Diss. (sammanfattning) Göteborg : Univ., 2010.

Submitted in fulfillment of the requirement for the degree of Doctor of Philosophy in the Faculty of Health Sciences at the University of the Witwatersrand, Johannesburg / Renewed interest in cannabinoid compounds arose since the discovery of the endocannabinoid system in the early 1990’s and its role in mediating the body’s energy balance. The aim of this study was to investigate the effect of an organic Cannabis sativa (hereafter referred to as C. sativa) extract on β-cell secretory function using an in vivo diet-induced obese rat model and an in vitro isolated rat pancreatic islet model and to determine the associated molecular changes within the pancreatic tissue. Materials and methods: Diet-induced obese Wistar rats and rats fed on standard pellets were subcutaneously injected, over a 28 day period, with an organic C. sativa extract or the vehicle (1% Tween 80® in saline). The effect of diet and treatment was evaluated using the intraperitoneal glucose tolerance tests (IPGTTs) and quantitative polymerase chain reaction (qPCR) analysis on rat pancreata. In vitro studies were conducted using isolated rat islets exposed to 11.1 (representative of normoglycemic conditions) and 33.3 mM glucose levels (representative of hyperglycemic conditions) over a 24-(D1; acute) and 96-hour (D4; chronic) period, and treated with C. sativa extract containing an equivalent of 2.5 (T1) and 5 ng/mL (T2) tetrahydrocannabinol (THC). Glucose-stimulated insulin secretion (GSIS), immunohistocytochemistry for apoptosis and proliferation detection and western blotting for detection of cannabinoid receptor type 1 (CB1), CB2 receptors and specific transduction factors were undertaken. Antagonist studies were conducted using AM251 (A1) and AM630 (A2) to block CB1 and CB2, respectively, to determine the role of cannabinoid receptors in insulin secretion. Results: The overall increase in body weight in the experimental groups occurred at a significantly slower rate than the control groups (P < 0.01), irrespective of diet. In the lean group, the area under the curve for glucose (AUCg) was significantly higher compared to the diet-induced obese group (P < 0.001), while C. sativa treatment significantly improved the AUCg in the lean rats (P < 0.05). The cafeteria diet did not induce hyperglycemia and insulin resistance in the obese rats and C. sativa treatment maintained a plasma glycemic profile similar to the obese control rats. The lower AUCg values in the obese group may, in part, be due to the inclusion of milk products (shown to be beneficial in reducing diabetes) in the cafeteria diet. qPCR analysis showed that the cafeteria diet induced down-regulation of the following genes in the obese control group, relative to lean controls: UCP2 (P < 0.01), c-MYC (P < 0.05) and FLIP (P < 0.05), and upregulation of CB1 (P < 0.01), GLUT2 (P < 0.001), UCP2 (P < 0.001) and PKB (P < 0.05), relative to the obese control group, while c-MYC levels were down-regulated (P < 0.05), relative to the lean control group. In the in vitro study, results showed C. sativa treatment decreased chronic insulin secretion in islets cultured under normoglycemic condition for D1 (P < 0.05), but not for D4. In islets cultured under hyperglycemic conditions, C. sativa treatment for the D4 period showed a significant increase in their chronic insulin secretion (HD4T1, P = 0.07; HD4T2, P < 0.001), increase in basal insulin secretion (HD4T1, P < 0.001; HD4T2, P < 0.001), increase in GSIS (HD4T1, P < 0.05; HD4T2, P < 0.001), reduction in glucose-stimulated:basal insulin production (HD4T1, P < 0.05; HD4T2, P < 0.05), reduction in insulin content (HD4T1, P < 0.001), increase in the percentage basal : content ratio (HD4T1, P < 0.001; HD4T2, P < 0.01) and increase in the percentage GSIS : content ratio (HD4T1, P < 0.001; HD4T2, P < 0.05), relative to ND4C islets. In antagonist studies, A2 preconditioning did not affect suppress the stimulatory effect of C. sativa treatment on chronic insulin secretion under normo- and hyperglycemic conditions, relative to the NC and HC islets, respectively. qPCR studies showed that C. sativa exposure induced a 2.2-fold increase in CB1 gene expression, relative to normoglycemic control islets (P < 0.05), while c-MYC and FLIP expression was significantly reduced by 12% (ND4T1, P < 0.05) and 37% (HD4T1, P < 0.05), respectively. C. sativa treatment also induced increased secretion of anti-inflammatory cytokines/chemokines under hyperglycemic conditions. Conclusion: These results suggest that C. sativa protects pancreatic islets against the negative effects of obesity (in vivo studies) and hyperglycemia (in vitro studies). In light of these findings, further investigation into the potential of C. sativa as a complementary therapeutic agent in the treatment of the deleterious effects of hyperglycemia in diabetic patients is warranted. In addition, the significant effect of C. sativa treatment on adipose tissue in experimental rats needs further investigation to determine how the cannabinoids affect the mechanisms of adipogenesis and lipolysis in diet-induced obesity. Keywords: Diet-Induced Obesity, Cannabinoids, C. sativa, THC, β-cell, AM251, AM630.

