Carolina G. Goncalves

Effects of omega-3 fatty acids on orexigenic and anorexigenic modulators at the onset of anorexia

In cancer anorexia, a decrease in food intake (FI) occurs concomitant with changes in orexigenic peptides such as neuropeptide Y (NPY) and anorexigenic peptides such as alpha-melanocyte-stimulating hormone (alpha-MSH) and anorexigenic neurotransmitter serotonin. omega-3 Fatty acid (omega-3FA) inhibits cytokine synthesis, and delays tumor appearance, tumor growth, and onset of anorexia in tumor-bearing rats. We hypothesize that, in cancer anorexia, omega-3FA is associated with quantitative reversal of hypothalamic NPY, alpha-MSH, and serotonin receptor (5-HT(1B)-receptor) enhancing FI. Fischer rats were divided into: MCA tumor bearing fed chow (TB-Chow) or omega-3FA diet (TB-omega-3FA) and controls: non-tumor bearing fed chow (NTB-Chow) or omega-3FA diet (NTB-omega-3FA). Rats were euthanized at anorexia and brains were removed for hypothalamic immunohistochemical study, using NPY, alpha-MSH, and 5-HT(1B)-receptor-specific antibodies and slides assessed by image analysis. Immunostaining specificity was controlled by omission of primary or secondary antibodies and pre-absorption test. At anorexia, FI decreased (P < 0.05) in TB-Chow but did not change in TB-omega-3FA rats. In TB-omega-3FA vs. TB-Chow, NPY immunoreactivity increased 38% in arcuate nucleus (ARC; P < 0.05), and 50% in magnocellular paraventricular nucleus (mPVN; P < 0.05). alpha-MSH decreased 64% in ARC and 29% in mPVN (P < 0.05). 5-HT(1B)-receptor immunoreactivity decreased 13% only in supraoptic nucleus (P < 0.05). No immunoreactivity was found in the control sections. omega-3FA modified hypothalamic peptides and 5-HT-(1B)-receptor immunoreactivity at anorexia, concomitant with an increase in FI, were probably mediated by omega-3FA inhibition of tumor-induced cytokines.

Gastric bypass up-regulates insulin signaling pathway

OBJECTIVE In the severely obese, Roux-en-Y gastric bypass (RYGB) reverses diabetes before body weight loss occurs. We determined changes in protein expression of insulin receptor (IR), its substrates (IRS1 and IRS2), and their phosphorylated state (p-IR and p-IRS1/2) in skeletal muscle (SM), liver and adipose tissue (AT), and GLUT4 in SM and AT, 14 and 28 d after RYGB to gaining insight into the time-related dynamics of insulin transduction pathway that may contribute to diabetes resolution. BACKGROUND RYGB induces a rapid weight loss followed by a slower weight loss period, leading to reversal of diabetes. We hypothesize that diabetes reversal is due to RYGB-induced up-regulation of insulin signaling pathway. METHODS Diet-induced obese rats had RYGB or sham-operation (obese-controls). Daily food intake, body weight, glucose, insulin, and adiponectin were measured. IR, IRS1, IRS2, p-IR, and p-IRS1/2 were measured in SM, liver, and AT and GLUT4 in SM and AT, 14 and 28 d after RYGB, respectively, reflecting the rapid and slower weight loss periods after RYGB. RESULTS On day 14, in RYGB rats versus obese-controls, food intake, body weight, and fat mass decreased. Rats became normo-glycemic and had low insulin levels and elevated glucose:insulin ratio and decreased adiponectin concentrations. This persisted to day 28, except that adiponectin rose. No change in IR occurred on day 14, in RYGB rats versus obese-controls. By day 28 RYGB rats had a higher IR expression in SM and liver, but no changes in AT. RYGB induced a time-related increase in p-IR in liver and in pIRS1/2 in SM and liver. An increase in GLUT4 occurred by day 28 in SM and AT. CONCLUSIONS Improvement in diabetes occurred after RYGB due to up-regulation in key insulin pathway proteins at several levels, predominantly in SM and liver in association with ongoing caloric restriction, body weight, and fat mass loss.

Normalization of hypothalamic serotonin (5-HT1B) receptor and NPY in cancer anorexia after tumor resection: An immunocytochemical study

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.

