Altérations périphériques et centrales dans un modèle murin de restriction alimentaire chronique : rôle de la ghréline

Chronic food restriction is one of the major features observed in anorexia nervosa (AN), especially in the restrictive type. This major eating disorder affects mainly teenager girls and young women. Additionally to the restriction behavior, important physical activity is observed in a large number of patients (40-80% of cases). This disease induces various physiological alterations that concern neuroendocrine, metabolic and bone (osteopenia, osteoporosis) pathways, which have dramatic consequences on the patient’s health. Moreover, many arguments suggest that AN could be considered like an "addictiv" disorder supported by an addiction to weight loss and/or food restriction or physical activity. It thus suggests modifications of the central dopaminergic reward system. Furthermore, whatever the origins or the causes of this disorder, AN leads to peripheral and central alterations that might be involved in an "adaptation" phase allowing patients surviving to these drastic conditions. For some patients, a phase of "chronicity" is described in which these physiological changes may worsen the patient conditions and contribute, when exhaustion is amplifying, to death. Our study points out ghrelin, an orexigenic hormone whose plasma concentrations are significantly increased in AN patients. Mainly secreted by stomach cells, it targets multiple peripheral organs as well as numerous neuronal structures in the brain. At the peripheral level, this hormone acts among others in the liver whose main function is the maintenance of glucose homeostasis. It acts also on the adipose tissue to promote its growth that is associated with lipid storage and on muscle resulting in a reduction of triglycerides stock. At the central nervous system level, ghrelin have various targets like the structures involved in the homeostatic as well as hedonic (motivation/reward) control of food intake through the hypothalamus and the meso-cortico-limbic system respectively.To study the involvement of ghrelin in the potential adaptive mechanisms, and even in the worsening of the disease, we have developed an animal model of chronic food restriction associated or not with physical activity, mimicking the physiological symptoms of AN. Our first objective was to characterize and to phenotype the mouse model by evaluating various physiological (metabolic, endocrine) factors in order to study in our second objective the role of ghrelin as a potential predictor of disease progression.We showed that our mouse model constitutes a pertinent model to study on a long term duration the physiological and central altérations described in the restrictive type AN. Moreover, we showed that moderate physical activity associated with food restriction had stabilizing effects on numerous metabolic parameters that may reduce an early exhaustion of energy stocks. Concerning the role of ghrelin in such model, its plasma concentrations were increased like in AN patients and were suggested to contribute to the adaptive regulation of energy metabolism.La restriction alimentaire chronique correspond à un des troubles du comportement alimentaire observé en particulier dans l’anorexie mentale (AN) de type restrictif, pathologie qui touche essentiellement les adolescentes et les jeunes femmes. En plus de ce comportement restrictif, une activité physique importante est observée chez un grand nombre de patientes (40 à 80% des cas). Cette maladie se traduit par de nombreuses altérations physiologiques comme des perturbations neuroendocrines, métaboliques, osseuses (ostéopénie, ostéoporose) et ce quelle que soit la cause psychiatrique qui a conduit au développement de ce comportement. De plus, de nombreux arguments suggèrent que l’AN pourrait être considérée comme un trouble « addictif » qui se manifesterait par une addiction à la perte de poids et/ou à la restriction alimentaire ou encore à l’activité physique suggérant une altération du système dopaminergique de récompense. Ainsi, quelles que soient les origines de la maladie, l’AN entraîne des perturbations périphériques et centrales susceptibles d’être impliquées dans une première phase dite « d’adaptation » permettant aux malades de survivre à ces conditions drastiques. Les patients peuvent par la suite tomber dans une seconde phase de « chronicisation » dans laquelle ces mêmes facteurs pourraient être responsables de la dégradation de l’état des malades et conduire, dans les cas les plus graves d’épuisement, à la mort.Notre étude a comme pivot la ghréline, hormone orexigène, dont les concentrations plasmatiques sont augmentées significativement chez les patients anorexiques. Sécrétée principalement en périphérie par les cellules de l’estomac, elle va cibler plusieurs organes aussi bien périphériques que centraux. En particulier, au niveau périphérique, cette hormone agit au niveau du foie dont la principale fonction connue est le maintien de l’homéostasie glucidique. Elle agit également au niveau du tissu adipeux qui est alors stimulé, favorisant ainsi sa croissance avec un stockage des réserves et au niveau musculaire en entrainant entre autre une diminution des réserves de triglycérides. Au niveau du système nerveux central, parmi les sites d’action de la ghréline, on trouve les structures impliquées aussi bien dans le contrôle, qualifié d’homéostatique, de la prise alimentaire représenté par l’hypothalamus, que dans le contrôle, dit hédonique (motivation/récompense), de ce même comportement correspondant au circuit méso-limbique. Pour étudier son implication dans les mécanismes adaptatifs, et éventuellement, dans l’aggravation de la maladie, nous avons mis au point un modèle animal de restriction alimentaire chronique mimant les symptômes physiologiques de l’AN. Notre premier objectif a été de caractériser (« phénotypage ») ce modèle sur le plan physiologique (métabolique, endocrinien) afin de l’utiliser pour notre deuxième objectif : évaluation du rôle de la ghréline comme potentiel facteur prédictif de l’évolution de la maladie.Les données obtenues valident notre modèle comme un modèle pertinent pour étudier sur le long terme les altérations physiologiques et centrales décrites dans l’AN de type restrictif. Nous montrons que l’exercice physique modéré associé à la restriction alimentaire a des effets stabilisateurs sur de nombreux paramètres métaboliques limitant ainsi un épuisement prématuré des ressources énergétiques. En ce qui concerne la ghréline, les concentrations plasmatiques élevées observées dans notre modèle pourraient contribuer également à une régulation adaptative du métabolisme énergétique