INTRODUÇÃO: A obesidade é uma doença crônica e de etiologia multifatorial, relacionada a fatores genéticos, ambientais e comportamentais. Apresenta associação com diversas alterações metabólicas já na infância, levando ao aumento do risco de doenças cardiovasculares na vida adulta. O tratamento envolve mudança de estilo de vida, com orientação de dieta balanceada e estímulo à atividade física. O tratamento nesta faixa etária tem apresentado dados limitados, além de altas taxas de abandono. Um tipo original de orientação alimentar é através da contagem de equivalentes calóricos, onde as calorias são convertidas em pontos. O objetivo deste estudo foi avaliar a variação do escore Z do índice de massa corpórea (ZIMC) de adolescentes obesos submetidos à orientação de dois grupos de dieta hipocalórica: tradicional e baseada no sistema de pontos, assim como avaliar variáveis antropométricas, composição corporal, alterações metabólicas, ingestão alimentar e o automonitoramento. MÉTODOS: Estudo clínico randomizado com duração de 24 semanas, com 66 adolescentes com idade média de 13,7 ± 0,7 anos de ambos os gêneros, com escore do IMC >= 2 a <= 4 da curva ajustada para gênero e idade da Organização Mundial da Saúde. Foram verificados peso, estatura, pressão arterial e circunferência abdominal, intensidade de atividade física e automonitoramento, assim como efetuada a orientação nutricional a cada visita. Parâmetros laboratoriais, aplicação da escala de compulsão alimentar periódica, composição corporal e estadiamento puberal, foram avaliados no início e final do seguimento. Os pacientes foram divididos em dois grupos: um que recebeu orientação de dieta hipocalórica tradicional e preenchia o registro de consumo alimentar (RCA) de três dias (Grupo A) e outro que recebeu orientação de dieta hipocalórica baseada no sistema dos pontos e preenchia o RCA diário (Grupo B). RESULTADOS: Quarenta e quatro pacientes concluíram o tratamento. Houve redução do ZIMC nos dois grupos (p < 0,0001), porém a redução observada no Grupo A não foi diferente da observada no Grupo B (p=0,87). Ocorreu aumento da massa livre de gordura (%), redução da circunferência abdominal, pressão arterial sistólica e diastólica, além da massa gorda (%). Houve diferença no escore de compulsão alimentar entre as visitas 1 e 8, o qual se manteve durante o estudo. Verificamos melhora de todos os parâmetros laboratoriais, com diminuição significativa de insulina, HOMA-IR, gama-GT e ALT, não havendo diferença entre os dois grupos. Houve redução do valor energético total nos dois grupos, acompanhada do aumento percentual de proteínas, redução de carboidratos e manutenção dos lipídios. O automonitoramento médio não foi relacionado à variação do ZIMC. CONCLUSÃO: Dieta hipocalórica com orientação tradicional ou baseada no sistema de pontos levou a redução do ZIMC, de marcadores metabólicos e do valor energético total em adolescentes obesos de forma semelhante nesta coorte de pacientes / INTRODUCTION: Obesity is a chronic illness and multifactorial etiology, related to genetic factors, environmental and behavioral. Features association with several metabolic abnormalities in childhood, leading to increased risk of cardiovascular disease in adult life. The treatment involves lifestyle change, with balanced diet guidance and encouraging physical activity. The treatment in this age group have brought limited data, in addition to high drop-out rates. A unique type of food guidance is the equivalent calorie count, where calories are converted into points. The objective of this study was to evaluate the variance of Z score of body mass index (ZIMC) of obese adolescents undergoing orientation of two groups of low-calorie diet: traditional and based on the points system, as well as evaluate anthropometric variables, body composition, food intake, metabolic changes and self-monitoring. METHODS: randomized clinical study with duration of 24 weeks, with 66 adolescents with an average age of 13.7 ± 0.7 years of both genders, with scores of BMI >= 2 to <= 4 curve adjusted for gender and age of the World Health Organization. Were verified weight, height, blood pressure and waist circumference, intensity of physical activity and self- monitoring, as well as performed the nutritional guidance to each visit. Laboratory parameters, applying the scale of binge eating, pubertal, stage and body composition were evaluated at the beginning and end of the action. The patients were divided into two groups: one that received guidance of traditional low-calorie diet and meet the food