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• The consumption of alcoholic beverages injures the liver through concurrent tissue oxidation and suppression of reduced glutathione synthesis, activity, and recycling.

We provide a practical approach to the complex management problem of chyle leaks that occur after surgical procedures or trauma, or when they occur spontaneously in association with malignancies. The volume of chyle loss causes significant problems due to loss of fluid, electrolytes, proteins, and lymphocytes, causing deleterious effects on wound healing and immunity. Enteral feeding is not always possible as long chain fatty acids are absorbed through the intestinal lacteals, the original source of chyle. Regular diets increase the leak and delay healing. Nutritional support involves coordinated care between healthcare providers to provide a combination of various modalities, including nil by mouth, parenteral nutrition, enteral feeding with formula modifications, and oral diet.

The postulated mechanisms by which the food in our diet might influence the development of cancer involve two distinct sequences: first, the process of carcinogenic initiation — conversion of a normal cell to a neoplastic cell, followed by promotion and progression. The induction of a cancer by a dietary constituent is a multistep process occurring over a period of months to years. Most of these substances are not carcinogenic until metabolically activated via a tissue-mediated chemical alteration. Hypotheses linking the presence or absence of an immune response with the occurrence of cancer have existed for decades. A distinction should be made between immunosurveillance against developing malignancy and immune response to existing tumors. Immune function is adversely affected in both animals and humans by protein-energy malnutrition. The presence of protein-energy malnutrition (PEM) in humans influences both cellular and humoral immune function.

En agosto de 1976, un joven llamado LeRoy cayó desde una cornisa fracturándose el fémur. Se sospechó una hemorragia interna importante. Durante una laparotomía se comprobó que todos los órganos internos estaban intactos y los cirujanos ortopédicos arreglaron la fractura. Treintadías después, LeRoy murió. Había comido poco; diariamente, tan solo había recibido tres litros de la glucosa, el equivalente a 510 calorías, por vía intravenosa. La glucosa fue insuficiente para satisfacer sus necesidades nutricionales, perdiendo más del 20% de su peso corporaldurante su estancia en el hospital. La causa de la muerte se debió a "desnutrición médicamente inducida". Mientras tanto, un artículo científico documentó que la prevalencia de desnutrición en los hospitales de Boston era del 44% y que la desnutrición en sí era un predictor de altas tasas de complicaciones y muerte.Como resultado, los médicos sensibilizados formaron una sociedad que creó programas de formación y alentó la formación de equipos de nutrición en los hospitales. La industria comercializó fórmulas de nutrición y catéteres. Las complicaciones en enfermos hospitalizados cayeron en picado, mientras que las tasas de supervivencia aumentaron. California aprobó una legislación para regular el soporte nutricional. Aunque la industria de la atención sanitaria reconoce la importancia de la nutrición en los cuidados al paciente, el Congreso no proporcionó apoyo fiscal para los equipos de nutrición. Como resultado, los hospitales disolvieron sus equipos de nutrición de reciente creación. La educación y las habilidades en nutrición disminuyeron, y las complicaciones hospitalarias y las tasas de mortalidad aumentaron de nuevo.

Aim: To determine if central serotonin (5-HT)-induced satiety is altered in obesity. Methods: Obese and lean Zucker rats received infusion of 5-HT (5 μg/0.5 μl/h) or saline into the ventromedial nucleus of the hypothalamus (VMN) for 2 weeks. Results: In lean rats, 5-HT decreased body weight (7%) and total food intake (15%) which was due to a decreased meal size during the dark phase. In obese rats, a decrease of food intake was also observed in the dark phase, but it was compensated by an increased food intake during the light phase, resulting in no significant changes of total food intake and body weight. In obese rats, meal number but not meal size was affected by 5-HT delivery. Body fat content was not affected by 5-HT in obese rats, while cessation of 5-HT delivery in lean rats resulted in 13% increase. Conclusion: Intra-VMN 5-HT in obese rats did not increase meal-associated satiety as it did in lean rats, but modulated hunger. These results show that the Zucker obese phenotype is characterized by VMN resistance to 5-HT, which may contribute to neurobiological mechanisms of increased meal size and food intake and may diminish anti-obesity effects of serotonergic anorexiants.

PURPOSE OF REVIEW: This review presents some difficulties encountered to develop and translate immunonutrition into clinical practice, and suggests moving forward to a pharmaconutrition approach. RECENT FINDINGS: Immunonutrition suffers from inconclusive and contradictory data due to the design of many of experiments and clinical studies conducted so far. The concept of a single immunonutrient formula applicable to various types of patients has also contributed to leave the medical world in a state of uncertainty. We propose to move forward to the concept of pharmaconutrition where a disease-dedicated nutrition therapy is developed following a rigorous step-by-step procedure. Nutrients are selected according to their pharmacological properties and after an in-depth evaluation of their biological interactions when mixed together. The optimum administration schedule (i.e. dose, route, timing and duration) of the new formulae is then determined in well conducted projective clinical trials where it is administered apart from the standard nutrition to ensure full delivery of the expected doses. SUMMARY: This review suggests moving forward to a pharmaconutrition approach where a rigorous step-by-step procedure would allow overcoming of the difficulties encountered to translate immunonutrition into clinical practice.

