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Introduction et but de l’etude Le microbiote intestinal vit en relation symbiotique forte avec l’hote et participe activement au controle du poids corporel par le biais de la production de proteines, peptides et metabolites [1] . La souche probiotique H. alvei HA4597® (HA4597) a ete adaptee pour produire en grande quantite la proteine « caseinolytique peptidase B » (ClpB), un mimetique du neuropeptide anorexigene α-melanocyte-stimulating hormones (α-MSH). Recemment, des etudes sur des modeles d’obesite chez le rongeur ont demontre que HA4597 reduisait la prise de poids et l’adiposite [2] , [3] . Dans cette etude clinique, l’efficacite de HA4597 sur la perte de poids de sujets en surpoids a ete evaluee versus placebo. Materiel et methodes Au total, 230 sujets en surpoids sans anomalie metabolique (103 H/127 F) ont ete inclus dans une etude prospective, randomisee en double aveugle d’une duree de 12 semaines. Apres consentement eclaire, tous les sujets ont recu des conseils dietetiques standardises pour suivre un regime hypocalorique (−20 %) et maintenir leur activite physique habituelle. Les sujets du groupe HA4597 ont recu 2 capsules/jour fournissant 1,2 × 1011 bacteries par jour et les sujets du groupe Placebo (P) 2 capsules de P. Le critere de jugement principal etait la proportion de sujets atteignant une perte de poids d’au moins 3 % a 12 semaines dans chaque groupe. Les analyses statistiques en intention de traiter ont ete realisees en utilisant les tests exact Fischer, Mann–Whitney et Wilcoxon apparie. Resultats et analyse statistique L’IMC moyen a l’inclusion etait de 27,8 ± 1, non-different entre les deux groupes et sans difference de composition corporelle. Le pourcentage de sujets repondeurs sur le critere de jugement principal etait significativement plus eleve (+33 %) dans le groupe HA4597 vs P (54,9 vs 41,4 %, p = 0,048). De plus, une augmentation de la sensation de rassasiement (p = 0,009) et une plus grande reduction du tour de hanche (p = 0,001) ont ete observees dans le groupe HA4597 vs P. La tolerance clinique et biologique etait bonne dans les deux groupes. Conclusion Un traitement de 12 semaines avec la souche probiotique H. alvei 4597® augmente significativement la perte de poids, le rassasiement et favorise la reduction du tour de hanche chez des sujets en surpoids suivant un regime hypocalorique modere. Ces resultats demontrent l’interet de l’utilisation de H. alvei HA4597® dans le cadre de la prise en charge de l’exces de poids.

International audience; Anorexia nervosa is a severe eating disorder often associated with physical hyperactivity and is more frequently observed in female sex. Activity-Based Anorexia (ABA) model combines physical activity (PA) and reduced food intake and thus allows a better understanding of the mechanisms underlying anorexia nervosa. We aimed to assess sex differences in response to ABA model in C57Bl/6 mice. Twenty four male and 16 female C57BL/6 mice were studied. ABA mice were placed in individual cages with a continuously recorded activity wheel. ABA mice had a progressive limited food access from 6 h/day (day 6) to 3 h/day (day 9) until the end of the protocol (day 17). Body weight and food intake were daily measured. We studied physical activity during 24 h, during the dark phase (D-PA) and the light phase (L-PA). We also evaluated the feeding anticipatory physical activity (A-PA), the physical activity during food intake period (FI-PA) and the post-prandial physical activity (PP-PA). We observed 16.7% of mortality in males (4 out of 24 mice) during ABA protocol while no female mice died (p = 0.09). At day 17, food intake was significantly higher in females than in males (p < 0.05) that was associated with a lower body weight loss than in females (p < 0.05). Before limited food access, no gender differences in wheel running activity were observed. From day 9, A-PA significantly increased over time in males (p < 0.05 vs females) while females exhibited higher FI-PA and PP-PA (p < 0.05 vs males). Correlations between wheel running activities and, respectively, food intake and body weight loss showed gender differences, in particularly for L-PA and A-PA. Our results suggest a greater susceptibility of male mice to develop ABA, males and females exhibit different patterns of physical activity after limitation of food access. Underlying mechanisms should be further investigated.

International audience; Stimulation of feeding is necessary for treatment of pathological conditions of chronic malnutrition due to anorexia. Ghrelin, a hunger hormone, is one of the candidate for pharmacological treatments of anorexia, but because of its instability in plasma has limited efficacy. We previously showed that plasmatic IgG protect ghrelin from degradation and that IgG from obese subjects and mice may increase ghrelin׳s orexigenic effect. In this study we tested if ghrelin alone or combined with IgG may improve feeding in chronically food-restricted mice with or without physical activity-based anorexia (ABA) induced by free access to a running wheel. Mice received a single daily intraperitoneal injection of ghrelin (1 nM) together or not with total IgG (1 nM) from obese ob/ob or lean mice before access to food during 8 days of 3 h/day feeding time. We found that both ghrelin and ghrelin combined with IgG from obese, but not lean mice, prevented ABA, however, they were not able to diminish body weight loss. Physical activity was lower during the feeding period and was increased shortly after feeding in mice receiving ghrelin together with IgG from obese mice. In food-restricted mice without ABA, ghrelin treatments did not have significant effects on food intake. Thus, this study supports pharmacological use of ghrelin or ghrelin combined with IgG from obese animals for treatment of anorexia accompanied by elevated physical activity. The utility of combining ghrelin with protective IgG should be further determined in animal models of anorexia with unrestricted access to food.