consumption record (RCA), three days (Group A) and another that received low-calorie diet guidance based on the system of points and meet the daily RCA (Group B). RESULTS: forty-four patients have completed treatment. There was a reduction of Z BMI in both groups (p 0.0001 < ), however the reduction observed in the Group was not different from that observed in Group B (p = 0.87). There was increased fat free mass (%), abdominal circumference, systolic and diastolic blood pressure and body fat (%). There was difference in binge eating score between 1 and 8 visits, which remained during the study. We improved all laboratory parameters, with significant decrease of insulin and HOMA-IR, gamma GT and ALT, and there is no difference between the two groups. There was a reduction of the total energy in both groups, accompanied by the increasing percentage of protein, carbohydrate and maintenance reduction of lipids. The average self-monitoring was not related to the variation of Z BMI. CONCLUSION: low-calorie diet with traditional or orientation based on points system led to reduction of metabolic markers, Z BMI and total energy value in obese adolescents similarly in this cohort of patients

INTRODUÇÃO: A obesidade é uma doença crônica e de etiologia multifatorial, relacionada a fatores genéticos, ambientais e comportamentais. Apresenta associação com diversas alterações metabólicas já na infância, levando ao aumento do risco de doenças cardiovasculares na vida adulta. O tratamento envolve mudança de estilo de vida, com orientação de dieta balanceada e estímulo à atividade física. O tratamento nesta faixa etária tem apresentado dados limitados, além de altas taxas de abandono. Um tipo original de orientação alimentar é através da contagem de equivalentes calóricos, onde as calorias são convertidas em pontos. O objetivo deste estudo foi avaliar a variação do escore Z do índice de massa corpórea (ZIMC) de adolescentes obesos submetidos à orientação de dois grupos de dieta hipocalórica: tradicional e baseada no sistema de pontos, assim como avaliar variáveis antropométricas, composição corporal, alterações metabólicas, ingestão alimentar e o automonitoramento. MÉTODOS: Estudo clínico randomizado com duração de 24 semanas, com 66 adolescentes com idade média de 13,7 ± 0,7 anos de ambos os gêneros, com escore do IMC >= 2 a <= 4 da curva ajustada para gênero e idade da Organização Mundial da Saúde. Foram verificados peso, estatura, pressão arterial e circunferência abdominal, intensidade de atividade física e automonitoramento, assim como efetuada a orientação nutricional a cada visita. Parâmetros laboratoriais, aplicação da escala de compulsão alimentar periódica, composição corporal e estadiamento puberal, foram avaliados no início e final do seguimento. Os pacientes foram divididos em dois grupos: um que recebeu orientação de dieta hipocalórica tradicional e preenchia o registro de consumo alimentar (RCA) de três dias (Grupo A) e outro que recebeu orientação de dieta hipocalórica baseada no sistema dos pontos e preenchia o RCA diário (Grupo B). RESULTADOS: Quarenta e quatro pacientes concluíram o tratamento. Houve redução do ZIMC nos dois grupos (p < 0,0001), porém a redução observada no Grupo A não foi diferente da observada no Grupo B (p=0,87). Ocorreu aumento da massa livre de gordura (%), redução da circunferência abdominal, pressão arterial sistólica e diastólica, além da massa gorda (%). Houve diferença no escore de compulsão alimentar entre as visitas 1 e 8, o qual se manteve durante o estudo. Verificamos melhora de todos os parâmetros laboratoriais, com diminuição significativa de insulina, HOMA-IR, gama-GT e ALT, não havendo diferença entre os dois grupos. Houve redução do valor energético total nos dois grupos, acompanhada do aumento percentual de proteínas, redução de carboidratos e manutenção dos lipídios. O automonitoramento médio não foi relacionado à variação do ZIMC. CONCLUSÃO: Dieta hipocalórica com orientação tradicional ou baseada no sistema de pontos levou a redução do ZIMC, de marcadores metabólicos e do valor energético total em adolescentes obesos de forma semelhante nesta coorte de pacientes / INTRODUCTION: Obesity is a chronic illness and multifactorial etiology, related to genetic factors, environmental and behavioral. Features association with several metabolic abnormalities in childhood, leading to increased risk of cardiovascular disease in adult life. The treatment involves lifestyle change, with balanced diet guidance and encouraging physical activity. The treatment in this age group