O objetivo deste estudo foi analisar o comportamento dos níveis plasmáticos de grelina, em relação aos fatores de risco cardiometabólico, em uma população multiétnica de eutróficos e de obesos..A grelina é um peptídeo produzido predominantemente pelas células oxínticas gástricas, que desempenha importante papel na homeostase energética, promovendo estímulo do apetite e aumento do peso corporal, além de participar do controle do metabolismo lipídico e glicídico, interagindo diretamente com os fatores de risco cardiometabólico. Este é um estudo transversal. Duzentos indivíduos entre 18 e 60 anos com diferentes graus de índice de massa corporal (IMC) compuseram a amostra, assim dividida: cem eutróficos (IMC < 25 kg/m2) e 100 obesos (IMC &#8805; 30 kg/m2). Todos foram avaliados para parâmetros antropométricos, determinação da pressão arterial (aferida por método oscilométrico através de monitor automático) e variáveis metabólicas (métodos usuais certificados). A grelina acilada foi mensurada pela técnica de sanduíche ELISA; a leptina, pelo método Milliplex MAP. O marcador inflamatório proteína C reativa ultrassensível(PCRUS)foi estimado por nefelometria ultrassensível. A insulina foi determinada por quimioluminescência e o HOMA-IR calculado pelo produto insulinemia (U/ml) X níveis de glicemia de jejum (mmol/L) / 22.5. Foram excluídos do estudo aqueles com história de comorbidades crônicas, doenças inflamatórias agudas, dependência de drogas e em uso de medicação nos dez dias anteriores à entrada no estudo. As concentrações de grelina acilada mostraram tendência de redução ao longo dos graus de adiposidade (P<0,001); a leptina se comportou de maneira oposta (P<0,001). Os níveis de grelina se correlacionaram negativamente com IMC (r = -.36; P<0,001), circunferência da cintura (CC) (r=-.34; P<0,001), relação cintura/quadril (RCQ) (r=-.22; P=0,001), diâmetro abdominal sagital (DAS) (r=-.28; P<0,001), pressão arterial sistólica (PAS) (r=-.21; P=0,001), insulina (r=-.27; P<0,001), HOMA-IR (r=-.24; P=0,001) e PCRUS (r=-.29; P<0,001); e positivamente com o HDL-colesterol (r=.30; P<0,001).A PCRUS acompanhou o grau de resistência insulínica e os níveis de grelina também mostraram tendência de redução ao longo dos tercis de resistência insulínica (P=0,001). Em modelo de regressão linear múltipla as principais associações independentes da grelina acilada foram sexo feminino (P=0,005) e HDL-colesterol (P=0,008), ambos com associação positiva e IMC (P<0,001) (associação negativa). Esses achados apontam para uma associação da grelina acilada com melhor perfil metabólico, já que seus níveis se correlacionaram positivamente com HDL-colesterol e negativamente com indicadores de resistência insulínica e atividade inflamatória. / The aim of this study was to analyze the behaviour of ghrelin levels in relation to cardiometabolic risk factors, in a multiethnic population of lean and obese subjects. Ghrelin is a peptide produced mainly by oxyntic gastric cells. It has an important role in energetic balance, stimulating appetite and weight gain, with a role in lipid and carbohydrate metabolism. It interacts directly with the cardiometabolic risk factors. This is a cross-sectional study. Two hundred individuals between 18 and 60 years with varying degrees of body mass index (BMI) comprised the sample, divided as follows: one hundred eutrophic (BMI < 25 kg/m2), 50 men and 50 women and 100 obese (BMI &#8805; 30 kg/m2), 50 men and 50 women. All were evaluated by anthropometric parameters, blood pressure determination (measured by the oscilometric method using an automatic monitor) and metabolic variables (usual methods certificates). The acylated ghrelin was measured by sandwich ELISA technique; leptin by Milliplex MAP method. The inflammatory marker sensitive C reactive protein (hsCRP) was estimated by ultrasensitive nephelometry. Insulin was determined by quimioluminescency and HOMA-IR calculated as the product of insulin (U/ml) X fasting glucose levels (mmol/L) / 22.5. Those subjects with a history of chronic comorbidities, acute inflammatory diseases, drug addiction and on medication in the ten days prior to study entry were withdrawn from the study. There was a trend of decreasing acylated ghrelin (P<0,001) and increasing leptin levels (P<0,001), respectively, along increasing degrees of adiposity. Acylated ghrelin levels were negatively correlated with