Cancer anorexia frequently characterizes the clinical journey of patients with cancer and affects patients' morbidity, mortality, and quality of life. A constellation of symptoms concur to the diagnosis of anorexia, and early satiety, changes in taste/smell, and nausea are the more frequently reported. The pathogenesis of cancer anorexia is multifactorial, but accumulating evidence indicates that the hypothalamic melanocortin and neuropeptide Y systems become resistant to peripheral inputs. This results in increased melanocortin activity and reduced neuropeptide Y function, thereby leading to the promotion of catabolic stimuli (i.e., reduced energy intake, increased energy expenditure, possibly increased muscle proteolysis, and adipose tissue loss). Interestingly, hypothalamic proinflammatory cytokines and serotonin, among other factors, are key in triggering hypothalamic resistance. In the clinical setting, cancer anorexia develops with heterogeneous presenting symptoms (i.e., early satiety and/or nausea and/or changes of taste) and varying degrees of severity. Available evidence suggests that the constellation of symptoms characterizing this syndrome should be considered, at least in part, as different phenotypes of common neurochemical/metabolic alterations in the presence of a chronic inflammatory state.

Objective Roux-en-Y gastric bypass (RYGB) produces rapid and dramatic weight loss in very heavy obese patients. Up to 20% cannot sustain their weight loss beyond 2 to 3 y after surgery. Methods To identify putative etiologic factors producing post-RYGB weight regain, a literature survey of metabolic changes in very obese and a review of our diet-induced obese RYGB rat model data was done. Results Weight regain suggests an imbalance in physiologic mechanisms regulating appetite and metabolic rate. Weight regain occurred in 25% of our rats, produced by return to presurgical energy intake levels. The 75% of rats that sustained weight loss secreted a significantly larger amount of peptide YY (PYY) while suppressing leptin secretion; those that failed were unable to develop or sustain a sufficiently large plasma PYY:leptin ratio. Metabolic consequences of this failure included reversal of initial postsurgical increases in peripheral fatty acid oxidation, anorexigenic activity in the hypothalamic arcuate nucleus and paraventricular nucleus, and the expression of uncoupling protein-2 in adipose tissues, and decreases in hepatic lipogenesis, free tri-iodothyronine secretion, expression of orexigenic activity in the arcuate nucleus and paraventricular nucleus, expression of adenosine monophosphate kinase in adipose tissues, skeletal muscle mitochondrial mass, and endocannabinoid content and appetite. Conclusion Weight regain after RYGB occurs in approximately 20% of patients and constitutes a serious complication. Weight regain–promoting consequences are attributed to a failure to sustain elevated plasma PYY concentrations, indicating that combining RYGB with pharmacologic stimulation of PYY secretion in patients after RYGB who exhibit inadequate PYY concentration may increase long-term success of surgical weight reduction in morbidly obese adults.

Agouti-related protein (AgRP) is an orexigenic neuropeptide produced by neurons in the hypothalamic arcuate nucleus (ARC) that is a key component of central neural circuits that control food intake and energy expenditure. Disorders in energy homeostasis, characterized by hypophagia and increased metabolic rate, frequently develop in animals with either acute or chronic diseases. Recently, studies have demonstrated that proopiomelanocortin-expressing neurons in the ARC are activated by the proinflammatory cytokine IL-1beta. In the current study, we sought to determine whether inflammatory processes regulate the expression of AgRP mRNA and to characterize the response of AgRP neurons to IL-1beta. Here, we show by real-time RT-PCR and in situ hybridization analysis that AgRP mRNA expression in rodents is increased in models of acute and chronic inflammation. AgRP neurons were found to express the type I IL-1 receptor, and the percentage of expression was significantly increased after peripheral administration of lipopolysaccharide. Furthermore, we demonstrate that IL-1beta inhibits the release of AgRP from hypothalamic explants. Collectively, these data indicate that proinflammatory signals decrease the secretion of AgRP while increasing the transcription of the AgRP gene. These observations suggest that AgRP neurons may participate with ARC proopiomelanocortin neurons in mediating the anorexic and metabolic responses to acute and chronic disease processes.

Purpose of review In the USA, approximately 3% of adults are morbidly obese, in whom behavior modification and drug therapy is ineffective in inducing major weight loss. Surgery is their only reliable option. The Roux-en-Y gastric bypass accounts for 90% of all bariatric surgeries because it achieves the best weight loss results. Many studies describe weight loss and changes in metabolic blood parameters after Roux-en-Y gastric bypass. We compare recent human data with the findings in our rats to validate the versatility of using a Roux-en-Y gastric bypass rat model to explore the multifactorial molecular and physiological dimensions of weight loss and weight regain. Recent findings Not only mechanical factors but also changes in gastrointestinal and adipose hormones and hypothalamic neuropeptides contribute to Roux-en-Y gastric bypass induced weight loss by promoting catabolic processes. Nevertheless, the exact mechanisms of weight loss remain unknown. Summary To investigate these catabolic mechanisms we used our Roux-en-Y gastric bypass rat model in diet induced obese rats. We found clear morphometric, physiological and biochemical parallelisms between humans and our rats. It is likely that Roux-en-Y gastric bypass induces similar changes in hypothalamic neuropeptides which can only be studied using the rat model. It therefore provides a useful research tool for exploring and studying the development of adjuvant antiobesity therapies.