have brought limited data, in addition to high drop-out rates. A unique type of food guidance is the equivalent calorie count, where calories are converted into points. The objective of this study was to evaluate the variance of Z score of body mass index (ZIMC) of obese adolescents undergoing orientation of two groups of low-calorie diet: traditional and based on the points system, as well as evaluate anthropometric variables, body composition, food intake, metabolic changes and self-monitoring. METHODS: randomized clinical study with duration of 24 weeks, with 66 adolescents with an average age of 13.7 ± 0.7 years of both genders, with scores of BMI >= 2 to <= 4 curve adjusted for gender and age of the World Health Organization. Were verified weight, height, blood pressure and waist circumference, intensity of physical activity and self- monitoring, as well as performed the nutritional guidance to each visit. Laboratory parameters, applying the scale of binge eating, pubertal, stage and body composition were evaluated at the beginning and end of the action. The patients were divided into two groups: one that received guidance of traditional low-calorie diet and meet the food consumption record (RCA), three days (Group A) and another that received low-calorie diet guidance based on the system of points and meet the daily RCA (Group B). RESULTS: forty-four patients have completed treatment. There was a reduction of Z BMI in both groups (p 0.0001 < ), however the reduction observed in the Group was not different from that observed in Group B (p = 0.87). There was increased fat free mass (%), abdominal circumference, systolic and diastolic blood pressure and body fat (%). There was difference in binge eating score between 1 and 8 visits, which remained during the study. We improved all laboratory parameters, with significant decrease of insulin and HOMA-IR, gamma GT and ALT, and there is no difference between the two groups. There was a reduction of the total energy in both groups, accompanied by the increasing percentage of protein, carbohydrate and maintenance reduction of lipids. The average self-monitoring was not related to the variation of Z BMI. CONCLUSION: low-calorie diet with traditional or orientation based on points system led to reduction of metabolic markers, Z BMI and total energy value in obese adolescents similarly in this cohort of patients

Trata-se de pesquisa realizada em hospital da rede pública estadual de São Paulo, especializado em cardiologia com pacientes obesos em acompanhamento ambulatorial pelo Serviço de Nutrição e Dietética (SND) dessa instituição. As formas de intervenção nutricional investigadas foram: atendimento individual, em grupo (controle) e grupo multiprofissional (com nutricionista e psicóloga). Na fase preliminar do estudo, realizou-se pesquisa de opinião que possibilitou o embasamento das variáveis analisadas. Na fase principal, os participantes foram divididos em grupos, sendo realizadas duas entrevistas individuais no intervalo de seis meses. Foram investigados apenas os pacientes de alta. Compararam-se os resultados obtidos quanto ao peso corporal, índice de massa corpórea, circunferência do abdome; o acompanhamento dos fatores de risco cardiovascular (hipertensão arterial, diabetes melito, dislipidemias) foi feito através da variação das medidas de pressão arterial e níveis sanguíneos de glicose, triglicérides, colesterol total e frações. Analisaram-se as opiniões sobre as facilidades e dificuldades para seguir as orientações recebidas por meio de instrumento próprio, não validado. No atendimento em grupo, foram obtidos resultados satisfatórios, porém não ideais, e verificou-se que os participantes passaram a valorizar o apoio familiar. No atendimento individual, os participantes conseguiram maior redução da glicemia e triglicérides, porém isso não pode ser atribuído exclusivamente à dieta. No atendimento em grupo multiprofissional, houve mudança de comportamento com valorização desse tipo de atendimento. / The study was performed in a cardiology specialty hospital of Sao Paulo state public system with obese outpatients followed up by the Sector of Nutrition and Dietetics of the institution. Nutritional intervention actions that were assessed include: individual visit, group approach (control) and multiprofessional group (including dietitian and psychologist). In the preliminary phase of the study, an opinion survey was performed, which supported many of the studied variables. In the main phase of the study, the participants were divided into groups, and 