BMI (r = -.36; P<0,001), waist circumference (r=-.34; P<0,001), waist-to-hip ratio (r=-.22; P=0,001), sagittal abdominal diameter (r=-.28; P<0,001) , systolic blood pressure (r=-.21; P=0,001) , insulin (r=-.27; P<0,001), HOMA-IR (-.24; P=0,001) and high sensitive C reactive protein (hsCRP) (r=-.29; P<0,001); the correlation of acylated ghrelin with HDL-cholesterol was positive (r=.30; P<0,001).The hsCRP followed insulin resistance degree and acyated ghrelin levels also showed decreasing linear trend along increasing HOMA-IR tertiles (P=0,001). In a linear multiple regression model the independent positive correlates of ghrelin were female sex (P=0,005) and HDL-cholesterol (P=0,008), while BMI associated negatively and independently with ghrelin levels (P<0,001). These findings suggest an association of ghrelin with a better metabolic profile, since its levels were positively correlated with HDL-cholesterol and negatively associated with insulin resistance and inflammatory activity indicators.

Current methods of energy restriction are not successful for achieving long-term weight loss and maintenance for the majority of individuals. As a result, the prevalence of obesity and obesity related diseases continue to increase. This calls for the development of novel lifestyle interventions to combat the obesity epidemic. Hunger has been highlighted as a major factor influencing the long-term success of weight management methods and therefore how a given dietary intervention affects the appetite regulatory system may dictate the success of the diet by augmenting long-term adherence. In addition, the effect of a given dietary intervention on exercise may determine its suitability for exercising individuals and may influence the energy deficit that can be achieved by the diet. This thesis investigated the acute effects of two novel methods of dietary restriction; breakfast omission and severe energy restriction. The main aims for this thesis were to determine the effect of these methods of energy restriction on ad-libitum energy intake, subjective appetite sensations, and peripheral concentrations of hormones involved in appetite regulation. In addition, this thesis also investigated the effects of these methods of energy restriction on metabolism and glycaemic control at rest, and performance and perceived exertion during exercise. This work found that moderate and severe energy deficits induced by breakfast omission and 24 h of severe energy restriction, respectively, resulted in either no (Chapter VIII) or partial (Chapters IV and VII) energy intake compensation over the subsequent 24-48 h. Subjective appetite was increased during (Chapters IV, V, VII and VIII) and shortly after (Chapter VII) energy restriction, but this effect was transient and was offset after an ad-libitum (Chapters IV and VII) or standardised (Chapters V and VIII) meal. In addition, none of the work presented in this thesis demonstrated an appetite hormone response to energy restriction that was indicative of compensatory eating behaviour. Compared to breakfast omission, breakfast consumption resulted in an increased in resting energy expenditure and carbohydrate oxidation, with a concurrent reduction in fat oxidation during the morning. However, there were no differences after lunch (Chapter V). In response to a standardised breakfast, resting energy expenditure was suppressed (Chapter VII) or not different (Chapter VIII) the following morning, after 24 h severe energy restriction compared to energy balance. Plasma NEFA and fat oxidation was greater, carbohydrate oxidation was reduced, and postprandial insulin sensitivity was impaired in the after 24 h severe energy restriction (Chapter VI, VII and VIII). In Chapter IV, omission of breakfast in the morning was shown to reduce exercise performance in evening, even after provision of an ad-libitum lunch 4 h before. However, there was no difference in perception of effort during steady state exercise, independent of breakfast consumption or omission in the morning (Chapters IV and V). Collectively, breakfast omission and 24 h severe energy restriction reduce energy intake and promote an appetite regulatory response conducive to maintenance of a negative energy balance. Chronic intervention studies are now required to confirm whether these effects persist after long-term practice of these dietary interventions.

