Diss. (sammanfattning) Linköping : Univ., 2002. / Härtill 4 uppsatser.

No description available.

Accurate predictions of binding free energies from computer simulations are an invaluable resource for understanding biochemical processes and drug action. The primary aim of the work described in the thesis was to predict and understand ligand binding to several proteins of major pharmaceutical importance using computational methods. We report a computational strategy to quantitatively predict the effects of alanine scanning and ligand modifications based on molecular dynamics free energy simulations. A smooth stepwise scheme for free energy perturbation calculations is derived and applied to a series of thirteen alanine mutations of the human neuropeptide Y1 G-protein coupled receptor and a series of eight analogous antagonists. The robustness and accuracy of the method enables univocal interpretation of existing mutagenesis and binding data. We show how these calculations can be used to validate structural models and demonstrate their ability to discriminate against suboptimal ones. Site-directed mutagenesis, homology modelling and docking were further used to characterize agonist binding to the human neuropeptide Y2 receptor, which is important in feeding behavior and an obesity drug target.  In a separate project, homology modelling was also used for rationalization of mutagenesis data for an integron integrase involved in antibiotic resistance. Blockade of the hERG potassium channel by various drug-like compounds, potentially causing serious cardiac side effects, is a major problem in drug development. We have used a homology model of hERG to conduct molecular docking experiments with a series of channel blockers, followed by molecular dynamics simulations of the complexes and evaluation of binding free energies with the linear interaction energy method. The calculations are in good agreement with experimental binding affinities and allow for a rationalization of three-dimensional structure-activity relationships with implications for design of new compounds. Docking, scoring, molecular dynamics, and the linear interaction energy method were also used to predict binding modes and affinities for a large set of inhibitors to HIV-1 reverse transcriptase. Good agreement with experiment was found and the work provides a validation of the methodology as a powerful tool in structure-based drug design. It is also easily scalable for higher throughput of compounds.

Diabetes melito ou intolerância à glicose estão presentes em até 80% dos pacientes com adenocarcinoma de pâncreas. Portadores desta neoplasia têm resistência à insulina e alteração na secreção de insulina em resposta à glicose, o que pode levar ao aparecimento ou piora de diabetes. Para identificar genes diferencialmente expressos, que podem representar fatores diabetogênicos produzidos pelo adenocarcinoma de pâncreas, utilizou-se a comparação de microarranjos de oligonucleotídeos hibridizados com RNA complementar (cRNA) de tumores pancreáticos de pacientes com e sem diabetes melito no pré-operatório. Uma lâmina foi hibridizada com cRNA de dois pacientes portadores de diabetes melito, e outra com cRNA de dois pacientes com tolerância normal à glicose pelo teste oral. Considerando a expressão ajustada para os controles internos dos microarranjos, 293 genes estavam duas ou mais vezes mais expressos na lâmina dos portadores de diabetes melito; destes, 25 genes estavam pelo menos cinco vezes mais expressos. Duzentos e noventa e sete genes estavam pelo menos duas vezes mais expressos na lâmina dos pacientes com tolerância normal à glicose, dos quais 54 genes estavam cinco ou mais vezes mais expressos nestes indivíduos. Dos genes mais expressos nos tumores dos indivíduos portadores de diabetes melito, três deles, FAM3D, do inglês Family with Sequence Similarity number 3 member D, neuropeptídeo Y (NPY), e proteína de ligação do cálcio S100A8, foram estudados por reação em cadeia da polimerase em tempo real. A expressão do FAM3D foi 4070 (1000-37588) nas amostras de tumores de pacientes com diabetes melito, contra 109 (10-1112) nas de pacientes não-diabéticos (com intolerância à glicose ou com tolerância normal à glicose) (p<0,05). A expressão do NPY foi 0,46 (0,19-0,91) nos tumores dos portadores de diabetes, contra 0,32 (0,21- 0,58) nos tumores dos não-diabéticos (p = NS). Quanto à expressão de S100A8, foi 0,52 (0,27-0,60) nos tumores dos diabéticos, e 0,34 (0,16-1,44) nos não-diabéticos. Estudo imunohistoquímico mostrou que o FAM3D está expresso no núcleo e no citoplasma de células de