2 individual interviews were conducted within a 6-month interval. Only patients who had been discharged were assessed. The results concerning body weight, body mass index, abdominal circumference, and follow up of cardiovascular risks (arterial hypertension, diabetes mellitus, dyslipidemia) were compared using variation of blood pressure measures and blood levels of glucose, triglycerides and total and fractioned cholesterol. We also checked whether patients found it easy or difficult to follow the received instructions, using our own non-validated instrument. In the group activities, results were satisfactory but not optimal and participants started to value family support. In the individual approach, participants reached higher reduction of glucose and triglyceride levels, but they could not be explained exclusively by the diet. In the multiprofessional group, there was change in behavior and recognition of multiprofessional approach.

Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro / O cálcio tem se mostrado útil na regulação do metabolismo energético, favorecendo a perda de peso. Visto que tanto o desmame precoce como a exposição materna à nicotina na lactação são fatores condicionantes para o desenvolvimento de obesidade, hiperleptinemia e resistência à insulina, além de outras alterações endócrinas na idade adulta, decidimos avaliar os possíveis efeitos da suplementação dietética com cálcio sobre as disfunções apresentadas pelos seguintes modelos experimentais: 1) Desmame precoce (DP): ratas lactantes foram envolvidas com atadura para interromper o acesso da prole ao leite nos 3 últimos dias da lactação. As proles das ratas controles tiveram livre acesso ao leite materno durante todo o período da lactação (21 dias). 2) Exposição materna à nicotina (N): Dois dias após o nascimento, ratas lactantes receberam implantes de minibombas osmóticas contendo solução de nicotina (6 mg/kg/dia, 14 dias) ou salina (C), nas mesmas condições. Aos 120 dias de idade, as proles de ambos os modelos de obesidade experimental receberam dieta padrão ou dieta suplementada com cálcio (10g de carbonato de cálcio/kg de ração). O sacrifício ocorreu aos 180 dias de idade. Os dados foram considerados significativos quando p<0,05. Corroborando dados anteriores do nosso grupo, as proles de ambos os modelos de programação (N e DP) apresentaram maior gordura corporal total e visceral, hiperleptinemia, resistência hipotalâmica a leptina e distúrbios na homeostase glicêmica. Além disto, verificamos que as proles N e DP também exibiram aumento dos níveis séricos de 25-hidroxivitamina D3. Todos essas alterações endócrino-metabólicas foram corrigidas pelo tratamento com suplementação com cálcio. Além disso, a prole DP aos 180 dias mostrou hiperfagia e hipertrigliceridemia, que também foram normalizados pela suplementação dietética com cálcio. A prole N apresentou hipotireoidismo, maior conteúdo de catecolaminas e maior expressão de tirosina hidroxilase (TH). A terapia com cálcio reverteu a disfunção adrenal, embora não tenha sido eficaz para normalizar a hipofunção tireoideana. Assim, a suplementação dietética com cálcio normalizou a maioria dos parâmetros da síndrome metabólica observadas nos dois modelos de plasticidade ontogenética. É possível que a redução da adiposidade central induzida pela terapia com cálcio, por si, tenha sido o principal mecanismo que resultou na melhora dos parâmetros estudados. Uma vez que a suplentação de cálcio reverteu as concentrações séricas de 25-hidroxivitamina D3 dos animais obesos, é possível que o efeito anti-obesidade do cálcio também ocorra via ação do calcitriol sobre o adipócito. / Calcium influences energy metabolism regulation and causes body weight loss. Since early weaning and maternal nicotine exposure during lactation programs for obesity, hyperleptinemia, insulin resistance and others endocrine dysfunctions, we studied the possible effect of dietary calcium supplementation on endocrine dysfunctions in these two experimental model of obesity: 1) Early Weaning (EW): lactating rats were involved with a bandage to interrupt the lactation during the last 3 days of standard lactation, and C (control) - dams whose pups had free access to milk during all lactation (21 days). 