Fundação Carlos Chagas Filho de Amparo a Pesquisa do Estado do Rio de Janeiro / A compulsão alimentar está associada a diversas doenças, entre elas, a obesidade.Com o intuito de pesquisar a diferença hormonal ligada ao controle da fome e da saciedade associada ao episódio de compulsão alimentar (ECA), avaliou-se a concentração sérica dos hormônios que regulam este processo em mulheres adultas. Métodos: O estudo experimental foi composto de 3 grupos (n=23), sendo: grupo Eutrófico (GE;n=8), grupo obeso sem ECA (GO;n=7) e obesas com ECA (ECA;n=8). Todas as mulheres que participaram do estudo freqüentavam os serviços de saúde da Policlínica Piquet Carneiro. Foram dosados os hormônios: Grelina Total, Glucagon, Adiponectina, Amilina, Peptídeo C, GLP-1, Insulina e Leptina séricos nos tempos: jejum, 15 e 60 minutos após a ingestão da refeição fornecida. As refeições ingeridas foram controladas em energia, 55% carboidratos, 15% proteínas, 30% lipídios. Os dados foram analisados como valores médios por grupo em software SAS, considerando p<0,05. Resultados: A idade das mulheres estudadas variou de 32 a 50 anos. A concentração de adiponectina encontrada, que é inversamente proporcional a adiposidade, foi significativamente menor no grupo ECA em relação aos demais grupos (p=0,01). Em relação à leptina, o grupo GO apresentou concentração maior em relação aos demais grupos (p<0,0001). Já, a concentração de grelina encontrada foi significativamente menor no grupo ECA em relação aos demais grupos (p=0,02). Foram encontradas concentrações significativamente maiores de insulina no grupo GO em relação aos demais grupos (p=0,04). A concentração de amilina encontrada foi significativamente maior no grupo GO em relação aos outros grupos (p=0,01). A concentração de GLP-1 encontrada no grupo GO foi maior em média, porém esta diferença não foi estatisticamente significativa entre os grupos (p=0,25). A concentração de Peptídeo C encontrada no grupo GO foi maior em relação aos outros grupos (p=0,003). Apesar da concentração de Glucagon no grupo ECA ser maior em relação aos demais grupos, estes valores não eram diferentes estatisticamente (p=0,13). Nossos achados mostraram que obesas ECA tem perfil hormonal diferente de obesas sem ECA. A baixa concentração de grelina do grupo de obesas ECA e a alta concentração de insulina, peptídeo C e amilina nas obesas com e sem ECA pode estar relacionado com o aumento da ingestão alimentar e com o desequilíbrio energético. / Binge eating is associated to several diseases, including obesity. In order to study the hormonal control of hunger and satiety that is commonly involved in binge-eating process; we evaluated the serum concentration of these hormones in adult women. The experimental study was composed of 3 groups, n= 23: Lean (GE, n = 8), Obese without binge (GO, n = 7) and obese with binge (BEE, n = 8). All women who participated in the study attended the health services of the Polyclinic Piquet Carneiro. Serum hormones were assayed: total ghrelin, glucagon, adiponectin, Amylin, c-Peptide, glucagon like peptide (GLP-1), insulin and Leptin in fasting, 15 and 60 minutes after food intake. Meals were controlled in energy, 55% carbohydrates, 15% protein, 30% lipids. Data were analyzed as average values per group in SAS software, considering p <0.05. Results: Women`s age ranged from 32 to 50 years. The adiponectin concentration, which is inversely proportional to adiposity, was significantly lower in BEE group than the other groups (p=0.01). Leptin of the GO group presented higher concentration than the others (p<0.0001). Ghrelin concentration was significantly lower in BEE group than the other groups (p=0.02). We found a significantly higher concentration of insulin in GO group in comparison to the others (p = 0.04). Amylin concentration was significantly higher in GO group in comparison to the other groups (p=0.01). GLP-1 concentration of GO group was higher on average, but not statistically significant between groups (p=0.25). Cpeptide concentration found in GO group was higher than the others (p=0.003). Despite glucagon concentration in the BEE group was greater than the other groups, these values were not statistically different (p=0.13). Our findings shown that BEE group have different hormonal profile than GO and GE. The lowest concentration of ghrelin found in BEE group and the highest concentration of insulin, C-peptide and amylin found in both obese group with and without binge eating may be related to increased food intake and energy imbalance.