Recent advances in the development of new therapeutic strategies combining conventional adjuvant radio/chemotherapy with nutritional manipulations with n-3 polyunsaturated fatty acids (PUFAs) are presented.Studies in cell culture and tumour-bearing animals have reported the ability of long-chain n-3 PUFAs to enhance the cytotoxicity of several anticancer drugs. In colon cancer, combination of n-3 PUFAs with 5-fluorouracil resulted in an additive growth inhibitory effect on different cell lines. Moreover, recent findings suggest that eicosapentaenoic or docosahexaenoic acid may be used to enhance tumour radiosensitivity while reducing mucosal/epidermal radiotoxicity similar to radioprotective agents. The underlying mechanism is probably mediated through lipid peroxidation because the antitumour effect of n-3 PUFAs is shared with the n-6 PUFA, arachidonic acid, and abolished by vitamin E. In vivo, the use of n-3 PUFAs may provide an additional advantage compared with n-6 PUFAs. Downregulation of eicosanoid synthesis from cyclooxygenase II may reduce angiogenesis, inflammation and metastasis induction.New insights suggest that n-3 PUFAs may play an important role not only in cancer prevention but also in cancer management. They may act synergistically with radio/chemotherapy to kill tumour cells by increasing oxidative stress while reducing angiogenesis, inflammation and metastasis induction.

Gastrointestinal (GI) hormones play an important role in GI secretion, motility, and eating behaviors. It was recently suggested that GI hormones may have a trophic role in GI tract. Here we demonstrate that two principal GI hormones, anorexigenic peptide YY (PYY) and orexigenic ghrelin, affect neural tube development. Chronic administration into the pregnant mice or transgenic overexpression of PYY led to a neural tube defect (NTD) in the embryos that was blocked by ghrelin. PYY Y1 receptor antagonist prevented the occurrence of NTD induced not only by PYY but also by vitamin A, a well-known teratogen in humans and animals. Y1 receptor deficiency also engendered NTDs, indicating the need to maintain normal Y1 receptor signaling. The present study is the first linking GI hormones to the leading cause of infant mortality and provides a novel insight for neurogenesis in which materno-fetal communication through GI hormones appears to be important.

There are no indications to prescribed special diets for postoperative patients. Low-sodium and low-fat or low-cholesterol diets are examples of restricted diets, especially in patients with heart disease and atherosclerosis. These restricted diets are unpalatable. Postoperative nausea, paralytic ileus, and vomiting caused by residual anesthetic effects and opioids used for pain control further contribute to the problem. Long-term adherence to these diets is necessary to derive benefits. Prescribing regular and palatable diets in the immediate postoperative period to meet protein and energy goals is important for wound healing and is commensurate with best clinical practices. In the following, we review the pertinent literature and offer clinical evidence that routine special diet orders for postoperative patients are not necessary.

Obesity is a significant quality of life-impairing health problem affecting industrialized nations. However, despite carrying a large fat mass, some very obese individuals exhibit normal metabolic profiles (metabolically healthy obesity). The physiological factors underlying their protective and favorable metabolic profiles remain poorly defined.A search of the National Library of Medicine PubMed database was performed using the following keywords: Metabolically healthy obese, metabolically normal obese, insulin resistance, metabolically unhealthy normal weight, and uncomplicated obesity.This article reviewed factors associated with severe obesity that lacks complications, and suggests putative activities by which these obese individuals avoid developing the clinical features of metabolic syndrome, or the metabolic complications associated with severe obesity.Despite the knowledge that visceral fat deposition is the seminal factor that ultimately causes insulin resistance (IR) and the detrimental inflammatory and hormonal profile that contributes to increase risk for cardiovascular disease, it remains unknown whether metabolically healthy obesity (MHO) has genetic predisposing factors, and whether MHO ultimately succumbs to IR and the metabolic syndrome, indicating a need for prophylatic bariatric surgery.

European ethical and legal positions with regard to EN vary slightly from country to country but are based on a common tradition derived from Graeco Roman ideas, religious thought and events of the 20th century. The Hippocratic tradition is based on 'beneficience' (do good) and 'non-maleficience' (do no harm). Religious thinking is based upon the presumption of providing food and drink by whatever means unless burden outweighs benefit. The concept of 'autonomy' (the patients right to decide) arose following in the decades after the Second World War and is enshrined in Human Rights law. The competent patient has the right to participate in decision making and to refuse treatment although the doctor is not obliged to give treatment which he or she considers futile or against the patient's interests. The incompetent patient is protected by law. The fourth principle is that of 'justice' i.e. equal access to healthcare for all. The law regards withholding and withdrawing treatment as the same. It also defines the provision of food and drink by mouth as basic care and feeding by artificial means as a medical treatment. It requires doctors to act in the best interests of the patient.

Tumor growth leads to anorexia and decreased food intake, the regulation of which is via the integrated hypothalamic peptidergic and monoaminergic system. Serotonin (5-HT), an anorectic monoamine acts primarily via 5-HT 1B -receptors in hypothalamic nuclei while neuropeptide Y (NPY) acts an orexigenic peptide. We previously reported that 5-HT 1B -receptors are up regulated while NPY is down regulated in tumor-bearing (TB)-related anorexia, contributing to food intake reduction. In anorectic TB rats we hypothesize that after tumor resection when food intake has reverted to normal, normalization of 5-HT 1B -receptor and NPY will occur. The aim of this study was to demonstrate normalization of these hypothalamic changes compared to Controls. In anorectic tumor-bearing rats after tumor resection (TB-R) and in sham-operated (Control) rats, distribution of 5-HT 1B -receptors and NPY in hypothalamic nuclei was analyzed using peroxidase antiperoxidase immunocytochemical methods. Image analysis of immunostaining was performed and the data were statistically analyzed. Immunostaining specificity was controlled by omission of primary or secondary antibodies and pre-absorption test. Our results show that after TB-R versus Controls a normalization of food intake, 5-H- 1B -receptor and NPY expression in the hypothalamus occurs. These data, discussed in context with our previous studies, support the hypothesis that tumor resection results not only in normalization of food intake but also in reversible changes of anorectic and orexigenic hypothalamic modulators.