Hypothalamic 5-HT1B-receptor changes in anorectic tumor bearing rats.

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 Students 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 serotonins influence on the magnocellular hypothalamic nuclei during developing of cancer anorexia, which is associated with a decrease in food intake.

Omega-3 fatty acids and anorexia

Purpose of reviewTo review the mechanisms of action of ω-3 fatty acids and their role in the brain, as well as their therapeutic implications in anorexia. Recent findingsRecent studies have demonstrated that ω-3 fatty acids modulate changes in the concentrations and actions of several orexigenic and anorexigenic neuropeptides in the brain, including neuropeptide Y, α-melanocyte stimulating hormone and the neurotransmitters serotonin and dopamine. In patients with acute and chronic inflammatory conditions, low tissue concentrations of ω-3 fatty acids and high concentrations of proinflammatory cytokines are found, in association with anorexia and decreased food intake. The data suggest that ω-3 fatty acid supplementation suppresses proinflammatory cytokine production and improves food intake by normalizing hypothalamic orexigenic peptides and neurotransmitters. SummaryBased on current data, ω-3 fatty acid supplementation has a role in the treatment of anorexia by stimulating the production and release of orexigenic neurotransmitters in food intake regulatory nuclei in the hypothalamus.

Renal glomerular and tubular injury after gastric bypass in obese rats

OBJECTIVE Roux-en-Y gastric bypass (RYGB) surgery is the most common surgical intervention for long-term weight loss in morbidly obese patients. By decreasing obesity-associated hyperfiltration, diabetes, and hypertension, RYGB is touted to stabilize, if not prevent, progression of chronic renal disease. To test this, the renal histology of diet-induced obese rats that underwent RYGB surgery was compared with that of pair-fed and sham obese controls. METHODS Sprague-Dawley rats, fed a high-fat, low-oxalate diet to induce gross obesity, were randomized to RYGB (n = 6), gastrointestinal-intact sham-operated obese controls (sham, n = 4), or gastrointestinal-intact sham-operated obese pair-fed controls (fed, n = 8). Daily body weight and food intake were recorded. On postoperative day 42, renal histology and immunohistochemistry were examined. Renal pathology was assessed by a categorical glomerular lesion score and a quantitative glomerular/tubular scoring system by experienced veterinary pathologists. Osteopontin and ED-1 (monocyte/macrophage cell) stainings were estimated by the percentage of stained area and the number of counted cells/high-power field, respectively. RESULTS Compared with sham and fed controls, RYGB rats had significant decreases in body weight (P < 0.001), more glomerular lesions (P = 0.02), and received higher glomerular and tubular lesion scores (P < 0.01). RYGB rodents had significantly stronger staining for osteopontin within the inner medullary region (P < 0.005) and ED-1 within the outer medullary region (P < 0.02) compared with sham and fed controls. CONCLUSION In this diet-induced obese rat model, RYGB is associated with chronic glomerulosclerosis and tubulointerstitial nephritis, confirmed by histology and immunohistochemistry. Prospective studies to better define the injurious mechanisms in this model are underway.

Catabolic outcome from non-gastrointestinal malignancy-related malabsorption leading to malnutrition and weight loss.

Purpose of reviewMalnutrition of cancer patients is a significant cause of mortality and morbidity. Recent findingsThe 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-α 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. SummaryThe 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.

Message to surgeons: the expected norm in elective complex GI cancer surgery is use of perioperative immunonutritional therapy that also saves hospital costs!