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.

O objetivo deste estudo foi analisar o comportamento dos níveis plasmáticos de grelina, em relação aos fatores de risco cardiometabólico, em uma população multiétnica de eutróficos e de obesos..A grelina é um peptídeo produzido predominantemente pelas células oxínticas gástricas, que desempenha importante papel na homeostase energética, promovendo estímulo do apetite e aumento do peso corporal, além de participar do controle do metabolismo lipídico e glicídico, interagindo diretamente com os fatores de risco cardiometabólico. Este é um estudo transversal. Duzentos indivíduos entre 18 e 60 anos com diferentes graus de índice de massa corporal (IMC) compuseram a amostra, assim dividida: cem eutróficos (IMC < 25 kg/m2) e 100 obesos (IMC &#8805; 30 kg/m2). Todos foram avaliados para parâmetros antropométricos, determinação da pressão arterial (aferida por método oscilométrico através de monitor automático) e variáveis metabólicas (métodos usuais certificados). A grelina acilada foi mensurada pela técnica de sanduíche ELISA; a leptina, pelo método Milliplex MAP. O marcador inflamatório proteína C reativa ultrassensível(PCRUS)foi estimado por nefelometria ultrassensível. A insulina foi determinada por quimioluminescência e o HOMA-IR calculado pelo produto insulinemia (U/ml) X níveis de glicemia de jejum (mmol/L) / 22.5. Foram excluídos do estudo aqueles com história de comorbidades crônicas, doenças inflamatórias agudas, dependência de drogas e em uso de medicação nos dez dias anteriores à entrada no estudo. As concentrações de grelina acilada mostraram tendência de redução ao longo dos graus de adiposidade (P<0,001); a leptina se comportou de maneira oposta (P<0,001). Os níveis de grelina se correlacionaram negativamente com IMC (r = -.36; P<0,001), circunferência da cintura (CC) (r=-.34; P<0,001), relação cintura/quadril (RCQ) (r=-.22; P=0,001), diâmetro abdominal sagital (DAS) (r=-.28; P<0,001), pressão arterial sistólica (PAS) (r=-.21; P=0,001), insulina (r=-.27; P<0,001), HOMA-IR (r=-.24; P=0,001) e PCRUS (r=-.29; P<0,001); e positivamente com o HDL-colesterol (r=.30; P<0,001).A PCRUS acompanhou o grau de resistência insulínica e os níveis de grelina também mostraram tendência de redução ao longo dos tercis de resistência insulínica (P=0,001). Em modelo de regressão linear múltipla as principais associações independentes da grelina acilada foram sexo feminino (P=0,005) e HDL-colesterol (P=0,008), ambos com associação positiva e IMC (P<0,001) (associação negativa). Esses achados apontam para uma associação da grelina acilada com melhor perfil metabólico, já que seus níveis se correlacionaram positivamente com HDL-colesterol e negativamente com indicadores de resistência insulínica e atividade inflamatória. / The aim of this study was to analyze the behaviour of ghrelin levels in relation to cardiometabolic risk factors, in a multiethnic population of lean and obese subjects. Ghrelin is a peptide produced mainly by oxyntic gastric cells. It has an important role in energetic balance, stimulating appetite and weight gain, with a role in lipid and carbohydrate metabolism. It interacts directly with the cardiometabolic risk factors. This is a cross-sectional study. Two hundred individuals between 18 and 60 years with varying degrees of body mass index (BMI) comprised the sample, divided as follows: one hundred eutrophic (BMI < 25 kg/m2), 50 men and 50 women and 100 obese (BMI &#8805; 30 kg/m2), 50 men and 50 women. All were evaluated by anthropometric parameters, blood pressure determination (measured by the oscilometric method using an automatic monitor) and metabolic variables (usual methods certificates). The acylated ghrelin was measured by sandwich ELISA technique; leptin by Milliplex MAP method. The inflammatory marker sensitive C reactive protein (hsCRP) was estimated by ultrasensitive nephelometry. Insulin was determined by quimioluminescency and HOMA-IR calculated as the product of insulin (U/ml) X fasting glucose levels (mmol/L) / 22.5. Those subjects with a history of chronic comorbidities, acute inflammatory diseases, drug addiction and on medication in the ten days prior to study entry were withdrawn from the