Obese individuals often have increased appetite despite normal plasma levels of the main orexigenic hormone ghrelin. Here we show that ghrelin degradation in the plasma is inhibited by ghrelin-reactive IgG immunoglobulins, which display increased binding affinity to ghrelin in obese patients and mice. Co-administration of ghrelin together with IgG from obese individuals, but not with IgG from anorectic or control patients, increases food intake in rats. Similarly, chronic injections of ghrelin together with IgG from ob/ob mice increase food intake, meal frequency and total lean body mass of mice. These data reveal that in both obese humans and mice, IgG with increased affinity for ghrelin enhances ghrelin’s orexigenic effect, which may contribute to increased appetite and overeating.

During an acute, systemic inflammation, the liver is triggered by blood-borne pro-inflammatory cytokines such as Tumor Necrosis Factor alpha, Interleukin-1beta and Interleukin-6. The end result is an up- or down-regulated synthesis and/or activation of liver-enriched transcription factors that in turn regulate many target genes coding for resident or secreted acute phase proteins. In this review, various classifications of these acute phase proteins are presented. Major inflammation-driven changes in the synthesis and/or activity of the hepatic transcription factors are illustrated. Some of their up- or down-regulated target genes are used as paradigms of the various transcriptional mechanisms that take place on gene promoters during an acute, systemic inflammation. Finally, further specific features of inflammation-associated gene transcription in liver from acute phase onset to resolution are provided.

chelotte. Enteral glutamine stimulates protein synthesis and decreases ubiquitin mRNA level in human gut mucosa. Am J Physiol Gastrointest Liver Physiol 285: 266-G273, 2003. First published April 17, 2003 10.1152/ ajpgi.00385.2002.-Effects of glutamine on whole body and intestinal protein synthesis and on intestinal proteolysis were assessed in humans. Two groups of healthy volunteers received in a random order enteral glutamine (0.8 mmol ⅐ kg body wt Ϫ1 ⅐ h Ϫ1 ) compared either to saline or isonitrogenous amino acids. Intravenous [ 2 H5]phenylalanine and [ 13 C]leucine were simultaneously infused. After gas chromatography-mass spectrometry analysis, whole body protein turnover was estimated from traced plasma amino acid fluxes and the fractional synthesis rate (FSR) of gut mucosal protein was calculated from protein and intracellular phenylalanine and leucine enrichments in duodenal biopsies. mRNA levels for ubiquitin, cathepsin D, and m-calpain were analyzed in biopsies by RT-PCR. Glutamine significantly increased mucosal protein FSR compared with saline. Glutamine and amino acids had similar effects on FSR. The mRNA level for ubiquitin was significantly decreased after glutamine infusion compared with saline and amino acids, whereas cathepsin D and m-calpain mRNA levels were not affected. Enteral glutamine stimulates mucosal protein synthesis and may attenuate ubiquitin-dependent proteolysis and thus improve protein balance in human gut. intestine; protein metabolism; nutrients GLUTAMINE IS THE MAJOR FUEL for enterocytes, and it promotes intestinal growth and metabolism and maintains the structure and function of intestinal mucosa, especially in situations of gut injury (38) or after gut resection in animals (37). In vitro, glutamine stimulated intestinal cell proliferation (33). Numerous studies have reported the benefits of a glutamine enteral or parenteral nutritional supplementation on gut barrier (20,42). In animal studies, glutamine supply decreased the alterations of gut mucosa induced by prolonged starvation (20) or an experimental enterocolitis (2) by increasing the weight of the mucosa, the height of villi, and DNA and protein content. In humans, glutamineenriched parenteral nutrition maintained villus height and limited the increase of gut permeability (42). Treatment of patients with glutamine, growth hormone, and diet modifications after gut resection was reported to be beneficial on water and electrolyte absorption in an early uncontrolled study (5), but this has not been confirmed by more recent controlled studies (36).Additionally, enteral infusion of a high glutamine load in volunteers altered whole body leucine fluxes in a manner indicating a reduced protein oxidation and an increased protein synthesis (16). The beneficial effects of glutamine on gut mucosa could be partly due to a stimulation of protein synthesis as shown in animal studies, in vitro (17) and in vivo (41). In previous studies, we have shown that glutamine was well absorbed in human intestine (13) and stimulated ϳ40% duoden...