tumores pancreáticos, tanto de indivíduos com diabetes melito quanto de não-diabéticos, assim como no citoplasma de células de ilhotas pancreáticas e de células ductais normais do pâncreas. Concluímos que o FAM3D é uma proteína expressa em tecido pancreático normal e tumoral, e que existe maior conteúdo do mRNA do FAM3D nos adenocarcinomas de pâncreas de portadores de diabetes melito do que nos de não-diabéticos. / Pancreatic ductal adenocarcinoma is closely related to diabetes mellitus; up to 80% of pancreas adenocarcinoma patients have diabetes or impaired glucose tolerance. Pancreas adenocarcinoma patients have both insulin resistance and altered insulin secretion in response to glucose, and impaired glucose metabolism has been reported in muscle of tumor patients, involving glycogen metabolism and post-receptor insulin signaling. But despite progress in research about this issue, precise mechanisms responsible for the interaction of pancreatic adenocarcinoma and diabetes mellitus remain unknown. The aim of this study was to identify differentially expressed genes between pancreas adenocarcinoma of patients who had and who did not have diabetes mellitus before surgery. Clinical and laboratorial data of 33 patients with pancreatic adenocarcinoma were evaluated, and tumor gene expression was analyzed by microarray method between two patients who had diabetes mellitus and two who did not have glycemic homeostasis impairment, and later used quantitative reverse transcriptase polymerase chain reaction (RT-qPCR) in twelve tumor fragments mRNA to confirm obtained data. Pancreatic adenocarcinoma patients who had diabetes mellitus had higher HOMA-IR (p < 0.05) and a trend to lower HOMA-beta indexes than non-diabetic patients. icroarray revealed 293 genes twice more expressed in the pool of diabetic patients as compared to the pool of normal glucose tolerance patients. Of these, 25 were five times more expressed in diabetic patients? pancreatic adenocarcinomas. Three genes were chosen for RT-qPCR: Family with Sequence Similarity number 3 member D (FAM3D), neuropeptide Y (NPY), and calcium-binding protein S100A8. FAM3D expression was 4070 (1000-37588) in diabetic patients tumors versus 109 (10-1112) in non-diabetic (impaired glucose and normal glucose tolerance) patients? tumors (p<0.05). NPY expression was 0.46 (0.19- 0.91) in diabetic patients and 0.32 (0.21-0.58) in non-diabetic patients? tumors (p=NS). Calcium-binding protein S100A8 expression was 0.52 (0.27-0.60) in diabetic and 0.34 (0.16-1.44) in non-diabetic patients (p=NS). Immunohistochemistry revealed that FAM3D protein was expressed in pancreatic adenocarcinoma cells in a diffuse nuclear and cytoplasmic pattern. It was also expressed in the cytoplasm of islets of Langerhans and normal pancreatic ducts cells. The present study indicates that cytokine-like FAM3D protein is expressed in normal and tumoral pancreatic tissue, and that FAM3D mRNA content is higher in pancreatic adenocarcinoma in diabetic than in non-diabetic patients.

O comportamento alimentar de uma espécie é determinado por um conjunto de características filogenéticas, ontogenéticas, e epigenéticas, e regulado por fatores internos e externos ao organismo. Os fenômenos naturais que regem a vida no nosso planeta são periódicos em sua maioria, e a oferta de alimentos não é exceção. Cada safra é seguida de uma entressafra, e este ritmo sincroniza diversos outros ritmos, exógenos e endógenos, capazes de determinar a sobrevivência de espécies. Uma das estratégias adaptativas mais primitivas e bem sucedidas na dinâmica oscilatória da natureza é o acúmulo de reservas. Nossa espécie, nos últimos 50 anos, vive uma situação de grande oferta de alimentos, período este extremamente pequeno, se visto sob a ordem de grandeza da evolução humana. Este fenômeno tem sido determinante na prevalência do depósito de energia e em decorrência, do surgimento da obesidade e suas consequentes patologias. O hipotálamo está intimamente associado à homeostase energética e ao comportamento alimentar. No núcleo arqueado hipotalâmico encontram-se populações neuronais orexigênicas e anorexigênicas, dentre as quais, as que expressam os neuroreceptores POMC, NPY e o substrato de receptor de insulina IRS2. A modificação da expressão destas proteínas tem sido associada à alterações do comportamento alimentar, bem como à impressão e programação metabólica, capazes de induzir obesidade em ratos adultos. A correlação desta circuitaria neuronal com o comportamento alimentar, porém, ainda não está suficientemente compreendida. A detecção do estado de fome-saciedade