study. There was a trend of decreasing acylated ghrelin (P<0,001) and increasing leptin levels (P<0,001), respectively, along increasing degrees of adiposity. Acylated ghrelin levels were negatively correlated with BMI (r = -.36; P<0,001), waist circumference (r=-.34; P<0,001), waist-to-hip ratio (r=-.22; P=0,001), sagittal abdominal diameter (r=-.28; P<0,001) , systolic blood pressure (r=-.21; P=0,001) , insulin (r=-.27; P<0,001), HOMA-IR (-.24; P=0,001) and high sensitive C reactive protein (hsCRP) (r=-.29; P<0,001); the correlation of acylated ghrelin with HDL-cholesterol was positive (r=.30; P<0,001).The hsCRP followed insulin resistance degree and acyated ghrelin levels also showed decreasing linear trend along increasing HOMA-IR tertiles (P=0,001). In a linear multiple regression model the independent positive correlates of ghrelin were female sex (P=0,005) and HDL-cholesterol (P=0,008), while BMI associated negatively and independently with ghrelin levels (P<0,001). These findings suggest an association of ghrelin with a better metabolic profile, since its levels were positively correlated with HDL-cholesterol and negatively associated with insulin resistance and inflammatory activity indicators.

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.

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.

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.

Adolescents with type 1 diabetes (T1DM) are given nutritional education, but the knowledge about their adherence to the food recommendations and associations between dietary intake and metabolic control is poor. Gastrointestinal symptoms are more prevalent in adults with T1DM than in healthy controls, which may be due to disturbed gastrointestinal motility. The meal content affects the gastric emptying rate and the postprandial glycaemia in healthy adults and adults with type 2 diabetes. Meal ingestion also elicits several postprandial hormonal changes of importance for gastrointestinal motility and glycaemia. Eating disorders are more prevalent in young females with T1DM than in healthy females, and are associated with poor metabolic control. The prevalence of eating disorders in adolescent boys with T1DM is not known.  This thesis focuses on eating and gastrointestinal function in adolescents with T1DM. Three population-based, cross-sectional studies demonstrated that adolescents with T1DM consume healthy foods more often and have a more regular meal pattern than age- and sex-matched controls. Yet both boys and girls are heavier than controls. The intake of saturated fat is higher and the intake of fibre is lower than recommended in adolescents with T1DM. Patients with poor metabolic control consume more fat and less carbohydrates than patients with better metabolic control. Gastrointestinal symptoms are common in adolescents with T1DM, but the prevalence is not increased compared with controls. Gastrointestinal symptoms in patients are associated with female gender, daily cigarette smoking, long duration of diabetes, poor metabolic control during the past year, and an irregular meal pattern. Adolescent boys with T1DM are heavier and have higher drive for thinness than healthy boys, but do not differ from them in scales measuring psychopathology associated with eating disorders.   In a randomized, cross-over study, we found that a meal with a high fat and energy content reduces the initial (0–2 hours) postprandial glycaemic response and delays gastric emptying in adolescents with T1DM given a fixed prandial insulin dose compared with a low-fat meal. The glycaemic response is significantly associated with the gastric emptying rate. Both a high- and a low-fat meal increase the postprandial concentrations of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) and suppress the postprandial ghrelin levels in adolescents with T1DM. The postprandial changes of these hormones are more pronounced after the high-fat meal. Insulin-like growth factor binding-protein (IGFBP) –1 concentrations decrease after insulin administration irrespective of meal ingestion. The GLP-1 response is negatively associated with the gastric emptying rate. The fasting ghrelin levels are negatively associated with the postprandial glycaemic response, and the fasting IGFBP-1 levels are positively associated with the fasting glucose levels.  