2) Maternal nicotine exposure (N): Two days after birth, it was implanted on the mothers, osmotic minipumps containing nicotine solution (6 mg/Kg/day, 14 days) or saline (C) in the same condition. At 120 days-old, all offspring received dietary calcium supplementation (10g of calcium carbonate/Kg of rat chow) or standard diet. Rats were killed at 180 days-old. Significant data were p<0.05. As expected, N and DP offspring showed higher visceral and total body fat mass, hyperleptinemia, hypothalamic leptin resistance and insulin resistance. In addition they presented higher serum 25-hydroxyvitamin D3. All these disturbances were corrected after calcium supplementation. Besides, adult EW offspring displayed hyperphagia and hypertriglyceridemia that was normalized with calcium therapy. Also, N offspring presented hypothyroidism, higher tyrosine hydroxylase expression and higher adrenal catecholamine content. Despite calcium treatment have normalized adrenal dysfunction, it did not reverse the hypothyroidism. So, dietary calcium supplementation seems to revert most of the metabolic syndrome parameters observed in our two developmental plasticity models. It is conceivable that the reduction in fat mass per se, induced by calcium therapy, is the main mechanism that improves all parameters. Because serum 25-hydroxyvitamin D3 levels were corrected by calcium supplementation in obese offspring, it is possible that the anti-obesity effect of calcium occurs through calcitriol action on the adipocyte.

Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro / O cálcio tem se mostrado útil na regulação do metabolismo energético, favorecendo a perda de peso. Visto que tanto o desmame precoce como a exposição materna à nicotina na lactação são fatores condicionantes para o desenvolvimento de obesidade, hiperleptinemia e resistência à insulina, além de outras alterações endócrinas na idade adulta, decidimos avaliar os possíveis efeitos da suplementação dietética com cálcio sobre as disfunções apresentadas pelos seguintes modelos experimentais: 1) Desmame precoce (DP): ratas lactantes foram envolvidas com atadura para interromper o acesso da prole ao leite nos 3 últimos dias da lactação. As proles das ratas controles tiveram livre acesso ao leite materno durante todo o período da lactação (21 dias). 2) Exposição materna à nicotina (N): Dois dias após o nascimento, ratas lactantes receberam implantes de minibombas osmóticas contendo solução de nicotina (6 mg/kg/dia, 14 dias) ou salina (C), nas mesmas condições. Aos 120 dias de idade, as proles de ambos os modelos de obesidade experimental receberam dieta padrão ou dieta suplementada com cálcio (10g de carbonato de cálcio/kg de ração). O sacrifício ocorreu aos 180 dias de idade. Os dados foram considerados significativos quando p<0,05. Corroborando dados anteriores do nosso grupo, as proles de ambos os modelos de programação (N e DP) apresentaram maior gordura corporal total e visceral, hiperleptinemia, resistência hipotalâmica a leptina e distúrbios na homeostase glicêmica. Além disto, verificamos que as proles N e DP também exibiram aumento dos níveis séricos de 25-hidroxivitamina D3. Todos essas alterações endócrino-metabólicas foram corrigidas pelo tratamento com suplementação com cálcio. Além disso, a prole DP aos 180 dias mostrou hiperfagia e hipertrigliceridemia, que também foram normalizados pela suplementação dietética com cálcio. A prole N apresentou hipotireoidismo, maior conteúdo de catecolaminas e maior expressão de tirosina hidroxilase (TH). A terapia com cálcio reverteu a disfunção adrenal, embora não tenha sido eficaz para normalizar a hipofunção tireoideana. Assim, a suplementação dietética com cálcio normalizou a maioria dos parâmetros da síndrome metabólica observadas nos dois modelos de plasticidade ontogenética. É possível que a redução da adiposidade central induzida pela terapia com cálcio, por si, tenha sido o principal mecanismo que resultou na melhora dos parâmetros estudados. Uma vez que a suplentação de cálcio reverteu as concentrações séricas de 25-hidroxivitamina D3 dos animais obesos, é possível que o efeito anti-obesidade do cálcio também ocorra via ação do calcitriol sobre o adipócito. / Calcium influences energy metabolism regulation and causes body weight loss. Since early weaning and maternal nicotine exposure during lactation programs for obesity, hyperleptinemia, insulin resistance and others endocrine dysfunctions, we studied the possible effect of dietary calcium supplementation on endocrine dysfunctions in these two experimental model of obesity: 1) Early Weaning (EW): lactating rats were involved with a bandage to interrupt the lactation during the last 3 days of standard lactation, and C (control) - dams whose pups had free access to milk during all lactation (21 days). 