Anorexia represents a common and debilitating clinical problem in patients with several forms of cancer, in particular lung cancer, but its mechanisms are not completely understood. Recently, the caseinolytic-protease-B (ClpB) homologue protein, produced by common gut bacteria, such as Escherichia coli, was identified as an antigen-mimetic of α-melanocyte-stimulating hormone (α-MSH), an anorexigenic neuropeptide. ClpB was previously detected in human plasma and displayed satietogenic properties; however, its possible relevance to cancer anorexia has not yet been investigated.To address this question, we analyzed plasma ClpB concentrations as well as levels and affinities of anti-ClpB and α-MSH-reactive antibodies in patients with lung cancer with and without anorexia as compared with body mass index-matched healthy controls with normal appetite.We found that plasma ClpB concentrations were significantly lower in non-anorexic patients with cancer than those of the control group (P = 0.028). In contrast, patients with cancer and anorexia had lower levels of anti-ClpB immunoglobulins (Ig)M (P0.0001) and of both α-MSH IgM and IgG (P0.05) with respect to controls. Moreover, in patients with cancer and anorexia, anti-ClpB IgG showed a trend of lower affinities compared with non-anorexic patients (P = 0.05).Taken together, the results revealed a reduced humoral immune response to ClpB in patients with cancer and anorexia, which may lead to an enhanced satietogenic effect of this enterobacterial protein contributing to the mechanisms of reduced appetite.

Objectives The biological background of sex-related differences in the development of eating disorders (EDs) is unknown. Recent data showed that gut bacteria Escherichia coli induce autoantibodies against anorexigenic α-melanocyte-stimulating hormone (α-MSH) associated with psychopathology in ED. The aim of this study was to compare the effects of E. coli on feeding and autoantibodies against α-MSH and adrenocorticotropic hormone (ACTH), between female and male rats. Methods Commensal E. coli K12 were given in a culture medium daily to adult Wistar rats by intragastric gavage over a 3-wk period; control rats received culture medium only. Results Before gavage, E. coli K12 DNA was detected in feces of female but not male rats. E. coli provision was accompanied by an increase in body weight gain in females, but a decrease in body weight gain and food intake in males. Independent of E. coli treatment, plasma levels of anti-α-MSH and ACTH immunoglobulin (Ig)G were higher in female than male rats. Females responded to E. coli by increasing α-MSH IgG levels and affinity, but males by increasing α-MSH IgM levels. Affinity of IgG for ACTH was increased in both E. coli -treated females and males, although with different kinetics. IgG from females stimulated more efficiently α-MSH-induced cyclic adenosine monophosphate production by melanocortin 4 receptor-expressing cells compared with IgG from males. Discussion Sex-related response to how E. coli affects feeding and anti-melanocortin hormone antibody production may depend on the presence of these bacteria in the gut before E. coli supplementation. These data suggest that sex-related presence of certain gut bacteria may represent a risk factor for ED development.

Anorexia nervosa is a severe eating disorder often leading to malnutrition and cachexia, but its pathophysiology is still poorly defined. Chronic food restriction during anorexia nervosa may induce gut barrier dysfunction, which may contribute to disease development and its complications. Here we have characterized intestinal barrier function in mice with activity-based anorexia (ABA), an animal model of anorexia nervosa.Male C57Bl/6 ABA or limited food access (LFA) mice were placed respectively in cages with or without activity wheel. After 5 days of acclimatization, both ABA and LFA mice had progressively limited access to food from 6 h/d at day 6 to 3 h/d at day 9 and until the end of experiment at day 17. A group of pair-fed mice (PF) was also compared to ABA.On day 17, food intake was lower in ABA than LFA mice (2.0 ± 0.18 g vs. 3.0 ± 0.14 g, p 0.001) and weight loss was more pronounced in ABA and PF compared to LFA mice (23.6 ± 1.6% and 24.7 ± 0.7% vs. 16.5 ± 1.2%; p 0.05). Colonic histology showed decreased thickness of the muscularis layer in ABA compared to LFA mice (p 0.05). Colonic permeability was increased in both ABA and PF compared to LFA mice (p 0.05) but jejunal paracellular permeability was not affected. Expression of claudin-1 in the colon was lower in the ABA than the LFA group (p 0.05), whereas occludin expression remained unaffected.Increased colonic permeability and histological alterations found in ABA mice suggest that intestinal barrier dysfunction may also occur in anorexia nervosa. The role of these alterations in the pathophysiology of anorexia nervosa should be further evaluated.