Purpose of review Malnutrition of cancer patients is a significant cause of mortality and morbidity. Recent findings The contributory factors in cancers anatomically involving the gastrointestinal tract are self-evident. However, how non-gastrointestinal malignancies affect gastrointestinal structure and function is not clear. The aim of this paper is to review the relationship between non-gastrointestinal malignancies and malabsorption, which leads to malnutrition, weight loss and increased mortality. In non-gastrointestinal cancer patients, intestinal morphological atrophy occurs, whereas in the jejunum absorption is impaired. Cytokines including IL-1 and TNF-alpha primarily induce delayed gastric emptying and also act directly on intestinal mucosa to induce malabsorption. These cytokines also directly act on several gastrointestinal hormones including cholecystokinin, neuropeptides including corticotropin-releasing factor, and via the vagus to decrease gastrointestinal motility. Summary The combination of small intestine atrophy and delayed gastrointestinal motility are some of the reasons for malabsorption in cancer patients with non-gastrointestinal malignancies that contribute to the catabolic process.

Serotonin (5-HT) is an anorectic monoamine and its regulatory effects on feeding are mediated primarily via 5-HT1B-receptors localized in the hypothalamic nuclei, which, apart from the brain stem, are among the most crucial areas of food intake regulation. The distribution of 5-HT1B-receptors in the hypothalamic nuclei was studied in tumor-bearing (TB) rats at the onset of anorexia and in sham-operated control rats, using the peroxidase-anti-peroxidase immunocytochemical method and specific polyclonal antiserum. Semiquantitative image analysis of 5-HT1B-receptor immunostaining was performed on high-resolution digital photomicrographs using the NIH Scion Image analysis program and the data were compared using Student's t-test. Immunostaining detected 5-HT1B-receptor proteins in the same hypothalamic structures in the Controls as in the TB rats. Qualitative and semiquantitative analysis revealed a significant increase in 5-HT1B-receptor expression in the magnocellular neurons of paraventricular and supraoptic hypothalamic nuclei in TB rats versus Controls. In contrast, changes were not significant in the parvocellular portion of paraventricular nucleus or in the lateral hypothalamus including perifornical region. These findings emphasize serotonin's influence on the magnocellular hypothalamic nuclei during developing of cancer anorexia, which is associated with a decrease in food intake.

Tumor growth is associated with profound metabolic and neurochemical alterations, which can lead to the onset of anorexia-cachexia syndrome. Anorexia is defined as the loss of the desire to eat, while cachexia results from progressive wasting of skeletal muscle mass--and to a lesser extent adipose tissue--occurring even before weight loss becomes apparent. Cancer anorexia-cachexia syndrome is highly prevalent among cancer patients, has a large impact on morbidity and mortality, and impinges on patient quality of life. However, its clinical relevance is frequently overlooked, and treatments are usually only attempted during advanced stages of the disease. The pathogenic mechanisms of cachexia and anorexia are multifactorial, but cytokines and tumor-derived factors have a significant role, thereby representing a suitable therapeutic target. Energy expenditure in anorexia is frequently increased while energy intake is decreased, which further exacerbates the progressive deterioration of nutritional status. The optimal therapeutic approach to anorectic-cachectic cancer patients should be based on both changes in dietary habits, achieved via nutritional counseling; and drug therapy, aimed at interfering with cytokine expression or activity. Our improved understanding of the influence a tumor has on the host's metabolism is advancing new therapeutic approaches, which are likely to result in better preservation of nutritional status if started concurrently with specific antineoplastic treatment.

Obesity is increasing in severity and prevalence in the United States and represents a major public health issue. No effective pharmacologic treatment leading to sustained weight loss currently exists. The growing interest in the regulation of food intake stems from the current drug treatments for obesity, almost all of which interfere with the monoamine system. Our knowledge of potential interactions between the orexigenic and anorexigenic pathways is limited and fragmented, making the development of targeted drug therapy for obesity difficult. The present review of the interaction of neuropeptides and monoamines emphasizes the complexity of the central mechanisms that regulate feeding behavior. Two main systems are implicated in food intake regulation: neuropeptide Y (NPY) and pro-opiomelanocortin. alpha-Melanocyte-stimulating hormone is a tridecapeptide cleaved from pro-opiomelanocortin that acts to inhibit food intake. The predominant NPY orexigenic receptors are NPY-Y1 and NPY-Y5, and the two anorexigenic melanocortin receptors involved in hypothalamic food intake control are MC3-R and MC4-R. Both neuropeptides interact with monoamines in the hypothalamus to control physiologic states such as hunger, satiation, and satiety. Serotonin suppresses food intake and body weight, acting mainly through the serotonin 1B receptor. Dopamine regulates hunger and satiety by acting in specific hypothalamic areas, through the D1 and D2 receptors. Noradrenaline activation of alpha1- and beta2-adrenoceptors decreases food intake, and stimulation of the alpha2-adrenoceptor increases food intake. A better understanding of the detailed mechanisms underlying the pathogenesis of hyperphagia and hypophagia is needed to develop new therapeutic approaches to obesity.