nos ratos, fundamental no estudo da neurofisiologia relacionada ao comportamento alimentar, vem sendo obtida via de regra, por meio de procedimentos complexos de observação comportamental. O presente estudo contribui para o conhecimento de padrões de alimentação determinados por condições nutricionais, e sua relação com a expressão neurofisiológica hipotalâmica dos neurônios POMC, NPY e IRS2. Utilizando o modelo de programação metabólica de Plagemann (1999) obtivemos animais com 25% de sobrepeso em relação aos animais controle, hiperfágicos, e com padrões de tamanho e ritmo circadiano de refeição, distintos. Apesar dos níveis hormonais elevados de leptina (>100%, p<0,001) e insulina (>90%, p<0,05) em relação ao grupo controle, estes animais apresentaram baixa expressão no estado de fome, e alta expressão, na saciedade, de NPY hipotalâmico, sugerindo que o POMC estaria mais comprometido, a longo prazo, com a regulação do ritmo alimentar. A hiperinsulinemia e hiperleptinemia plasmática associada à reduzida expressão de POMC e IRS2 no ARC, corroboraram esta conclusão. Demonstramos também padrões de alimentação distintos. O método de registro da alimentação, baseado no som da roída foi validado como excelente, pelos registros obtidos nos vídeos, e mostrou-se eficiente. Quando os estados de fome-saciedade foram discriminados nos grupos controle e sobrepeso, os resultados da expressão hipotalâmica dos neuroreceptores estudados se mostraram associados aos particulares padrões de alimentação. / The feeding behavior of a specie is determined by a group of phylogenetic, ontogenetic, and epigenetic features, and regulated by internal and external factors to the organism. The natural phenomena that govern life in our planet are mainly periodic, and the food stocks is not an exception. Each harvest is followed by a time between harvests, and this rhythm synchronizes other several exogenous and endogenous rhythms, capable of determining the survival of species. One of the most primitive strategies of adaptative evolution of species, and what usually happens regarding the oscillatory dynamics of nature, is the reserve accumulation. Our species, in the last 50 years, has been living a situation of great food offer, such period is extremely small if analysed under the greatness order of the human evolution. This phenomenon has been decisive in the prevalence of the energy deposit and, in consequence, determining the appearance of obesity and its consequent pathologies. The hypothalamus is intimately associated to the energy homeostasis and the feeding behavior. In the arcuate nucleous are orexigenic and anorexigenic neuronal populations, that express the neuroreceptors POMC, NPY and insulin receptor substratum IRS2. The modification of these proteins expression, has been associated to alterations of the feeding behavior, as well as to the metabolic imprinting and programming, capable to induce obesity in adult rats. The correlation of this neuronal circuits with the alimentary behavior, however, it is not yet sufficiently understood. The detection of the hunger-satiation state in the rat, crucial in the neurophysiology studies related to the alimentary behavior, has been obtained through complex procedures of behavioral observation. The present study contributed to the knowledge of certain feeding patterns for nutritional conditions, and its relationship with the neurophysiological expression of POMC, NPY and IRS2 neurons. Using the metabolic programming model of Plagemann (1999) animals with 25% of overweight in relation to the control animals were obtained, hyperphagics, and with different size patterns and meal circadian rhythm. In spite of the high hormonal levels of leptin (>100%, p < 0,001) and insulin (>90%, p < 0,05) in relation to the control groups, these animals presented low expression in the hunger state, and high expression in the satiation of hypothalamic NPY, suggesting that POMC would be more committed, in the long term, with the regulation of the feeding rhythm. The hyperinsulinemia and plasmatic hyperleptinemia associated to the reduced POMC and IRS2 expression in the ARC, corroborated this conclusion. We also demonstrated different feeding patterns. The feeding registration method, based on the gnaw sound was validated as excellent, when comparedto a gold pattern, the registrations obtained in the videos, and it were considered efficient. When the hunger-satiation states were discriminated in the control and overweight groups, the results of the hypothalamic neuroreceptors expression studied showed association to the feeding patterns.