Anti-α-melanocyte-stimulating hormone (α-MSH) polyclonal antibodies have been used for α-MSH neutralization in functional studies, but the results are sometime inconsistent with the antibody expected blocking properties. The present study aimed to determine if rabbit (Rb) anti-α-MSH immunoglobulins (Ig) may inhibit or enhance α-MSH signaling on melanocortin receptor type 4 (MC4R) and α-MSH-induced anorexigenic effect if presented as immune complexes with α-MSH. Polyclonal Rb anti-α-MSH IgG were commercially available and their ability to bind α-MSH has been confirmed by the immunohistochemical detection of α-MSH neurons in the rat hypothalamus. In vitro assay of the cyclic-adenosine mono-phosphate (cAMP) secreted by cells transfected with MC4R was performed to analyze effect of Rb IgG on α-MSH-induced cAMP production. We found that adding Rb IgG to α-MSH resulted in stimulation of cAMP detected at lower peptide concentrations as compared to α-MSH alone. To determine effects of Rb IgG on food intake, rats were injected into the arcuate hypothalamic nucleus with either α-MSH, Rb IgG alone or Rb IgG preincubated with α-MSH. During 2 days after injections, food intake was increased in both groups of rats receiving Rb IgG. However, during following 4 days when food was restricted to 1h/day, only the Rb IgG group displayed higher food intake. Furthermore, after the refeeding, 24h food intake was lower in rats receiving Rb IgG - α-MSH immune complexes. This group of rats was also characterized by higher number of immunopositive neurons in the arcuate nucleus expressing α-MSH and agouti-related protein but not tyrosine hydroxylase. Taken together, these results show that Rb anti-α-MSH antisera, although efficient for immunohistochemical detection of α-MSH, does not always display α-MSH blocking properties but, in contrast, may enhance α-MSH binding to MC4R and increase α-MSH anorexigenic effects when presented as immune complexes with the peptide.

Introduction et but de l’etude L’anorexie mentale est un trouble du comportement alimentaire dont la prise en charge est multimodale. Des donnees recentes suggerent que le maintien de l’activite physique au cours de la renutrition dans la prise en charge de l’anorexie mentale serait benefique et pourrait impliquer le metabolisme de la kynurenine, un metabolite du tryptophane. Nous avons etudie l’impact de l’activite physique sur le metabolisme central de la kynurenine dans un modele animal d’anorexie, le modele Activity-Based Anorexia (ABA). Materiel et methodes Des souris C57bl/6 ont ete reparties en deux groupes : temoin, avec alimentation ad libitum ; et ABA avec acces limite a l’alimentation et activite physique sur roue. Les souris ABA ont eu acces a l’alimentation progressivement limite de 6 h/j a j6 a 3 h/j a j9. Apres installation de la denutrition, les souris ABA ont retrouve un acces ad libitum a l’alimentation. Elles ont alors ete reparties en deux groupes : ABA-PA, avec activite physique et ABA-NPA, sans activite physique. Les souris ont ete placees dans des boites a doubles compartimentations (sombre et eclaire) pour etude du comportement, a la phase aigue de la denutrition et apres renutrition. Apres sacrifice, des RT-qPCR ont ete realisees au niveau de l’hypothalamus, l’hippocampe et l’amygdale pour etudier les marqueurs de neuroplasticite (GluA1, GluA2, CamKIIb, ARC) et de neuroinflammation (IBA1, CD11b), et les enzymes impliquees dans le metabolisme du tryptophane et de la kynurenine (KAT, TDO, TPH1). Un dosage de la corticosterone plasmatique par elisa a egalement ete realise. Resultats Le test comportemental retrouvait un comportement altere chez les souris ABA-NPA par rapport aux souris ABA-PA apres renutrition. La concentration plasmatique de corticosterone etait significativement plus elevee dans le groupe ABA-NPA (75,4 ± 4,5 contre 51,6 ± 6,5, p Conclusion Le maintien de l’activite physique au cours de la renutrition dans le modele ABA a des effets anxiolytiques et semble modifier le metabolisme hypothalamique du tryptophane et de la kynurenine.

Objective Subjects with restrictive anorexia nervosa (AN) display increased basal plasma levels of ghrelin that normalize after refeeding. The mechanism responsible for increased ghrelin levels in AN is unknown. We studied if changes of ghrelin reactive autoantibodies (autoAbs) could explain elevated plasma ghrelin in AN. Methods Plasma levels of autoAbs reactive with ghrelin and des-acyl ghrelin were measured by enzyme-linked immunosorbent assay in subjects with AN before and 1 mo after hospitalization (refeeding) and compared with healthy controls and with plasma levels of ghrelin peptides. Results Decreased levels of immunoglobulin (Ig) G, IgM, and IgA classes of autoAbs reacting with acyl ghrelin were found in patients with AN. Addition of des-acyl ghrelin but not of acyl ghrelin peptides at 10−8 M to plasma before enzyme-linked immunosorbent assay showed in patients with AN but not in controls high levels of IgG autoAbs reacting with des-acyl ghrelin as a result of dissociation of des-acyl ghrelin autoAbs in immune complexes. Plasma levels of acyl and des-acyl ghrelin peptides correlated negatively with des-acyl ghrelin IgG autoAbs. Body mass index, which improved after refeeding, correlated with an increase of acyl ghrelin IgM autoAbs. Conclusion These results show that in patients with AN, ghrelin IgG autoAbs exist mainly as immune complexes with des-acyl ghrelin accompanied by a decrease of a free fraction of these autoAbs binding acylated and des-acyl ghrelin. This decrease of bioavailable ghrelin autoAbs may underlie a long-term elevation of plasma ghrelin levels and the resulting phenomenon of ghrelin resistance in malnourished patients with AN.