We conclude that nutritional education to adolescents with T1DM should focus more on energy intake and expenditure to prevent and treat weight gain. It should also focus on fat quality and fibre intake to reduce the risk of macrovascular complications and improve glycaemia. Gastrointestinal symptoms in adolescents with T1DM should be investigated and treated as in other people irrespective of having diabetes. However, adolescents with long duration of diabetes, poor metabolic control, and symptoms from the upper gut should have their gastric emptying rate examined during euglycaemia. There may be an increased risk for development of eating disorders in adolescent males with T1DM since they are heavier than healthy boys and have higher drive for thinness. This should be investigated in future, larger studies.  For the first time, we showed that a fat-rich meal delays gastric emptying and reduces the initial glycaemic response in patients with T1DM. The action profile of the prandial insulin dose to a fat-rich meal may need to be postponed and prolonged compared with the profile to a low-fat meal to reach postprandial normoglycaemia. Circulating insulin levels affect postprandial GIP, GLP-1, and ghrelin, but not IGFBP-1, responses less than the meal content. The pronounced GIP-response to a fat- and energy-rich meal may promote adiposity, since GIP stimulates lipogenesis. Such an effect would be disadvantageous for adolescents with T1DM since they already have increased body fat mass and higher weights compared with healthy adolescents. Adolescents with T1DM may have subnormal postprandial ghrelin suppression, which may be due to their increased insulin resistance or elevated growth hormone levels. This needs to be investigated in future, controlled studies.

La restriction alimentaire chronique correspond à un des troubles du comportement alimentaire observé en particulier dans l’anorexie mentale (AN) de type restrictif, pathologie qui touche essentiellement les adolescentes et les jeunes femmes. En plus de ce comportement restrictif, une activité physique importante est observée chez un grand nombre de patientes (40 à 80% des cas). Cette maladie se traduit par de nombreuses altérations physiologiques comme des perturbations neuroendocrines, métaboliques, osseuses (ostéopénie, ostéoporose) et ce quelle que soit la cause psychiatrique qui a conduit au développement de ce comportement. De plus, de nombreux arguments suggèrent que l’AN pourrait être considérée comme un trouble « addictif » qui se manifesterait par une addiction à la perte de poids et/ou à la restriction alimentaire ou encore à l’activité physique suggérant une altération du système dopaminergique de récompense. Ainsi, quelles que soient les origines de la maladie, l’AN entraîne des perturbations périphériques et centrales susceptibles d’être impliquées dans une première phase dite « d’adaptation » permettant aux malades de survivre à ces conditions drastiques. Les patients peuvent par la suite tomber dans une seconde phase de « chronicisation » dans laquelle ces mêmes facteurs pourraient être responsables de la dégradation de l’état des malades et conduire, dans les cas les plus graves d’épuisement, à la mort.Notre étude a comme pivot la ghréline, hormone orexigène, dont les concentrations plasmatiques sont augmentées significativement chez les patients anorexiques. Sécrétée principalement en périphérie par les cellules de l’estomac, elle va cibler plusieurs organes aussi bien périphériques que centraux. En particulier, au niveau périphérique, cette hormone agit au niveau du foie dont la principale fonction connue est le maintien de l’homéostasie glucidique. Elle agit également au niveau du tissu adipeux qui est alors stimulé, favorisant ainsi sa croissance avec un stockage des réserves et au niveau musculaire en entrainant entre autre une diminution des réserves de triglycérides. Au niveau du système nerveux central, parmi les sites d’action de la ghréline, on trouve les structures impliquées aussi bien dans le contrôle, qualifié d’homéostatique, de la prise alimentaire représenté par l’hypothalamus, que dans le