O comportamento alimentar de uma espécie é determinado por um conjunto de características filogenéticas, ontogenéticas, e epigenéticas, e regulado por fatores internos e externos ao organismo. Os fenômenos naturais que regem a vida no nosso planeta são periódicos em sua maioria, e a oferta de alimentos não é exceção. Cada safra é seguida de uma entressafra, e este ritmo sincroniza diversos outros ritmos, exógenos e endógenos, capazes de determinar a sobrevivência de espécies. Uma das estratégias adaptativas mais primitivas e bem sucedidas na dinâmica oscilatória da natureza é o acúmulo de reservas. Nossa espécie, nos últimos 50 anos, vive uma situação de grande oferta de alimentos, período este extremamente pequeno, se visto sob a ordem de grandeza da evolução humana. Este fenômeno tem sido determinante na prevalência do depósito de energia e em decorrência, do surgimento da obesidade e suas consequentes patologias. O hipotálamo está intimamente associado à homeostase energética e ao comportamento alimentar. No núcleo arqueado hipotalâmico encontram-se populações neuronais orexigênicas e anorexigênicas, dentre as quais, as que expressam os neuroreceptores POMC, NPY e o substrato de receptor de insulina IRS2. A modificação da expressão destas proteínas tem sido associada à alterações do comportamento alimentar, bem como à impressão e programação metabólica, capazes de induzir obesidade em ratos adultos. A correlação desta circuitaria neuronal com o comportamento alimentar, porém, ainda não está suficientemente compreendida. A detecção do estado de fome-saciedade nos ratos, fundamental no estudo da neurofisiologia relacionada ao comportamento alimentar, vem sendo obtida via de regra, por meio de procedimentos complexos de observação comportamental. O presente estudo contribui para o conhecimento de padrões de alimentação determinados por condições nutricionais, e sua relação com a expressão neurofisiológica hipotalâmica dos neurônios POMC, NPY e IRS2. Utilizando o modelo de programação metabólica de Plagemann (1999) obtivemos animais com 25% de sobrepeso em relação aos animais controle, hiperfágicos, e com padrões de tamanho e ritmo circadiano de refeição, distintos. Apesar dos níveis hormonais elevados de leptina (>100%, p<0,001) e insulina (>90%, p<0,05) em relação ao grupo controle, estes animais apresentaram baixa expressão no estado de fome, e alta expressão, na saciedade, de NPY hipotalâmico, sugerindo que o POMC estaria mais comprometido, a longo prazo, com a regulação do ritmo alimentar. A hiperinsulinemia e hiperleptinemia plasmática associada à reduzida expressão de POMC e IRS2 no ARC, corroboraram esta conclusão. Demonstramos também padrões de alimentação distintos. O método de registro da alimentação, baseado no som da roída foi validado como excelente, pelos registros obtidos nos vídeos, e mostrou-se eficiente. Quando os estados de fome-saciedade foram discriminados nos grupos controle e sobrepeso, os resultados da expressão hipotalâmica dos neuroreceptores estudados se mostraram associados aos particulares padrões de alimentação. / The feeding behavior of a specie is determined by a group of phylogenetic, ontogenetic, and epigenetic features, and regulated by internal and external factors to the organism. The natural phenomena that govern life in our planet are mainly periodic, and the food stocks is not an exception. Each harvest is followed by a time between harvests, and this rhythm synchronizes other several exogenous and endogenous rhythms, capable of determining the survival of species. One of the most primitive strategies of adaptative evolution of species, and what usually happens regarding the oscillatory dynamics of nature, is the reserve accumulation. Our species, in the last 50 years, has been living a situation of great food offer, such period is extremely small if analysed under the greatness order of the human evolution. This phenomenon has been decisive in the prevalence of the energy deposit and, in consequence, determining the appearance of obesity and its consequent pathologies. The hypothalamus is intimately associated to the energy homeostasis and the feeding behavior. In the arcuate nucleous are orexigenic and anorexigenic neuronal populations, that express the neuroreceptors POMC, NPY and insulin receptor substratum IRS2. The modification of these proteins expression, has been associated to alterations of the feeding behavior, as well as to the metabolic imprinting and programming, capable to induce obesity in adult rats. The correlation of this neuronal circuits with the alimentary behavior, however, it is not yet sufficiently understood. The detection of the hunger-satiation state in the rat, crucial in the neurophysiology studies related to the alimentary behavior, has been obtained through complex procedures of behavioral observation. The present study contributed to the knowledge of certain feeding patterns for nutritional conditions, and its relationship with the neurophysiological expression of POMC, NPY and IRS2 neurons. Using the metabolic programming model of Plagemann (1999) animals with 25% of overweight in relation to the control animals were obtained, hyperphagics, and with different size patterns and meal circadian rhythm. In spite of the high hormonal levels of leptin (>100%, p < 0,001) and insulin (>90%, p < 0,05) in relation to the control groups, these animals presented low expression in the hunger state, and high expression in the satiation of hypothalamic NPY, suggesting that POMC would be more committed, in the long term, with the regulation of the feeding rhythm. The hyperinsulinemia and plasmatic hyperleptinemia associated to the reduced POMC and IRS2 expression in the ARC, corroborated this conclusion. We also demonstrated different feeding patterns. The feeding registration method, based on the gnaw sound was validated as excellent, when comparedto a gold pattern, the registrations obtained in the videos, and it were considered efficient. When the hunger-satiation states were discriminated in the control and overweight groups, the results of the hypothalamic neuroreceptors expression studied showed association to the feeding patterns.