Background Abnormal vasopressin (VP) and oxytocin (OT) signaling may contribute to the altered activity of the hypothalamo-pituitary-adrenal (HPA) axis in major depression; however, the underlying mechanisms remain uncertain. This study characterized plasma levels and affinities of OT- and VP-reactive autoantibodies (autoAbs) in relation to disease severity and plasma cortisol response to physical exercise in patients with mild and moderate depression and healthy controls. Methods Physical exercise was used to elicit plasma cortisol response in 23 male patients with depression and 20 healthy controls and plasma samples were obtained before and after the exercise. Just before the exercise, patients and controls were evaluated by the Montgomery and Asberg Depression Rating Scale (MADRS) and divided according to depression severity (14 mild and 9 moderate). Plasma levels of total and free VP- and OT-reactive IgG, IgA and IgM autoAbs were measured by ELISA and affinity of IgG and IgM autoAbs were measured by plasmon resonance technique at baseline before the exercise and analyzed with relation to the MADRS and cortisol response. Immunohistochemistry was used to evaluate autoAbs binding to the rat hypothalamus. Results Plasma levels of OT- and VP-reactive total IgG autoAbs were lower in patients with moderate depression vs. controls and patients with mild depression. Plasma levels of both OT- and VP-free IgG autoAbs were negatively correlated with MADRS scores. Affinity values of IgG and IgM autoAbs for both OT and VP displayed 100 fold variability among patients or controls but no significant group differences were found. Patients with moderate depression displayed blunted response of cortisol secretion to physical exercise. Baseline levels of VP total IgG and IgM autoAbs correlated negatively and VP-free IgG autoAbs correlated positively with plasma cortisol after physical exercise. Immunostaining of magnocellular hypothalamic neurons of the supraoptic and paraventricular nuclei by plasma IgG was present in 35% of the depression and in 14% of the controls groups, but this staining was not abolished by plasma preabsorption with OT or VP peptides. Conclusion These data show that changes of levels but not affinity of OT- and VP-reactive autoAbs can be associated with the altered mood in subjects with moderate depression and that levels of VP-reactive autoAbs are associated with cortisol secretion.

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.

Resume Une reduction relative de la prise alimentaire chez les sujets âges par rapport au sujets jeunes est normalement presente dans la population generale et souvent appelee « anorexie liee a l’âge ». Dans la plupart des cas, l’anorexie liee a l’âge est un phenomene physiologique, mais peut, dans certains cas, etre un des composants d’un syndrome de fragilite et augmenter la morbi-mortalite. Cependant, les mecanismes responsables de l’anorexie liee a l’âge ne sont pas bien elucides. Dans cet article sont discutes les mecanismes biologiques pouvant declencher, chez les sujets âges et dans les modeles experimentaux, une resistance aux hormones peptidiques anaboliques et orexigenes telles que le neuropeptide Y, la ghreline et l’hormone de croissance. Les roles possibles de la contamination microbienne intestinale, du vieillissement du tube digestif et du systeme immunitaire sont egalement discutes.

Objective: Recent findings of autoantibodies directed against melanocortin peptides suggest that these autoantibodies may represent a source of variability in peptidergic signaling that can be responsible for altered appetite and emotion in eating disorders. However, it is still unknown if autoantibodies directed against some other appetite-regulating neuropeptides and peptide hormones exist in healthy human subjects and if these autoantibodies can regulate appetite and emotion. Methods: We determined the presence of autoantibodies against some key appetite-regulating neu- ropeptides and peptide hormones in sera of human subjects and in rats, and used animal models to study the role of -melanocyte-stimulating hormone autoantibodies in food intake and anxiety. Results: Immunoglobulin G and A autoantibodies against -melanocyte-stimulating hormone, neu- ropeptide Y, agouti-related protein, ghrelin, leptin, and some other neuropeptides or peptide hormones involved in appetite control were present in healthy humans and rats. Animal models including active and passive transfer showed that -melanocyte-stimulating hormone autoantibodies are involved in the regulation of feeding and anxiety. Sequence homology was found between neuropeptides and proteins from some members of intestinal microflora, whereas germ-free rats showed altered levels of autoanti- bodies directed against several neuropeptides. Conclusion: Autoantibodies directed against appetite-regulating neuropeptides and peptide hormones are emerging as important participants in the peptidergic mechanisms controlling motivated behavior. Furthermore, these autoantibodies could provide a link in the gut-brain axis and may represent new biological targets for the diagnosis and treatment of eating disorders. © 2008 Elsevier Inc. All rights reserved.

Resume Les troubles fonctionnels digestifs sont pratiquement constants au cours de l’anorexie mentale, et constituent une gene majeure pour les patients et un frein a la realimentation. Tous les etages du tube digestif peuvent etre touches : regurgitations, troubles de la vidange gastrique, meteorisme intestinal et constipation de transit ou distale. Les troubles digestifs sont un motif frequent de consultation pour les patients anorexiques et peuvent parfois retarder le diagnostic du trouble du comportement alimentaire en raison d’explorations digestives multiples et de la meconnaissance frequente de l’anorexie mentale par les gastroenterologues. La physiopathologie des troubles digestifs au cours de l’anorexie mentale reste mal connue, mais pourrait impliquer la denutrition, les dereglements neuropeptidergiques observes au cours de l’anorexie mentale ou des modifications immunologiques. Les symptomes digestifs doivent etre systematiquement recherches au cours de l’anorexie mentale et traites activement pour faciliter l’adhesion des patients au programme de realimentation orale ou de nutrition enterale. Inversement, il faut savoir suspecter un trouble du comportement alimentaire devant un tableau dyspeptique ou un syndrome de l’intestin irritable avec perte de poids.