Effects of Roux-en-Y gastric bypass (RYGB) on hypothalamic food intake regulation have not been investigated. The hypothalamic arcuate nucleus (ARC) and the magnocellular (m) and parvocellular (p) parts of the paraventricular nucleus (PVN) regulate hunger and satiety, and are under control of the orexigenic neuropeptide Y (NPY), and the anorexigenic alpha-melanocyte stimulating hormone (alpha-MSH) and serotonin (5-HT). We hypothesized that after RYGB, weight loss is associated with hypothalamic down regulation of NPY and up regulation of 5-HT and alpha-MSH.Obesity was induced in 12 Sprague Dawley rats using a high-energy diet for 7 weeks, and then the rats were divided into three groups (n = 4/group): RYGB, sham-operated pair-fed (PF), and sham-operated ad libitum (obese control). Ten days after operation, immunohistochemical quantification of NPY, alpha-MSH, and 5-HT(1B)-receptors in ARC and PVN was performed. Data were analyzed using ANOVA and Tukey's test.Body weight decreased in RYGB (417 +/- 21 g; mean +/- SE) and in PF (436 +/- 14 g) rats 10 days after operation compared with obese control rats (484 +/- 15 g; p0.05 for each comparison). NPY in ARC, pPVN, and mPVN decreased by 43%, 43%, and 61%, respectively in RYGB and by 55%, 42%, and 71% in PF, respectively, compared with obese controls (p0.05 for each pairwise comparison). RYGB versus PF did not show differences. alpha-MSH in ARC, pPVN and mPVN increased by 35%, 175%, and 67%, respectively in RYGB and by 29%, 162%, and 116% in PF, respectively, compared with obese controls (each p0.05). In mPVN, alpha-MSH significantly decreased by 23% in RYGB versus PF (p0.05). 5-HT-(1B)-receptor in pPVN increased by 58% in RYGB and by 26% in PF, compared with obese controls (p0.05). Compared with obese controls, 5HT-(1B)-receptor in mPVN increased by 39% in RYGB (p0.05) and by 9% in PF (p0.05). An increase of 5-HT-(1B)-receptor in pPVN and mPVN occurred in RYGB versus PF (p0.05).Obese rats that undergo weight loss after RYGB demonstrate changes in hypothalamic down regulation of NPY and up regulation of alpha-MSH and serotonin.

Nicotine increases satiety and reduces food intake (FI). We hypothesize that nicotine influences FI via alteration of serotonin (5HT) and dopamine (DA) concentration in ventromedial nucleus (VMN) and lateral hypothalamic area (LHA). Microdialysis cannulas were implanted into ipsilateral VMN and contralateral LHA. Nicotine or vehicle was infused for 60 min into VMN of overnight food-deprived rats, followed by ad lib food for 40 min. Hypothalamic changes in 5HT and DA concentrations were measured every 20 min. Intra-VMN nicotine induced a long-lasting increase in 5HT concentration and an increase in DA for a short duration in the VMN, associated with an increase in 5HT in the LHA. Our data suggest that the nicotine-induced hypophagia correlates with VMN and LHA monoaminergic changes.

Obesity affects 30% of the United States population and its detrimental effects are obesity-related metabolic diseases. For patients refractory to conventional weight loss therapy, gastric bypass surgery is one of the proven methods for inducing a sustained weight loss and reversing the metabolic sequelae of obesity. To understand the mechanisms of weight loss and the amelioration of related metabolic comorbid conditions, a reproducible animal model is needed. We report our developmental experience with rat models of sequential Roux-en-Y gastric bypass after reproducing the diet-induced obesity that characterizes the hallmarks of human obesity. Four experiments were performed to induce weight reduction through successive modifications: In Experiment 1 a 20% stapled gastric pouch with a 16 cm biliary-pancreatic limb and a 10 cm alimentary limb accomplished sufficient weight loss within 10 days to ameliorate metabolic changes associated with obesity, but the occurrence of gastrogastric fistulas prevented sustained weight loss; in Experiment 2 the model was improved by dividing the stomach to avoid gastrogastric fistula, but again sustained weight loss was not achieved; in Experiment 3 the biliary-pancreatic limb was lengthened from 16 to 30 cm, reducing the common channel to approximately 18 cm. Sustained weight loss was achieved for 28 days. In Experiment 4 the model in Experiment 3 was modified by dividing the stomach between two rows of staples. Sustained weight loss was observed for 67 days. We developed a reproducible rat model of Roux-en-Y gastric bypass. The existence of this model opens a new field of research in which to study the metabolic sequelae of obesity and the mechanisms of weight loss.

Background The hypothalamus is involved in regulation of food intake (FI) and fat deposition. Molecular mechanisms of weight loss after Roux-en-Y gastric bypass (RYGB) were studied by correlating changes in gene expression profiles in hypothalamic arcuate nucleus (ARC) and subcutaneous abdominal fat (SAF). Method Diet-induced obese rats were divided into RYGB, sham-operated (SO-Obese), and sham-operated pair-fed (PF) groups. A non-obese group on a regular chow diet served as control. Body weight (BW) and FI were measured. Rats were killed 10 days after the operation. Plasma was analyzed for biochemical indices, ARC and SAF were analyzed for gene expression profiles. Body SAF was also weighed. Data were analyzed by ANOVA and factor analysis. Results BW and FI decreased in RYGB versus SO-Obese, as reflected by decreased SAF (53%). Genes similarly expressed in ARC and SAF after RYGB were limited to several genes that predominantly related to metabolic pathways of carbohydrate, fat, neuropeptide, and cytokines. These expression profiles were similar to those seen in chow control and to those seen in a comparison of PF and SO-Obese. Conclusions RYGB-induced weight loss is associated with changes in gene profile expressions that could influence metabolic changes, contributing to weight loss.