2) Maternal nicotine exposure (N): Two days after birth, it was implanted on the mothers, osmotic minipumps containing nicotine solution (6 mg/Kg/day, 14 days) or saline (C) in the same condition. At 120 days-old, all offspring received dietary calcium supplementation (10g of calcium carbonate/Kg of rat chow) or standard diet. Rats were killed at 180 days-old. Significant data were p<0.05. As expected, N and DP offspring showed higher visceral and total body fat mass, hyperleptinemia, hypothalamic leptin resistance and insulin resistance. In addition they presented higher serum 25-hydroxyvitamin D3. All these disturbances were corrected after calcium supplementation. Besides, adult EW offspring displayed hyperphagia and hypertriglyceridemia that was normalized with calcium therapy. Also, N offspring presented hypothyroidism, higher tyrosine hydroxylase expression and higher adrenal catecholamine content. Despite calcium treatment have normalized adrenal dysfunction, it did not reverse the hypothyroidism. So, dietary calcium supplementation seems to revert most of the metabolic syndrome parameters observed in our two developmental plasticity models. It is conceivable that the reduction in fat mass per se, induced by calcium therapy, is the main mechanism that improves all parameters. Because serum 25-hydroxyvitamin D3 levels were corrected by calcium supplementation in obese offspring, it is possible that the anti-obesity effect of calcium occurs through calcitriol action on the adipocyte.

Trata-se de pesquisa realizada em hospital da rede pública estadual de São Paulo, especializado em cardiologia com pacientes obesos em acompanhamento ambulatorial pelo Serviço de Nutrição e Dietética (SND) dessa instituição. As formas de intervenção nutricional investigadas foram: atendimento individual, em grupo (controle) e grupo multiprofissional (com nutricionista e psicóloga). Na fase preliminar do estudo, realizou-se pesquisa de opinião que possibilitou o embasamento das variáveis analisadas. Na fase principal, os participantes foram divididos em grupos, sendo realizadas duas entrevistas individuais no intervalo de seis meses. Foram investigados apenas os pacientes de alta. Compararam-se os resultados obtidos quanto ao peso corporal, índice de massa corpórea, circunferência do abdome; o acompanhamento dos fatores de risco cardiovascular (hipertensão arterial, diabetes melito, dislipidemias) foi feito através da variação das medidas de pressão arterial e níveis sanguíneos de glicose, triglicérides, colesterol total e frações. Analisaram-se as opiniões sobre as facilidades e dificuldades para seguir as orientações recebidas por meio de instrumento próprio, não validado. No atendimento em grupo, foram obtidos resultados satisfatórios, porém não ideais, e verificou-se que os participantes passaram a valorizar o apoio familiar. No atendimento individual, os participantes conseguiram maior redução da glicemia e triglicérides, porém isso não pode ser atribuído exclusivamente à dieta. No atendimento em grupo multiprofissional, houve mudança de comportamento com valorização desse tipo de atendimento. / The study was performed in a cardiology specialty hospital of Sao Paulo state public system with obese outpatients followed up by the Sector of Nutrition and Dietetics of the institution. Nutritional intervention actions that were assessed include: individual visit, group approach (control) and multiprofessional group (including dietitian and psychologist). In the preliminary phase of the study, an opinion survey was performed, which supported many of the studied variables. In the main phase of the study, the participants were divided into groups, and 2 individual interviews were conducted within a 6-month interval. Only patients who had been discharged were assessed. The results concerning body weight, body mass index, abdominal circumference, and follow up of cardiovascular risks (arterial hypertension, diabetes mellitus, dyslipidemia) were compared using variation of blood pressure measures and blood levels of glucose, triglycerides and total and fractioned cholesterol. We also checked whether patients found it easy or difficult to follow the received instructions, using our own non-validated instrument. In the group activities, results were satisfactory but not optimal and participants started to value family support. In the individual approach, participants reached higher reduction of glucose and triglyceride levels, but they could not be explained exclusively by the diet. In the multiprofessional group, there was change in behavior and recognition of multiprofessional approach.