contrôle, dit hédonique (motivation/récompense), de ce même comportement correspondant au circuit méso-limbique. Pour étudier son implication dans les mécanismes adaptatifs, et éventuellement, dans l’aggravation de la maladie, nous avons mis au point un modèle animal de restriction alimentaire chronique mimant les symptômes physiologiques de l’AN. Notre premier objectif a été de caractériser (« phénotypage ») ce modèle sur le plan physiologique (métabolique, endocrinien) afin de l’utiliser pour notre deuxième objectif : évaluation du rôle de la ghréline comme potentiel facteur prédictif de l’évolution de la maladie.Les données obtenues valident notre modèle comme un modèle pertinent pour étudier sur le long terme les altérations physiologiques et centrales décrites dans l’AN de type restrictif. Nous montrons que l’exercice physique modéré associé à la restriction alimentaire a des effets stabilisateurs sur de nombreux paramètres métaboliques limitant ainsi un épuisement prématuré des ressources énergétiques. En ce qui concerne la ghréline, les concentrations plasmatiques élevées observées dans notre modèle pourraient contribuer également à une régulation adaptative du métabolisme énergétique. / Chronic food restriction is one of the major features observed in anorexia nervosa (AN), especially in the restrictive type. This major eating disorder affects mainly teenager girls and young women. Additionally to the restriction behavior, important physical activity is observed in a large number of patients (40-80% of cases). This disease induces various physiological alterations that concern neuroendocrine, metabolic and bone (osteopenia, osteoporosis) pathways, which have dramatic consequences on the patient’s health. Moreover, many arguments suggest that AN could be considered like an "addictiv" disorder supported by an addiction to weight loss and/or food restriction or physical activity. It thus suggests modifications of the central dopaminergic reward system. Furthermore, whatever the origins or the causes of this disorder, AN leads to peripheral and central alterations that might be involved in an "adaptation" phase allowing patients surviving to these drastic conditions. For some patients, a phase of "chronicity" is described in which these physiological changes may worsen the patient conditions and contribute, when exhaustion is amplifying, to death. Our study points out ghrelin, an orexigenic hormone whose plasma concentrations are significantly increased in AN patients. Mainly secreted by stomach cells, it targets multiple peripheral organs as well as numerous neuronal structures in the brain. At the peripheral level, this hormone acts among others in the liver whose main function is the maintenance of glucose homeostasis. It acts also on the adipose tissue to promote its growth that is associated with lipid storage and on muscle resulting in a reduction of triglycerides stock. At the central nervous system level, ghrelin have various targets like the structures involved in the homeostatic as well as hedonic (motivation/reward) control of food intake through the hypothalamus and the meso-cortico-limbic system respectively.To study the involvement of ghrelin in the potential adaptive mechanisms, and even in the worsening of the disease, we have developed an animal model of chronic food restriction associated or not with physical activity, mimicking the physiological symptoms of AN. Our first objective was to characterize and to phenotype the mouse model by evaluating various physiological (metabolic, endocrine) factors in order to study in our second objective the role of ghrelin as a potential predictor of disease progression.We showed that our mouse model constitutes a pertinent model to study on a long term duration the physiological and central altérations described in the restrictive type AN. Moreover, we showed that moderate physical activity associated with food restriction had stabilizing effects on numerous metabolic parameters that may reduce an early exhaustion of energy stocks. Concerning the role of ghrelin in such model, its plasma concentrations were increased like in AN patients and were suggested to contribute to the adaptive regulation of energy metabolism.