Title: Acipimox during Short-Term Exercise Exerts A Negative Feedback of Growth Hormone on Ghrelin Secretion in Patients with Bulimia Nervosa and in Healthy Women: The Role of Lipolysis Objective: Eating disorders, such as bulimia nervosa (BN) and anorexia nervosa (AN), are characterized by abnormal eating behavior. The main features of BN are binge-eating and inappropriate compensatory methods to prevent weight gain. The appetite-modulating peptide ghrelin is secreted by the stomach and shows a strong release of growth hormone (GH). A potential GH-ghrelin feedback loop between stomach and the pituitary has been recently reported. Acipimox (Aci), an analogue of nicotinic acid, inhibits lipolysis in adipose tissue (AT) and reduces plasma glycerol and free fatty acids (FFA) levels. Exercise and Aci are stimulators of GH secretion. We suppose that a negative feedback from increased GH levels during exercise may play a role in reducing plasma ghrelin levels. We surmised that altered baseline activity and exercise-induced activation of the sympathetic nervous system (SNS) results in excessive stimulation of lipolysis associated with negative energy balance and may lead to abnormal AT metabolism in patients with BN. Disruption of the gut-brain-AT axis might be involved in the pathogenesis of BN. The...

Diabetes melito ou intolerância à glicose estão presentes em até 80% dos pacientes com adenocarcinoma de pâncreas. Portadores desta neoplasia têm resistência à insulina e alteração na secreção de insulina em resposta à glicose, o que pode levar ao aparecimento ou piora de diabetes. Para identificar genes diferencialmente expressos, que podem representar fatores diabetogênicos produzidos pelo adenocarcinoma de pâncreas, utilizou-se a comparação de microarranjos de oligonucleotídeos hibridizados com RNA complementar (cRNA) de tumores pancreáticos de pacientes com e sem diabetes melito no pré-operatório. Uma lâmina foi hibridizada com cRNA de dois pacientes portadores de diabetes melito, e outra com cRNA de dois pacientes com tolerância normal à glicose pelo teste oral. Considerando a expressão ajustada para os controles internos dos microarranjos, 293 genes estavam duas ou mais vezes mais expressos na lâmina dos portadores de diabetes melito; destes, 25 genes estavam pelo menos cinco vezes mais expressos. Duzentos e noventa e sete genes estavam pelo menos duas vezes mais expressos na lâmina dos pacientes com tolerância normal à glicose, dos quais 54 genes estavam cinco ou mais vezes mais expressos nestes indivíduos. Dos genes mais expressos nos tumores dos indivíduos portadores de diabetes melito, três deles, FAM3D, do inglês Family with Sequence Similarity number 3 member D, neuropeptídeo Y (NPY), e proteína de ligação do cálcio S100A8, foram estudados por reação em cadeia da polimerase em tempo real. A expressão do FAM3D foi 4070 (1000-37588) nas amostras de tumores de pacientes com diabetes melito, contra 109 (10-1112) nas de pacientes não-diabéticos (com intolerância à glicose ou com tolerância normal à glicose) (p<0,05). A expressão do NPY foi 0,46 (0,19-0,91) nos tumores dos portadores de diabetes, contra 0,32 (0,21- 0,58) nos tumores dos não-diabéticos (p = NS). Quanto à expressão de S100A8, foi 0,52 (0,27-0,60) nos tumores dos diabéticos, e 0,34 (0,16-1,44) nos não-diabéticos. Estudo imunohistoquímico mostrou que o FAM3D está expresso no núcleo e no citoplasma de células de tumores pancreáticos, tanto de indivíduos com diabetes melito quanto de não-diabéticos, assim como no citoplasma de células de ilhotas pancreáticas e de células ductais normais do pâncreas. Concluímos que o FAM3D é uma proteína expressa em tecido pancreático normal e tumoral, e que existe maior conteúdo do mRNA do FAM3D nos adenocarcinomas de pâncreas de portadores de diabetes melito do que nos de não-diabéticos. / Pancreatic ductal adenocarcinoma is closely