Chemerin is a chemoattractant adipokine that regulates adipogenesis and may induce insulin resistance. Chemerin serum concentrations are elevated in obese, insulin-resistant, and inflammatory states in vivo. Here we investigate the role of omental (OM) and subcutaneous (SC) adipose tissue chemerin and CMKLR1 messenger RNA (mRNA) expression in human obesity. In addition, we test the hypothesis that changes in chemerin serum concentrations are primarily associated with reduced body fat mass in the context of 3 weight loss intervention studies. Chemerin serum concentration was measured in 740 individuals in a cross-sectional (n = 629) study including a subgroup (n = 161) for which OM and SC chemerin mRNA expression has been analyzed as well as in 3 interventions including 12 weeks of exercise (n = 60), 6 months of calorie-restricted diet (n = 19) studies, and 12 months after bariatric surgery (n = 32). Chemerin mRNA is significantly higher expressed in adipose tissue of patients with type 2 diabetes mellitus and correlates with circulating chemerin, body mass index (BMI), percentage body fat, C-reactive protein, homeostasis model assessment of insulin resistance, and glucose infusion rate in euglycemic-hyperinsulinemic clamps. CMKLR1 mRNA expression was not significantly different between the 2 fat depots. Obesity surgery–induced weight loss causes a significant reduction on both OM and SC chemerin expression. All interventions led to significantly reduced chemerin serum concentrations. Decreased chemerin serum concentrations significantly correlate with improved glucose infusion rate and reduced C-reactive protein levels independently of changes in BMI. Insulin resistance and inflammation are BMI-independent predictors of elevated chemerin serum concentrations. Reduced chemerin expression and serum concentration may contribute to improved insulin sensitivity and subclinical inflammation beyond significant weight loss.

Chemerin is a chemoattractant adipokine that regulates adipogenesis and may induce insulin resistance. Chemerin serum concentrations are elevated in obese, insulin-resistant, and inflammatory states in vivo. Here we investigate the role of omental (OM) and subcutaneous (SC) adipose tissue chemerin and CMKLR1 messenger RNA (mRNA) expression in human obesity. In addition, we test the hypothesis that changes in chemerin serum concentrations are primarily associated with reduced body fat mass in the context of 3 weight loss intervention studies. Chemerin serum concentration was measured in 740 individuals in a cross-sectional (n = 629) study including a subgroup (n = 161) for which OM and SC chemerin mRNA expression has been analyzed as well as in 3 interventions including 12 weeks of exercise (n = 60), 6 months of calorie-restricted diet (n = 19) studies, and 12 months after bariatric surgery (n = 32). Chemerin mRNA is significantly higher expressed in adipose tissue of patients with type 2 diabetes mellitus and correlates with circulating chemerin, body mass index (BMI), percentage body fat, C-reactive protein, homeostasis model assessment of insulin resistance, and glucose infusion rate in euglycemic-hyperinsulinemic clamps. CMKLR1 mRNA expression was not significantly different between the 2 fat depots. Obesity surgery–induced weight loss causes a significant reduction on both OM and SC chemerin expression. All interventions led to significantly reduced chemerin serum concentrations. Decreased chemerin serum concentrations significantly correlate with improved glucose infusion rate and reduced C-reactive protein levels independently of changes in BMI. Insulin resistance and inflammation are BMI-independent predictors of elevated chemerin serum concentrations. Reduced chemerin expression and serum concentration may contribute to improved insulin sensitivity and subclinical inflammation beyond significant weight loss.