year after RYGBP. Ghrelin levels rose with weight loss but declined 24-hours after surgery, like PP, indicating transient vagal nerve damage. Low levels of gastrin and PGI suggest a resting mucosa. We evaluated gut peptides: peptide YY (PYY), glucaogon like peptide-1 (GLP-1), pro-neurotensin (pro-NT) and PP, in lean (young and middle-aged), obese and postoperative RYGBP subjects pre- and postprandially. RYGBP subjects had exaggerated levels of PYY and GLP-1 postprandially and higher basal proNT levels, implying a ‘satiety peptide tone’ that may contribute to the maintenance of weight loss. In summary, RYGBP results in marked weight loss and alterations in gut and adipose tissue peptides involved in appetite regulation and energy homeostasis. These postoperative peptide changes may contribute to impressive weight loss observed after RYGBP.

The acute effects of exercise on appetite, ad libitum energy intake and gut hormone responses have received much attention over the past two decades. The experiments in this thesis have contributed to this research by examining appetite, acylated ghrelin, peptide-YY (PYY), leptin and ad libitum energy intake responses to two consecutive days of moderate-high intensity running. To achieve this 15 individuals aged 21 (2) y, with a BMI of 23.0 (1.9) kg·m-2 were recruited. Additionally, appetite, acylated ghrelin, PYY, glucagon-like peptide-1 (GLP-1), and ad libitum energy intake responses to an acute bout of moderate intensity treadmill exercise were compared in lean and overweight/obese (ow/ob) males and females. Two separate cohorts of individuals were recruited; 22 lean individuals and 25 ow/ob individuals (aged 38 (15) and 45 (12) y, with a BMI of 22 (2) and 29 (3) kg·m 2, for lean and ow/ob individuals, respectively). In Chapter 4, two consecutive days of 60 min treadmill running at 70% VO₂ peak did not produce compensatory changes in appetite or energy intake over two days. There were no main effects of trial for acylated ghrelin or leptin. However a main effect of trial for PYY indicated higher concentrations on the exercise than control trial. A meta-analysis was completed in Chapter 5, suggesting further research in the effects of acute exercise on appetite regulatory hormones in individuals who are ow/ob was necessary. In Chapter 6, 60 min of treadmill exercise at 60% VO₂ peak did not alter appetite sensations or energy intake in the 7 h after exercise in lean and ow/ob males and females. There were no main effects of sex, BMI or trial for acylated ghrelin; however, PYY and GLP-1 concentrations were higher in exercise than control trials. This thesis has demonstrated that over two days, high volume exercise does not stimulate compensatory appetite regulatory changes, in lean healthy males. In the short term, lean and ow/ob males and females respond similarly to acute exercise, showing no alterations in appetite or food intake responses, whilst PYY and GLP-1 concentrations are higher in exercise than control trials.

Made available in DSpace on 2015-07-22T20:49:55Z (GMT). No. of bitstreams: 0 Previous issue date: 2006-12-31 / Objetivo: Verificar as possíveis alterações provocadas pelos exercícios de força sobre a adiposidade periférica e visceral, perfil lipídico, glicídico e respostas hormonais, após doze semanas de intervenção, em adolescentes obesos. Métodos: Foram selecionados 126 adolescentes, de ambos os gêneros, com idade entre 14 e 19 anos, sedentários, e índice de massa corporal (IMC)95th; distribuídas em quatro grupos: controle (sem exercício físico), recreação, exercícios aeróbios e exercícios de força. Realizaram exercícios físicos durante 12 semanas, três sessões semanais com duração de uma hora. O grupo recreação não controlou a intensidade do treinamento, aeróbio treinou na intensidade do Limiar Ventilatório-I, o grupo força treinou a 70% de uma repetição máxima (1RM). A gordura corporal total, subcutânea e massa livre de gordura foram avaliadas por absorciometria de feixe duplo de raios-X (DEXA), a gordura visceral por ultrassonografia. O perfil lipídico pelo método de comparativo calorimétrico e o perfil hormonal por radioimunoinsaio. Resultados: Em relação à composição corporal, após doze semanas de tratamento, o treinamento de força promoveu uma redução significativa no IMC, massa corporal, gordura visceral e subcutânea nos meninos. No grupo aeróbio também observamos uma redução significativa na massa corporal, gordura corporal e subcutânea de meninos e somente gordura corporal em meninas. Houve preservação de massa magra em todos os grupos e gêneros. Quanto ao perfil lipídico, o treinamento aeróbio diminuiu o colesterol total e LDL-c em ambos os gêneros. A atividade de recreação reduziu os níveis plasmáticos de glicose e insulina, bem como o HOMA, somente nas meninas. Conclusões: Após 12 semanas de treinamento os exercícios de força foram mais eficientes em meninos, sobre a composição corporal, enquanto que para colesterou total e LDL-c o exercício aeróbio foi mais eficiente em ambos os gêneros. / Objective: Verify the possible changes promote by strength exercise to visceral and periferic adipose tissue, lipidic profile, glucose and hormonal aswers, after twelvy weeks of intervention, in obese adolescents Methods: was select 126 adolescents, both genders, aged between 14and 19 years, and body mass index (BMI) 95 th, distributed in four groups: control (no exercise), leasure activity, aerobic exercise and strength exercise. They performed physical exercise for 12 weeks, 3 sessions each week, with 1hour of duration. Training intensity was not controlled in the leasure activity group, aerobic group training was at intensity corresponding to ventilatory threeshold – I, strength exercise was performed at 70% of 1 Maximun Repetition. Total body fat, subcutaneous fat and lean body mass was assessed by whole-body dual-energy X-ray absormetry scan (DEXA), visceral adipose tissue assessed by ultrassonography. Lipidic profile was measured by calorimetry and hormonals assays by radioimmunoassay. Results: Relation to body composition, after treatment, strength training promoted significant decreased in the BMI, body mass, visceral and subcutaneous fat in boys. Aerobic training promoted same changes in boys and girls. There was lean body mass preservation in both genders in all groups. Aerobic training decreased total cholesterol and LDL – c in both genders. The leasure physical activity reduced the blood levels of glucose and insulin, ass well in HOMA, only in girls. Conclusions: Strength training was the more effective to promote changes in body composition in boys. However to total cholesterol and LDL – c aerobic training is better in both genders. / TEDE / BV UNIFESP: Teses e dissertações