related to diabetes mellitus; up to 80% of pancreas adenocarcinoma patients have diabetes or impaired glucose tolerance. Pancreas adenocarcinoma patients have both insulin resistance and altered insulin secretion in response to glucose, and impaired glucose metabolism has been reported in muscle of tumor patients, involving glycogen metabolism and post-receptor insulin signaling. But despite progress in research about this issue, precise mechanisms responsible for the interaction of pancreatic adenocarcinoma and diabetes mellitus remain unknown. The aim of this study was to identify differentially expressed genes between pancreas adenocarcinoma of patients who had and who did not have diabetes mellitus before surgery. Clinical and laboratorial data of 33 patients with pancreatic adenocarcinoma were evaluated, and tumor gene expression was analyzed by microarray method between two patients who had diabetes mellitus and two who did not have glycemic homeostasis impairment, and later used quantitative reverse transcriptase polymerase chain reaction (RT-qPCR) in twelve tumor fragments mRNA to confirm obtained data. Pancreatic adenocarcinoma patients who had diabetes mellitus had higher HOMA-IR (p < 0.05) and a trend to lower HOMA-beta indexes than non-diabetic patients. icroarray revealed 293 genes twice more expressed in the pool of diabetic patients as compared to the pool of normal glucose tolerance patients. Of these, 25 were five times more expressed in diabetic patients? pancreatic adenocarcinomas. Three genes were chosen for RT-qPCR: Family with Sequence Similarity number 3 member D (FAM3D), neuropeptide Y (NPY), and calcium-binding protein S100A8. FAM3D expression was 4070 (1000-37588) in diabetic patients tumors versus 109 (10-1112) in non-diabetic (impaired glucose and normal glucose tolerance) patients? tumors (p<0.05). NPY expression was 0.46 (0.19- 0.91) in diabetic patients and 0.32 (0.21-0.58) in non-diabetic patients? tumors (p=NS). Calcium-binding protein S100A8 expression was 0.52 (0.27-0.60) in diabetic and 0.34 (0.16-1.44) in non-diabetic patients (p=NS). Immunohistochemistry revealed that FAM3D protein was expressed in pancreatic adenocarcinoma cells in a diffuse nuclear and cytoplasmic pattern. It was also expressed in the cytoplasm of islets of Langerhans and normal pancreatic ducts cells. The present study indicates that cytokine-like FAM3D protein is expressed in normal and tumoral pancreatic tissue, and that FAM3D mRNA content is higher in pancreatic adenocarcinoma in diabetic than in non-diabetic patients.

Title: Acipimox during Short-Term Exercise Exerts A Negative Feedback of Growth Hormone on Ghrelin Secretion in Patients with Bulimia Nervosa and in Healthy Women: The Role of Lipolysis Objective: Eating disorders, such as bulimia nervosa (BN) and anorexia nervosa (AN), are characterized by abnormal eating behavior. The main features of BN are binge-eating and inappropriate compensatory methods to prevent weight gain. The appetite-modulating peptide ghrelin is secreted by the stomach and shows a strong release of growth hormone (GH). A potential GH-ghrelin feedback loop between stomach and the pituitary has been recently reported. Acipimox (Aci), an analogue of nicotinic acid, inhibits lipolysis in adipose tissue (AT) and reduces plasma glycerol and free fatty acids (FFA) levels. Exercise and Aci are stimulators of GH secretion. We suppose that a negative feedback from increased GH levels during exercise may play a role in reducing plasma ghrelin levels. We surmised that altered baseline activity and exercise-induced activation of the sympathetic nervous system (SNS) results in excessive stimulation of lipolysis associated with negative energy balance and may lead to abnormal AT metabolism in patients with BN. Disruption of the gut-brain-AT axis might be involved in the pathogenesis of BN. The...