Acurious headline of a column in the January 2, 2007 issue of USA Today read: “Omega-3 pours into cereal, orange juice, eggs, and pet food.” It stated that ‘Omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), found in fish, some nuts, and oils were the hottest food additive in 2007, because of their health and immuno-modulating effects in reducing inflammation, and thus thought to prevent heart disease, cancer, and arthritis. So, if our dogs are getting ‘Omega-3 fatty acids’ in their food, why not give it to our upper GI cancer patients, the majority of who suffer from debilitating cancer cachexia-anorexia syndrome and are at high risk of operative complications? Thus we read with enthusiasm in this issue of Annals, the paper by Ryan et al of a well designed controlled clinical study in patients undergoing esophagectomy to examine the effects of perioperative EPA-enriched enteral nutrition therapy on the nutritional, metabolic, and immunoinflammatory response and on postoperative complications. 1 The enthusiasm emanates, in part, from the success of demonstrating EPA’s anticatabolic properties. This achievement reflects the culmination of a long and tortuous journey of nutritional support in cachectic cancer patients in an attempt to decrease their perioperative morbidity. Warren in 1932 documented that cancer cachexia was a common cause of death in patients with cancer. 2 Studley in 1936 made the crucial observation in his gastrectomized patients, that the greater the preoperative weight loss in his patients, the higher the complication and mortality rate. 3 This seminal observation clearly linked nutritional status to postoperative outcome. Patients with upper gastrointestinal (GI) tumors have among the highest incidence of malnutrition, which correlates positively with high postoperative complication rates. 4 These complications are similar to those described by Studley 70 years ago: wound dehiscence, ileus, sepsis, pneumonia, prolonged hospital stays, poor quality of life and death. In the intervening years, numerous studies examined the effects of both pre- and postoperative nutrition therapy, either parenteral or enteral, to decrease surgery related complications. Initially, these studies focused on providing supraphysiological concentrations of different substrates to induce positive nitrogen balance postoperatively. In many of these studies, the observed reversal of weight loss was due to an increase in fat mass and in total body water (TBW). Our concepts in clinical nutrition evolved to include the understanding that specific nutrients had immunologic effects, particularly when given in pharmacological amounts. Thus began the ‘trial and error era’ of immunonutrition, not only in cancer patients and high risk elective surgical patients, but also in critically ill postoperative patients. The ‘immunonutritional mixtures’ that were added to conventional substrates known to improve metabolic processes included arginine, glutamine, nucleotides, antioxidants, and omega-3 fatty acids, often in different permutations. It required meta-analysis of many studies to conclude that immunonutrition improved clinical outcomes. 5 In retrospect, it may seem curious that for almost 20 years, studies were done in which different experimental compounds were administered simultaneously in an effort to determine the nebulous postoperative beneficial metabolic effects. But such was our knowledge base and the sense of frustration and urgency of the times, underpinning the need to address the ongoing critical issues as to which ‘immune compounds’ and to what amounts were needed to reverse the processes of cancer cachexia. The importance of Ryan et al’s study is its simplicity in examining the effects of one compound, EPA, in an ‘exemplar model of complex major surgery’ that often includes patients who also require neoadjuvant combined chemo- and radiotherapy. 1 This is an ideal model for testing the stated primary end-point of exploring the anticatabolic effect of EPA by preserving lean body mass (LBM). The protocol is user friendly, and when applied to our patients, in consultation with a

Non-Gl-Malignancy-Related Malabsorption Leads to Malnutrition and Weight Loss

Approximately 80% of patients with advanced-stage cancer have cancer anorexia-cachexia syndrome (CACS), in which one of the main manifestations is malnutrition [1]. CACS is characterised by anorexia, decreased food intake, tissue wasting, and body weight loss. It is also associated with changes in lipid, protein, and carbohydrate metabolism, leading to a decrease in fat and muscle mass, which independently influence mortality in cancer patients [2] [5]. Anorexia and reduced food intake occur during growth of the tumour, thus compromising host defences which, in turn, detrimentally influences outcome [1]. Reduced food intake and malabsorption reduce energy intake, even though energy expenditure is increased [6] [8].

Omega-3 Fatty Acids, Cancer Anorexia, and Hypothalamic Gene Expression

A number of novel pathways and mediators controlling food intake, body weight, and energy expenditure have been identified using molecular and genetic techniques [1, 2]. It is now accepted that body weight is regulated by a feedback loop, in which peripheral signals from the gut, liver, and fat provide nutritional information via hormones and afferent vagal input to integrated centres in the brainstem and the hypothalamus. At these sites, monoaminergic and peptidergic neurons interact to integrate and transduce the incoming signals, thereby modulating food intake [2]. In this type of regulation, orexigenic and anorexigenic neuromediators are in a constant balance to maintain homeostasis. In several clinical diseases, ranging from inflammatory conditions such as obesity to cancer, an imbalance among these neuromediators occurs, leading, respectively, to either hyperphagia, with an increase in food intake, or to anorexia, with a decrease in food intake [3, 4].