Cancer anorexia-cachexia syndrome is observed in 80% of patients in the advanced stages of cancer and is a strong independent risk factor for mortality. Numerous cytokines produced by tumor and immune cells, interacting with the neuropeptidergic system, mediate the cachectic effect of cancer. Since there is currently no effective pharmacological treatment and the anorexia-cachexia syndrome continues to be defined biochemically, we review the role of cytokines and neuropeptides in this process.Currently data suggest that cancer anorexia-cachexia syndrome results from a multifactorial process involving many mediators, including hormones (e.g. leptin), neuropeptides (e.g. neuropeptide Y, melanocortin, melanin-concentrating hormone and orexin) and cytokines (e.g. interleukin 1, interleukin 6, tumor necrosis factor alpha and interferon gamma). It is likely that close interrelation among these mediators exists in the hypothalamus, decreasing food intake and leading to cachexia.In the pathogenesis of cancer anorexia, cytokines play a pivotal role influencing the imbalance of orexigenic and anorexigenic circuits that regulate the homeostatic loop of body-weight regulation, leading to cachexia. Interfering pharmacologically with cytokine expression or neural transduction of cytokine signals can be an effective therapeutic strategy in anorectic patients before they develop cancer anorexia-cachexia syndrome.

Paraventricular (PVN) concentrations of neuropeptide Y (NPY), serotonin (5-HT) and dopamine (DA) in anorectic tumor-bearing (TB) rats were measured before and after tumor resection. At onset of anorexia in TB versus non-tumor bearing (NTB) Controls 5-HT increased from 12.19+/-0.49 pg/microg to 14.89+/-0.81 pg/microg ( P0.05 ) while DA and NPY decreased from 7.34+/-0.42 pg/microg to 4.97+/-0.56 pg/microg and 23.47+/-4.27 pg/microg to 13.64+/-1.44 pg/microg, respectively ( P0.05 ). After tumor resection, these neuromediators normalized when compared to sham-operated NTB rats. NTB pair-fed Controls were also studied. We conclude that the increased 5-HT and the decreased DA and NPY concentrations in PVN are associated with cancer anorexia and that the NPY food stimulatory effect is linked to serotoninergic and dopaminergic systems in hypothalamus.

Background. Most obese individuals have elevated concentrations of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), markers of inflammation closely associated with diabetes, hypertension, and stroke. Hypothesis. Obesity is a low-grade inflammatory disease, and Roux-en-Y gastric bypass (RYGB) reduces biochemical markers of inflammation and modifies gene expression in hypothalamic food intake/energy-related nuclei and subcutaneous abdominal fat (SAF). Methods. Obesity was induced in 24 3-week-old Sprague Dawley pups fed a high-energy diet (HED). Three groups (n = 8/group) were studied: RYGB, sham-operated pair-fed, and sham-operated ad libitum HED. Controls were nonobese rats fed chow (n = 6). Rats were killed 10 days after operation, and blood was collected to measure corticosterone and SAF and mesenteric fat to measure IL-6, TNF-α, and corticosterone. Total mRNA from arcuate nucleus and SAF purified for gene expression profiling. Data were analyzed with analysis of variance, Mann-Whitney test, and t test. Results. Before operation, the body weight of the obese groups was 493 ± 7 g and control = 394 ± 12g. The 10-day postoperative weight was RYGB = 417 ± 21 g, pair-fed = 436 ± 14 g, and ad libitum HED = 484 ± 15 g. Mesenteric and SAF weight decreased in RYGB. Mesenteric/SAF ratio of IL-6, TNF-α, corticosterone, and gene profiling showed decrease of inflammation after RYGB. Conclusion. Gastric bypass reduces biochemical markers of inflammation, suggesting that obesity is an inflammatory condition. (Surgery 2003;134:329-35.)

Purpose of review Leptin, a member of the interleukin-6 superfamily of proteins, modifies the gene expression and synthetic pathway of both orexigenic (appetite-stimulating) and anorexigenic (appetite-suppressing) molecules in the hypothalamus, thereby controlling adipocyte energy stores. Lack of leptin secretion or the inability of leptin to interact with these molecules via leptin receptors, prevent leptin's effects and lead to obesity. It is not well known, however, how these feeding-regulatory molecules are affected in cachexia associated with cancer and other critical conditions in which cytokines such as interleukin-1 and interleukin-6 may have a key role. Recent findings Decreased leptin and increased leptin-like signaling by cytokines in the hypothalamus are the hallmark of obesity and cachexia, respectively. Increased orexigenic and impaired anorexigenic signaling produces hyperphagia and obesity, while the reverse applies to anorexia-cachexia in which adaptive feeding response to starvation is lacking or insufficient. Summary Imbalanced operation of orexigenic and anorexigenic circuits perturbs the homeostatic loop of body weight regulation leading to either obesity or cachexia. Modifiers of the central effects on appetite and energy metabolism could restore the balance and be effective for treating both conditions. In cachexia this may especially be true when combined with agents that target muscle and protein breakdown.