One of the main secondary toxic side effects of antimitotic agents used to treat cancer patients is intestinal mucositis. This one is characterized by compromised digestive and absorptive functions, barrier integrity, and immune competence. At the same time, food intake is decreased, which may induce intestinal damages per se. The aim of the study was to characterize which alterations are specific to methotrexate, independently of the anorexic effect of the drug. Male Sprague-Dawley rats received subcutaneously saline solution as control group or 2.5 mg/kg of methotrexate during 3 days (D0-D2). Methotrexate-treated rats were compared with ad libitum and pair-fed controls. Histological examinations and specific markers of the immune and nonimmune gut barrier function were assessed at D4 or D7. Compared with ad libitum and pair-fed controls, methotrexate induced at D4 villus atrophy associated with epithelial necrosis. Mucosal protein synthesis rate and mucin contents of methotrexate treated rats were reduced. At the same time, cathepsin D proteolytic activity was increased compared with ad libitum and pair-fed controls, whereas calpain activity was increased when compared with the only pair-fed controls. These intestinal lesions were associated with various metabolic disturbances such as increased TNF-alpha level and inflammation score in the jejunum but also disturbances of amino acid concentrations in the duodenum and plasma. At D7, these alterations were partially or completely normalized. In addition to the consequences of a low food intake, methotrexate further impairs different biological processes leading to a dramatic loss of gut homeostasis. Targeted nutritional management of chemotherapy receiving patients should be set up to prevent or limit such alterations.

A role of gut-brain axis emerges in the pathophysiology of anorexia nervosa and maintaining adapted physical activity during refeeding remains discussed. We aimed to assess gastrointestinal protein metabolism and investigate the contribution of physical activity during refeeding in C57BL/6 mice with activity-based anorexia (ABA). ABA mice exhibited lower body weight and food intake with increase of lean mass/fat mass ratio and fat oxidation. Colonic permeability was increased in ABA. Ad libitum food access was then restored and ABA group was divided into two subgroups, with access to running wheel (ABA-PA) or not (ABA-NPA). After refeeding, fat free mass was completely restored only in ABA-PA. Colonic permeability was enhanced in ABA-NPA. Finally, muscle kynurenine conversion into kynurenic acid was lower in ABA-NPA who also exhibited altered behavior. Maintaining physical activity during refeeding may thus limit colonic hyperpermeability and improve behavior in anorectic mice.

Enteral leucine supplementation decreased proteasome activity in duodenal mucosa and enhanced cell proliferation through the PI3K/Akt/GSK-3α/β-catenin pathway. This trial was registered at clinicaltrials.gov as NCT01254110.

GCN2 and mTOR pathways are involved in the regulation of protein metabolism in response to amino acid availability in different tissues. However, regulation at intestinal level is poorly documented. The aim of the study was to evaluate the effects of a deprivation of essential amino acids (EAA) or glutamine (Gln) on these pathways in intestinal epithelial cells. Intestinal epithelial cell, HCT-8, were incubated during 6 h with 1/DMEM culture medium containing EAA, non EAA and Gln, 2/with saline as positive control of nutritional deprivation, 3/DMEM without EAA, 4/DMEM without Gln or 5/DMEM without Gln and supplemented with a glutamine synthase inhibitor (MSO, 4 mM). Intestinal permeability was evaluated by the measure of transepithelial electric resistance (TEER). Using [L-(2)H(3)]-leucine incorporation, fractional synthesis rate (FSR) was calculated from the assessed enrichment in proteins and free amino acid pool by GCMS. Expression of eiF2α (phosphorylated or not), used as marker of GCN2 pathway, and of 4E-BP1 (phosphorylated or not), used as a marker of mTOR pathway, was evaluated by immunoblot. Results were compared by ANOVA. Six-hours EAA deprivation did not significantly affect TEER and FSR but decreased p-4E-BP1 and increased p-eiF2α. In contrast, Gln deprivation decreased FSR and p-4E-BP1. MSO induced a marked decrease of TEER and FSR and an increase of p-eiF2α, whereas mTOR pathway remained activated. These results suggest that both mTOR and GCN2 pathways can mediate the limiting effects of Gln deprivation on protein synthesis according to its severity.

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