Introdução: A resistência insulínica (RI) decorrente da obesidade está relacionada a distúrbios hormonais que afetam o sistema reprodutor. Leptina e grelina são hormônios que regulam o balanço energético; porém, informações acerca da relação destes hormônios com a infertilidade são escassas. A dieta de baixo índice glicêmico (BIG) parece exercer impacto positivo sobre as alterações metabólicas decorrentes da RI. Objetivo: Verificar o efeito de uma dieta hipocalórica de baixo índice/carga glicêmica sobre parâmetros antropométricos e metabólicos, níveis de grelina e leptina e desfechos reprodutivos em mulheres inférteis com excesso de peso candidatas à fertilização in vitro (FIV). Métodos: Ensaio clínico randomizado. Foram analisadas vinte e seis mulheres inférteis com obesidade Grau I ou II ou pré-obesidade associada à circunferência da cintura aumentada. As pacientes foram alocadas no grupo Dieta Hipocalórica de BIG, ou no grupo Controle (manutenção do hábito alimentar) e acompanhadas por 12 semanas. Parâmetros avaliados: peso corporal, índice de massa corporal (IMC), percentual de gordura (%G), glicose, insulina, HOMA-IR, lipídios séricos, hormônios reprodutivos, grelina acilada, leptina, dose de gonadotrofinas, número e qualidade oocitária e embrionária, taxa de fertilização e de gestação. Resultados: Houve redução de 5,5% do peso corporal e também do IMC (p < 0,001), do %G (p = 0,002), dos níveis de glicose (p = 0,034) e de leptina (p = 0,013) no grupo BIG quando comparado ao grupo controle. Houve um aumento de 18% nos níveis de grelina no grupo BIG quando comparado ao controle, mas esse aumento não foi significativo (p > 0,05). O grupo BIG obteve 85,4% mais oócitos coletados, quando comparado ao grupo controle (7,75 ± 1,44 vs. 4,18 ± 0,87, respectivamente, p = 0.039) no ciclo de FIV. Não houve diferença entre os grupos na dose de gonadotrofinas, na qualidade oocitária e embrionária, e na taxa de fertilização. Três (21,4%) pacientes do grupo BIG apresentaram gestação espontânea durante o acompanhamento, gerando três nascidos vivos. Conclusões: A perda de 5,5% do peso corporal através da dieta hipocalórica BIG foi capaz de melhorar parâmetros antropométricos, metabólicos, reprodutivos e os desfechos de FIV, quando comparado às mulheres que mantiveram o peso corporal. Estes resultados dão sustentação à recomendação clínica de aconselhar mulheres com sobrepeso ou obesas a perderem peso através de uma dieta balanceada, preferencialmente com baixo índice/carga glicêmica, antes de serem submetidas a procedimentos de reprodução assistida. / Introduction: Insulin resistance (IR) resulting from obesity is related to hormonal disorders that affect reproductive system. Leptin and ghrelin are hormones that regulate energy balance; however, the relationship of these hormones with infertility is not clear. The low glycemic index (LGI) diet seems to exert a positive impact on obesity and metabolic changes resulting from IR. Objective: To verify the effect of a hypocaloric diet with low glycemic index/load on anthropometric and metabolic parameters, ghrelin and leptin levels and reproductive outcomes in overweight and obese infertile women candidates to in vitro fertilization (IVF). Methods: Randomized clinical trial. Twenty six infertile women with grade I and II obesity, or pre-obesity with increased waist circumference were analysed. Patients were assigned to hypocaloric LGI diet group or control group (maintenance of usual diet), and followed the protocol for 12 weeks. Parameters evaluated: body weight, body mass índex (BMI), body fat percentage (%BF), glucose, insulin, HOMA-IR, serum lipids, reproductive hormones, leptin, acylated ghrelin, gonadotrophin doses, number and quality of oocytes and embryos, fertilization and pregnancy rates Results: There was a 5.5% weight loss and also a reduction in BMI (p < 0.001), BF% (p = 0.002), glucose (p = 0.034) and leptin levels (p = 0.013) in the LGI group compared to control. There was a 18% increase in ghrelin levels in the LGI group compared to control, but this increase was not significant (p > 0.05). The LGI diet group had 85.4% more oocytes retrieved compared to control group (7.75 ± 1.44 vs. 4.18 ± 0.87, respectively, p = 0.039) in the IVF cycle. The gonadotrophin dose, oocyte and embryo quality, and fertilization rate were similar between groups (p > 0.05). Three (21.4%) patients in the LGI group experienced spontaneous pregnancy during the follow-up, generating three live births. Conclusion: The 5.5% weight loss trough the hypocaloric LGI diet was able to improve antropometric, metabolic, reproductive and IVF outcomes when compared with women that not lose weight. These results support the clinical recommendation to advise overweight and obese women to lose weight through a balanced diet, preferably with low glycemic index/load, prior to be submitted to assisted reproduction technologies.