Background & Aims: Pancreatic polypeptide (PP) belongs to a family of peptides including neuropeptide Y and peptide YY. We examined the role of PP in the regulation of body weight as well as the therapeutic potential of PP. Methods: We measured food intake, gastric emptying, oxygen consumption, and gene expression of hypothalamic neuropeptides, gastric ghrelin, and adipocytokines in mice after administering PP intraperitoneally. Peptide gene expression was also examined in PP-overexpressing mice. Vagal and sympathetic nerve activities were recorded after intravenous administration in rats. Effects of repeated administrations of PP on energy balance and on glucose and lipid metabolism were examined in both ob/ob obese mice and fatty liver Shionogi (FLS)- ob/ob obese mice. Results: Peripherally administered PP induced negative energy balance by decreasing food intake and gastric emptying while increasing energy expenditure. The mechanism involved modification of expression of feeding-regulatory peptides (decrease in orexigenic neuropeptide Y, orexin, and ghrelin along with an increase in anorexigenic urocortin) and activity of the vagovagal or vagosympathetic reflex arc. PP reduced leptin in white adipose tissue and corticotropinreleasing factor gene expression. The expression of gastric ghrelin and hypothalamic orexin was decreased in PP-overexpressing mice. Repeated administrations of PP decreased body weight gain and ameliorated insulin resistance and hyperlipidemia in both ob/ob obese mice and FLS- ob/ob obese mice. Liver enzyme abnormalities in FLS- ob/ob obese mice were also ameliorated by PP. Conclusions: These observations indicate that PP may influence food intake, energy metabolism, and the expression of hypothalamic peptides and gastric ghrelin.

As revealed by previous microdialysis studies, basal and food intake-accompanied dopamine release significantly differs in the hypothalamus of obese vs. lean Zucker rats. In the present study, we determined whether dopaminergic receptors are also compromised in obesity. Dopaminergic D1and D2 receptor mRNA expression was studied in the ventromedial hypothalamus (VMH), lateral hypothalamic area (LHA), and the adenohypophysis (AH) of obese and lean Zucker rats using RT-PCR technique. In obese Zucker rats, we found an upregulation of D1 receptor mRNA in the VMH and AH and a downregulation in the LHA, whereas D2 receptor mRNA was downregulated in both the VMH and LHA, but not changed in the AH, compared with lean rats. Also, an increase of D1 receptor staining was seen in the paraventricular nucleus of obese rats by immunohistochemistry. We selected the VMH to test if the observed changes in the dopamine receptor expression of obese rats induce behavioral sensitization to dopamine as expressed by hyperphagia. The overnight food-deprived rats received a single VMH injection (10 nmol) of sulpiride (D2receptor antagonist) or saline as control, then food was provided and 1-h food intake was measured. Food intake after sulpiride vs. saline injection was greater in obese rats but was not different in lean rats. Our data suggest that downregulation of D2 receptor in the hypothalamus at least in the VMH induces behavior sensitization for having large meals. Low D2 receptor expression may be causal for an exaggerated dopamine release observed in obese rats during food ingestion and for reduced satiety feedback effect of dopamine. High level of D1 receptor expression in the VMH and low in the LHA may also contribute to the specific feeding pattern in obese rats represented by large meal size and low meal number.

Our past microdialysis studies in ventromedial hypothalamic nucleus (VMN) and lateral hypothalamic area (LHA) of changes in dopamine concentrations in response to changes in food intake [characterized as feeding pattern (changes in meal number and size)] in anorexia of cancer show abnormal presynaptic dopaminergic neurotransmission. To determine postsynaptic receptor status, studies were done in tumor-bearing (TB) and non-tumor-bearing (NTB) free-feeding control rats while continuously measuring their food intake via a rat eater meter. When TB rats developed anorexia, TB and control rats were killed, and postsynaptic D1- and D2-receptor mRNA expression in LHA and VMN were measured via RT-PCR. At anorexia, food intake decreased initially by a decrease in meal number, whereas a concurrent increase in meal size occurred for 24 h in an attempt to maintain food intake constant. Then meal size also decreased. At this time, D1- and D2-receptor mRNA expressions in LHA and VMN of TB vs. controls were significantly upregulated. Verification of D1- or D2-receptor changes to changes in meal number and size at anorexia was made by injection of intra-VMN or -LHA dopaminergic receptor antagonists. Intra-VMN D1-receptor antagonist (SCH-23390) in TB rats decreased food intake mainly via a decrease in meal size. Intra-VMN D2-receptor antagonist (sulpiride) in TB rats increased food intake via an increase in meal number and in NTB free-feeding rats by an increase in meal size. Intra-LHA D1-receptor antagonist in TB rats had no effect on food intake or feeding pattern. Intra-LHA D2-receptor antagonist in TB and in NTB free-feeding rats increased food intake via an increase in meal number. Our data provide evidence that postsynaptic dopaminergic receptor subtypes in the hypothalamus are involved in the regulation of meal size, meal number, and thus food intake in anorectic TB rats.

Nicotine reduces appetite and body weight. Because the hepato-portal area senses different types of nutrients that transmit signals via vagal afferent nerves to the hypothalamus to modify food intake and feeding pattern, we investigated the effect of nicotine on a hepato-vagal-hypothalamic pathway. Low doses of nicotine (10 ng) injected into portal vein (i.p.v.) decreased, while high doses of nicotine increased (or = 10 ng) electrophysiological activity of hepatic vagal afferents. Stimulatory effect of high dose of nicotine on vagal hepatic afferents was blocked by a prior i.p.v. injection of curare (30 microg) or hexamethonium (1 mg). Furthermore, activities of gastric vagal and adrenal sympathetic efferents were suppressed by low-dose, but stimulated by high-dose i.p.v. nicotine. These reflex effects did not occur in hepatic vagotomized rats. Results of experiments demonstrate that in addition to nicotine's anorectic effect being mediated via a direct central action, nicotine also acts peripherally via hepatic vagal afferents from sensors of nicotine in the hepato-portal region.