Background Altered stress response is characteristic for subjects with abnormal aggressive and antisocial behavior, but the underlying biological mechanisms are unclear. We hypothesized that autoantibodies (autoAbs) directed against several stress-related neurohormones may exist in aggressive subjects. Methods Using enzyme-linked immunosorbent assay, we studied whether autoAbs directed against corticotropin (ACTH), α-melanocyte-stimulating hormone (α-MSH), oxytocin, and vasopressin are present in serum of male subjects with conduct disorder and prisoners with history of violence. Healthy blood donors served as control subjects. Results Both conduct disorder and prisoners groups displayed strongly increased levels of ACTH-reactive immunoglobulin G (IgG) and immunoglobulin M (IgM) autoAbs compared with control subjects. Levels of oxytocin-reactive IgM autoAbs were slightly increased in both groups of aggressive subjects, whereas levels of vasopressin-reactive IgG and IgM autoAbs were lower only in conduct disorder. No differences in the levels of α-MSH-reactive autoAbs were found between aggressive and control subjects. Conclusions High levels of ACTH-reactive autoAbs as well as altered levels of oxytocin- and vasopressin-reactive autoAbs found in aggressive subjects may interfere with the neuroendocrine mechanisms of stress and motivated behavior. Our data suggest a new biological mechanism of human aggressive behavior that involves autoAbs directed against several stress-related neurohormones.

The hypothalamic arcuate nucleus (Arc) and its neurons expressing agouti-related protein (AgRP) are key components of the forebrain circuitry involved in long-term regulation of energy homeostasis, including conveying leptin signaling to other hypothalamic and extrahypothalamic regions. In the present work, we investigated the postnatal development (P0, P5, P10, P15, and P21) of this system (AgRP transcript and peptide) in the mouse brain using in situ hybridization and immunohistochemistry. At all stages, AgRP mRNA expression was detected exclusively in the Arc. At P0, AgRP mRNA levels were low, and only a few AgRP-immunoreactive fibers were present reaching, rostrally, the bed nucleus of the stria terminalis and, caudally, the dorsal raphe nucleus. During the following period (P5-P21), the levels of AgRP mRNA gradually increased in the Arc along with a parallel increase in the AgRP fiber density in the hypothalamic regions responsible for control of appetite, including the paraventricular nucleus, as well as in extrahypothalamic regions, including locus coeruleus. These data provide evidence that, in the mouse, the maturation of the AgRP Arc system occurs mainly during the first three postnatal weeks. Together with the existing data on the physiology of appetite and body weight, our data suggest that the first three postnatal weeks in the mouse represents a critical period for the formation of brain mechanisms underlying appetite control via peripheral hormones.

Neuropeptide Y (NPY) neurons abundantly innervate the hypothalamus, where NPY is involved in the regulation and integration of a broad range of homeostatic functions. In order to understand NPY-mediated behavioral, autonomic and neuroendocrine effects, it is important to characterize in detail the distribution of the hypothalamic NPY receptors. In this review, we briefly summarize the origin of NPY and its two related peptides, peptide YY and pancreatic polypeptide in the hypothalamus. Moreover, based on the results obtained with histological techniques such as in situ hybridization, immunohistochemistry and ligand binding, we summarize data on the hypothalamic distribution of the known NPY receptors, the Y1 Y2, Y4 and Y5 receptors as best characterized to date. These NPY receptors are found with individual distribution patterns in many hypothalamic neurons including neuroendocrine motoneurons, magnocellular neurosecretory neurons and numerous neurons connecting the hypothalamus with the limbic and the autonomic nervous systems. The histochemical analyses allow characterization of coexisting molecules and in this way definition of the neurochemistry of NPY circuitries. By showing coexistence of various NPY receptors they provide a morphological basis for in vitro studies showing heterodimerization of NPY receptors. The NPY neurons and their circuitries underlie the integrative role of NPY as a pleiotropic neuropeptide in the regulation of homeostasis.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is an environmental contaminant originating from industrial waste. At sublethal concentrations it induces anorexia and weight loss as part of the so-called wasting syndrome. To gain insight into its possible underlying mechanisms, mRNA expression of some key hypothalamic neuropeptides involved in the regulation of body weight was studied using in situ hybridization histochemistry in adult male Sprague-Dawley rats 6 days after single oral administration of TCDD (15 microg/kg) and in age-paired control rats. In TCDD-treated rats which displayed a decrease in body weight gain vs. controls, arcuate nucleus expression of neuropeptide Y (NPY), proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) mRNA was increased. In the lateral hypothalamic area, melanin-concentrating hormone (MCH) mRNA expression was also increased, while levels of CART and orexin/hypocretin mRNA were not significantly changed. Since TCDD is known to bind to the aryl hydrocarbon receptor (AhR), the distribution of the AhR repressor (AhRR), which is co-expressed with AhR in the same cells, was studied by immunohistochemistry in the mouse hypothalamus using mouse AhRR specific antiserum. AhRR immunoreactivity was present in the nuclei of neurons found in all main hypothalamic groups including NPY, CART, MCH and orexin/hypocretin neurons. Xenobiotic response elements were found in these neuropeptide genes with the exception of MCH. Thus changes in expression of orexigenic and anorexigenic neuropeptides after TCDD treatment may help to explain the occurrence of the TCDD-induced weight loss, which may be either directly or indirectly related to the effects of TCDD on neuropeptide expression.