Background. Nicotine reduces body weight by reducing appetite. Estradiol modulates food intake. Menopause or ovariectomy (Ovx) increases food intake and body weight. Nicotine and estradiol individually influence hypothalamic dopamine (DA) and serotonin (5-HT), whose interaction influences food intake and body weight. We investigated whether lower weight gain in menopausal smokers is mediated via changes in hypothalamic DA/5-HT. Methods. Ovx or sham-operated female rats had 2 microdialysis guide cannulas simultaneously implanted in ipsilateral ventromedial nucleus of hypothalamus (VMN) and contralateral lateral hypothalamic area (LHA). Rats were divided into 4 groups and received a continuous subcutaneous infusion of nicotine or saline Ovx and sham. DA and 5-HT in LHA and VMN were measured by in vivo microdialysis. Results. Nicotine infusion decreased food intake and body weight in Ovx and sham groups. Increase in LHA-DA and VMN-5-HT in sham group occurred with nicotine, whereas an increase in VMN-DA in Ovx groups with and without nicotine and VMN-5-HT in Ovx group with nicotine was observed. Conclusions. In the presence of estradiol (ovary intact sham-operated rats), nicotine lowers food intake and body weight via increased LHA-DA and VMN-5-HT. In menopause (Ovx rats), nicotine lowers food intake and body weight only via increased VMN-DA and 5-HT. Data show that lower weight gain is mediated via changes in hypothalamic monoamines, primarily via ventromedial hypothalamus. (Surgery 2001;130:133-42.)

Previous studies suggest that the dopaminergic system in the supraoptic nucleus (SON) is involved not only in the water balance control but also in the food intake regulation. Since we reported that an injection of the D2 receptor antagonist, sulpiride, into specific hypothalamic nuclei (e.g. the LHA, or the VMN) increases food intake in anorectic tumor-bearing rats, as well as in normal rats, we hypothesized that an injection of sulpiride into the SON would also improve cancer anorexia. Sulpiride injection (4 microg/0.5 microl) into bilateral SON of anorectic tumor-bearing male rats significantly improved food intake via increases in both meal size and meal number. These data suggest that pharmacological manipulation of the hypothalamic dopaminergic system is feasible in amelioration of cancer anorexia.

Sialodacryoadenitis (SDA) is a highly contagious common viral infection in rats, akin to mumps in humans. Anorexia occurs during such viral infection. But the pattern of the decrease in food intake (a decrease in either meal size and meal number or both) during spontaneous viral infection has not been previously characterized. We observed the onset of anorexia and an abnormal feeding pattern during an opportunistic SDA viral infection in our rat colony. We thus studied seven male rats. Before the viral infection there was a positive association between food intake and meal number (P

Sex differences in many non-reproductive behaviors have been described in rodents and humans. Among the behaviors and responses that are sexually dimorphic in the rat are: activity, aggression, pain, and taste sensitivity, food intake and body weight regulation, learning and retention of certain kind of mazes, avoidance response, taste aversion, and performance on schedule reinforcement. In humans, similar sex differences are seen in verbal fluency, performance of spatial tasks, verbal memory tests, and fine motor skills. Depression and depressive diseases are more common in women while substance abuse and antisocial behavior is more common in men. Immunologically, the female sex is stronger, and there are clear gender differences in outcomes to same treatment modalities. This review examines the sexual dimorphism in non-reproductive behavior. Specifically gender differences in central mechanisms of food intake regulation including gender differences in hypothalamic monoaminergic systems influencing food intake.

In recognition of Dr. John M. Kinney’s significant and seminal contributions to the field of clinical nutrition [1], The Nestle Nutrition Institute, in conjunction with Nutrition: The International Journal of Applied and Basic Nutritional Sciences and with the Nutritional Sciences, Education and Research Fund, established three awards. The $6000 cash award is given to the first author of a paper that was accepted for publication in Nutrition on an annual basis. The topic areas are pediatric nutrition, general nutrition, and nutrition and

During sepsis, catabolism of proteins and associated changes in plasma amino acids occur. Tryptophan and tyrosine, and their derivatives serotonin (5-HT) and dopamine (DA), influence hypothalamic feeding-related areas and are associated with the onset of anorexia. We hypothesized that anorexia of sepsis is associated with changes in serotonin and dopamine in the ventromedial nucleus (VMN) of the hypothalamus. The aim of this study was to test our hypothesis by measuring intra-VMN changes of these two neurotransmitters at the onset of anorexia during sepsis. Fischer 344 male rats had an intracerebral guide cannula stereotaxically implanted into the VMN. Ten days later, in awake, overnight-food-deprived rats, a microdialysis probe was inserted through the in situ VMN cannula. Two hours thereafter, serial baseline serotonin and dopamine concentrations were measured. Then cecal ligation and puncture to induce sepsis or a control laparotomy was performed under isoflurane anesthesia. VMN microdialysis samples were serially collected every 30 min for 8 h after the surgical procedure to determine 5-HT and DA changes in response to sepsis. During the hypermetabolic response to sepsis, a strong association occurred between anorexia and a significant reduction of VMN dopamine concentration (P < 0.05; constant rate of dopamine decrease in the Study group of 0.99 pg per 2 h); no changes occurred in 5-HT in association with anorexia of sepsis. Six hours after operation, a single meal was offered for 20 min to assess the response of neurotransmitters to food ingestion. Food intake was minimal in anorectic septic rats (mean size of the after food-deprived meal in the Septic group was 0.03 ± 0.01 g, that of the Control group was 1.27 ± 0.14 g; P = 0.0001), while Control rats demonstrated anticipated changes in neurotransmitters in response to eating. We conclude that the onset of anorexia in septic rats is associated with a reduction in VMN dopamine.