Eating disorders constitute major medical health problems in the western world. Even though little is known about the mechanisms behind abnormal eating behavior, it has become clear that the central nervous system (CNS), particularly the hypothalamus, plays a significant role. The anorexic anx/anx mouse is a unique model for studying food intake and energy expenditure. The anx mutation is linked to marked alterations in hypothalamic distributions of signal substances known to have potent regulatory roles in the control of food intake. We have identified a mutation in anx/anx mice that is likely to cause the anorectic phenotype. Using RNA profiling, we have found 29 genes with differential expression in the anx/anx mouse brain. The anx gene, its protein product or molecules in the anx pathway may thus be interesting targets for development of new pharmaceuticals for the treatment of eating disorders. Based on the histochemical alterations found in the anx/anx mouse, we hypothesised and showed that many sera from anorectic/bulimic patients contain antibodies that bind specifically to the hypothalamic food intake regulatory system in rat. This finding represents a novel research avenue that may lead to a better understanding of eating disorders. It also suggests that targeted immunological approaches may be used in therapy.

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.)

M p s m K A c p c p a m g r b t f c s o D o M N C m c i f i t i w Z s How humans and animals regulate appetite and body eight has been explored in numerous studies dealing with enetic, biochemical, environmental, and psychological facors, yet the diseases that primarily affect these physiologic unctions remain largely unsolved issues of modern mediine. The origin of diseases such as anorexia and bulimia ervosa or binge-eating obesity is often referred to as mulifactorial, implying that a combination of the factors cited bove should fall into a certain pattern that would trigger isease development. Although this might be true, it does ot exclude that there exist biological changes in the organsm that may be common and critical for the development of ach specific form of eating or metabolic disease. Recent research by me and my colleagues has revealed a ew and unexpected biological mechanism that appears as a undamental part of the homeostatic control of motivated ehavior including food intake. In fact, based on clinical nd experimental data, we proposed that the regulation of ppetite and body weight is under constant control by the mmune system by secretion of autoantibodies (autoAbs) irected against neuropeptide or peptide hormones involved n the regulation of energy homeostasis [1,2]. Furthermore, e showed the first evidence that production of such autobs can be influenced by luminal antigens, indicating that hese autoAbs may serve as a link between nutrients or gut icroflora and brain control of appetite and emotion [3]. I am very grateful that the 12th John M. Kinney Award or General Nutrition was given to recognize the potential mportance of this discovery recently reported in Nutrition 3]. The path that led me to identify this new biological echanism was long and I believe could only become ossible due to complementary skills acquired in different aboratories in four countries during my research career.

Background: Tobacco smoking reduces appetite and body weight. Cessation of smoking leads to hyperphagia and weight gain. Food intake is a function of meal number (MN) and meal size (MZ) (ie, Food intake = MN × MZ). The effect of nicotine on these feeding components and their relationships to dopamine and serotonin in the lateral hypothalamic area (LHA) were determined. Methods: In Fischer-344 rats the effect of 7 days of systemic nicotine infusion on the feeding patterns was measured by rat eater meter and changes in serotonin (5HT) and dopamine (DA) in the LHA were measured by in vivo microdialysis. Results: Nicotine infusion caused hypophagia through a significant decrease in MN with a smaller decrease in MZ, resulting in a body weight reduction. 5HT and DA concomitantly increased in LHA. Stopping nicotine resulted in hyperphagia by a significant increase in MZ. Body weight normalized. 5HT and DA in LHA decreased after nicotine was stopped. Conclusion: Nicotine's hypophagic effect was associated with increased 5HT and DA in LHA, whereas hyperphagia after nicotine cessation was accompanied by decreased concentrations of the neurotransmitters. These findings suggest that nicotine affects appetite regulation, in part by modulation of LHA-DA and 5HT. (Surgery 1999;126:255-63.)

In the magnocellular hypothalamic neurons (MCN) of normal rats, tyrosine hydroxylase (TH) is expressed in response to hyperosmotic stimulation and co-exists with vasopressin. The present study shows that both Zucker obese (fa / fa) and heterozygous lean (Fa / fa) rats express TH in MCN independently of an osmotic challenge. The lack of L-DOPA and aromatic-L-aminoacid decarboxylase in the MCN showed the absence of mechanisms necessary for catecholamine synthesis in these cells. Therefore, TH in MCN seems to be functionally inactive and is not involved in catecholamine abnormalities observed in these rats. All TH-immunoreactive MCN co-expressed vasopressin mRNA while a part of them co-expressed oxytocin mRNA. This suggests a mechanism of regulation of TH expression in MCN which is different in Zucker rats and in dehydrated normal rats.

Introduction et but de l’etude L’anorexie mentale est frequemment associee a des troubles digestifs dont la physiopathologie implique la denutrition majeure et probablement des modifications du metabolisme proteique intestinal. Nous avons donc evalue dans un modele murin d’anorexie appele « activity-based anorexia » ou ABA, les taux de synthese proteique au niveau gastrique et intestinal avant et apres renutrition. Materiel et methodes Des souris mâles C57bl/6 ont ete reparties en 3 groupes: un groupe controle avec alimentation ad libitum (CT, n =16); un groupe controle avec acces limite a l’alimentation (LFA, n =16); un groupe ABA avec acces limite a l’alimentation et activite physique sur roue (ABA, n =24). Apres une phase d’acclimatation en cages individuelles de J0 a J5, les souris ABA et LFA ont eu un acces a l’alimentation progressivement limite de 6 h/jour a J6 a 3 h/jour a J9 jusqu’a la fin du protocole. A J17, phase aigue de la denutrition, les souris ont retrouve un acces ad libitum a l’alimentation. Les souris ABA ont alors ete reparties en deux sous-groupes: un sous-groupe avec activite physique (ABA-PA, n =8) et un sous-groupe sans activite physique (ABA-NPA, n =8). A J17 ou J22, une injection intra-peritoneale de phenylalanine deuteree (d5) a ete realisee 20 minutes avant le sacrifice. Les tissus gastriques et intestinaux ont ensuite ete preleves. L’enrichissement en d5-pheny-lalanine a ete mesure par GC-MS et le taux de synthese proteique (FSR) a ete ensuite calcule. Resultats et Analyse statistique Pendant la phase de denutrition, plus marquee dans le groupe ABA par rapport au groupe LFA (p Conclusion Nos resultats suggerent donc que la denutrition n’altere pas le taux de synthese proteique des muqueuses du tractus gastro-intestinal alors que la renutrition stimule fortement ce taux au niveau de l’estomac et de l’intestin grele. Les voies de signalisation impliquees sont en cours d’analyse. L’activite physique ne semble pas avoir d’effet sur le taux de synthese proteique des muqueuses gastro-intestinales. Conclusion Le choix de la reference influe sur la frequence de l’insuffisance ponderale, particulierement chez les enfants dont le Z-score IMC est proche de -2 ecart-types pour l’âge et le sexe. L’utilisation seule du Z-score IMC est insuffisante. L’examen clinique et l’anamnese sont indispensables pour porter le diagnostic de malnutrition proteino-energetique.

Introduction et but de l’etude Le controle de la prise alimentaire implique des voies cerebrales regulees par des hormones de faim (ghreline), de satiete (CCK, PYY) et de stockage energetique (leptine). De nombreuses etudes associent le phenotype metabolique de l’hote, tel que l’obesite, a la composition du microbiote intestinal (e.g. ratio bacteroidetes/firmicutes). Pourtant, malgre ces donnees recentes, la comprehension des mecanismes d’action des bacteries sur le controle de la prise alimentaire de l’hote reste meconnue. Le but de cette etude a ete de tester si des proteines bacteriennes peuvent influencer le controle de la prise alimentaire de l’hote et si cette influence depend de l’etat nutritionnel des bacteries. Materiel et methodes La bacterie commensale E. coli K12 a recu un milieu riche en nutriments toutes les 12 h pendant 5 jours afin de mimer 2 repas/jour chez l’homme. Les proteines bacteriennes ont ete extraites en deux temps : lors de la phase exponentielle (Exp) et lors de la phase stationnaire (Stat) de croissance. Par la suite, ces fractions proteiques ont ete comparees par electropho-reses bidimensionnelles et spectrometrie de masse. Puis, les effets de l’administration intraperitoneale de ces proteines bacteriennes a la dose de 0,1 mg/Kg, ont ete etudies sur la prise alimentaire de rats Wistar. Des analyses immunohistochimiques, sur les coupes de cerveaux de rat ont ete realisees 2 h apres l’injection de proteines bacteriennes pour detecter l’expression de c-fos (marqueur d’activite neuronale) dans les neurones anorexigenes a proopiomelanocortine (POMC) du noyau arque de l’hypothalamus et dans les neurones a calcitonin gene-related peptide (CGRP) du noyau central de l’amygdale. Resultats et Analyse statistique Des la 5 e administration de nutriments, la bacterie E. coli K1 2 alterne de maniere reguliere des phases Exp de croissance (20 min) et des phases Stat apres chaque nouvel apport de nutriments. Les analyses proteomiques revelent la presence de proteines differentiellement exprimees entre les deux phases Exp et Stat. Seule l’injection intraperitoneale de proteines bacteriennes en phase Stat reduit la prise alimentaire (2,0 ± 0,2 g vs 1,2 ± 0,3 g, P 0,05, test t de student) des rats et augmente l’expression du c-fos dans les neurones POMC (45,3 ± 3,8 cellules vs 58,4 ± 1,4 cellules, P 0,05, post-test de Tukey, ANOVA) et CGRP (54 ±7 % vs 92 ± 4%, P Conclusion Nos donnees montrent que les proteines issues des bacteries intestinales peuvent influencer directement le controle central de la prise alimentaire, selon leur phase de croissance; elles-memes alternees par l’apport de nutriments. Dans cette etude, l’effet satietogene provoque par les proteines bacteriennes extraites en phase Stat de croissance, suggere une implication du microbiote dans l’induction de la satiete de l’hote apres un repas.

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compared with animal-derived proteins. However, there are few data to support this contention. We assessed postprandial plasma amino acid profiles and whole-body protein synthesis following the ingestion of 35 g wheat protein hydrolysate compared with casein and whey in healthy, older males. Methods: Healthy older males (73±1 y) received a primed continuous infusion of L-[C6]-phenylalanine and L-[H2]tyrosine and ingested 35 g wheat protein hydrolysate (WHEAT; n = 12), whey (WHEY; n = 12), or micellar casein (CAS; n = 12). Plasma and muscle samples were collected at regular intervals. Repeated measures ANOVA was used to identify differences between groups over time. Results: Plasma leucine concentrations increased following protein ingestion (P < 0.01), to a similar extent following WHEAT and CAS (P = 0.86) and to a greater extent following WHEY (P < 0.01). In agreement, peak leucine concentrations averaged 351±11, 316±24, and 580±18mM for WHEAT, CAS, and WHEY, respectively (WHEAT vs CAS P = 0.40; WHEY vs WHEAT and CAS P < 0.01). Whole-body protein synthesis increased following protein ingestion in all groups (P < 0.01), with no significant differences between groups (P = 0.13). Postprandial muscle protein synthesis rates will be assessed by determining the incorporation of L-[C6]-phenylalanine into myofibrillar protein. Conclusion: Ingesting wheat protein hydrolysate increases plasma amino acid availability and stimulates whole-body protein synthesis as effectively as casein in healthy, older males.

The article by Saiki and colleagues [1] published in the Metabolism entitled “Circulating angiotensin II is associated with body fat accumulation and insulin resistance in obese subjects with type 2 diabetes mellitus” is very interesting in that it points out clearly the association between circulating angiotensin levels and the pathophysiology of obesity and diabetes. At first glance, this is rather unusual, as why would a hormone intimately implicated in cardiovascular and water balance functions be involved with fat accumulation and insulin resistance. However, these “unusual” associations have given rise to a series of reports, all independent at the time, which now taken together make sense [2-4]. It would appear that the common feature in the origin not only of hypertension but also of obesity and diabetes is hypovolemia. This is a physiologic state that comes about through reduced fluid intake and has as primary signal the release of renin that generates angiotensin II in the blood. Interestingly, neurochemical changes characteristic of extracellular dehydration have been found in the brain of obese Zucker rats, a model of obesity and type 2 diabetes [5]. Moreover, in animal studies on obesity, inhibition of the reninangiotensin system produces an increased fluid intake that has been suggested to lead to lipolysis and subsequent weight loss [3]. In other studies, it has been noted that inhibition of the renin-angiotensin system allows cells to restore membrane glucose transport and to increase insulin sensitivity [4]. It was thus proposed that this would restore to normal cellular carbohydrate and fat metabolism [4]. However, insulin signaling is linked also to cell volume regulation [6]; and cell volume regulation would be dependent on body hydration state. We thus come back to the regulation of hypovolemia. It is thus not surprising to find that circulating angiotensin levels are elevated in conditions of obese subjects with type 2 diabetes mellitus [1], and it would be interesting to propose that increased water intake be encouraged along with renin-angiotensin system blockade in cases of obesity and diabetes.

Introduction et but de l’etude Le traitement par methotrexate (MTX) est associe a une enterocolite et a une anorexie. Cette anorexie pourrait etre liee aux consequences de l’inflammation intestinale ou a un effet central direct du MTX, ou a une association de ces deux mecanismes, agissant in fine sur les centres hypothalamiques regulant la prise alimentaire. Physiologiquement, l’hypothalamus repond a une carence energetique par une surexpression des neuropeptides orexigenes, et une repression des neuropeptides anorexigenes. Le but de cette etude etait de preciser si l’enterocolite associee au traitement par le MTX est responsable des modifications d’expression des ARNm des neuropeptides hypothalamiques impliques dans la regulation de l’appetit. Materiel et methods Des rats mâles Sprague-Dawley ont recu une injection de MTX (2,5 mg/Kg s.c. pendant 3 jours). Deux series de rats controles pair-fed et nourris ad-libitum ont recu du serum physiologique. Les rats ont ete sacrifies au 5e ou au 19e jour apres la premiere injection, et l’induction de l’inflammation intestinale a ete verifiee par histomorphometrie. Apres isolement de l’hypothalamus entier, les taux d’expression des ARNm des neuropeptides ont ete mesures par PCR en temps reel. Les resultats ont ete compares par test ANOVA et post-tests de Tukey, avec p Resultats C’est a J5 que sont observees la reduction maximale de la prise alimentaire et du poids des rats, et l’inflammation muqueuse colique la plus intense (p Conclusions Ces resultats suggerent que le MTX est capable d’alterer les mecanismes neuropeptidergiques de regulation de la prise alimentaire et ponderostatiques secondaires a une carence energetique. Des etudes complementaires sont necessaires pour mieux comprendre les mecanismes directs ou indirects par lesquels le MTX interfere avec la regulation de la prise alimentaire, et preciser les possibilites d’interventions pharmaconutritionelles specifiques.