Overexpression of Wild-Type Human Alpha-Synuclein Causes Metabolism Abnormalities in Thy1-aSYN Transgenic Mice

Parkinson’s disease is a progressive neurodegenerative disorder characterized by loss of dopaminergic neurons, pathological accumulation of alpha-synuclein and motor symptoms, but also by non-motor symptoms. Metabolic abnormalities including body weight loss have been reported in patients and could precede by several years the emergence of classical motor manifestations. However, our understanding of the pathophysiological mechanisms underlying body weight loss in PD is limited. The present study investigated the links between alpha-synuclein accumulation and energy metabolism in transgenic mice overexpressing Human wild-type (WT) alpha-synuclein under the Thy1 promoter (Thy1-aSYN mice). Results showed that Thy1-aSYN mice gained less body weight throughout life than WT mice, with significant difference observed from 3 months of age. Body composition analysis of 6-month-old transgenic animals showed that body mass loss was due to lower adiposity. Thy1-aSYN mice displayed lower food consumption, increased spontaneous activity, as well as a reduced energy expenditure compared to control mice. While no significant change in glucose or insulin responses were observed, Thy1-aSYN mice had significantly lower plasmatic levels of insulin and leptin than control animals. Moreover, the pathological accumulation of alpha-synuclein in the hypothalamus of 6-month-old Thy1-aSYN mice was associated with a down-regulation of the phosphorylated active form of the signal transducer and activator of transcription 3 (STAT3) and of Rictor (the mTORC2 signaling pathway), known to couple hormonal signals with the maintenance of metabolic and energy homeostasis. Collectively, our results suggest that (i) metabolic alterations are an important phenotype of alpha-synuclein overexpression in mice and that (ii) impaired STAT3 activation and mTORC2 levels in the hypothalamus may underlie the disruption of feeding regulation and energy metabolism in Thy1-aSYN mice

Peripheral and central alterations in a chronic model of food restriction : role of ghrelin

La restriction alimentaire chronique correspond à un des troubles du comportement alimentaire observé en particulier dans l’anorexie mentale (AN) de type restrictif, pathologie qui touche essentiellement les adolescentes et les jeunes femmes. En plus de ce comportement restrictif, une activité physique importante est observée chez un grand nombre de patientes (40 à 80% des cas). Cette maladie se traduit par de nombreuses altérations physiologiques comme des perturbations neuroendocrines, métaboliques, osseuses (ostéopénie, ostéoporose) et ce quelle que soit la cause psychiatrique qui a conduit au développement de ce comportement. De plus, de nombreux arguments suggèrent que l’AN pourrait être considérée comme un trouble « addictif » qui se manifesterait par une addiction à la perte de poids et/ou à la restriction alimentaire ou encore à l’activité physique suggérant une altération du système dopaminergique de récompense. Ainsi, quelles que soient les origines de la maladie, l’AN entraîne des perturbations périphériques et centrales susceptibles d’être impliquées dans une première phase dite « d’adaptation » permettant aux malades de survivre à ces conditions drastiques. Les patients peuvent par la suite tomber dans une seconde phase de « chronicisation » dans laquelle ces mêmes facteurs pourraient être responsables de la dégradation de l’état des malades et conduire, dans les cas les plus graves d’épuisement, à la mort.Notre étude a comme pivot la ghréline, hormone orexigène, dont les concentrations plasmatiques sont augmentées significativement chez les patients anorexiques. Sécrétée principalement en périphérie par les cellules de l’estomac, elle va cibler plusieurs organes aussi bien périphériques que centraux. En particulier, au niveau périphérique, cette hormone agit au niveau du foie dont la principale fonction connue est le maintien de l’homéostasie glucidique. Elle agit également au niveau du tissu adipeux qui est alors stimulé, favorisant ainsi sa croissance avec un stockage des réserves et au niveau musculaire en entrainant entre autre une diminution des réserves de triglycérides. Au niveau du système nerveux central, parmi les sites d’action de la ghréline, on trouve les structures impliquées aussi bien dans le contrôle, qualifié d’homéostatique, de la prise alimentaire représenté par l’hypothalamus, que dans le contrôle, dit hédonique (motivation/récompense), de ce même comportement correspondant au circuit méso-limbique. Pour étudier son implication dans les mécanismes adaptatifs, et éventuellement, dans l’aggravation de la maladie, nous avons mis au point un modèle animal de restriction alimentaire chronique mimant les symptômes physiologiques de l’AN. Notre premier objectif a été de caractériser (« phénotypage ») ce modèle sur le plan physiologique (métabolique, endocrinien) afin de l’utiliser pour notre deuxième objectif : évaluation du rôle de la ghréline comme potentiel facteur prédictif de l’évolution de la maladie.Les données obtenues valident notre modèle comme un modèle pertinent pour étudier sur le long terme les altérations physiologiques et centrales décrites dans l’AN de type restrictif. Nous montrons que l’exercice physique modéré associé à la restriction alimentaire a des effets stabilisateurs sur de nombreux paramètres métaboliques limitant ainsi un épuisement prématuré des ressources énergétiques. En ce qui concerne la ghréline, les concentrations plasmatiques élevées observées dans notre modèle pourraient contribuer également à une régulation adaptative du métabolisme énergétique.Chronic food restriction is one of the major features observed in anorexia nervosa (AN), especially in the restrictive type. This major eating disorder affects mainly teenager girls and young women. Additionally to the restriction behavior, important physical activity is observed in a large number of patients (40-80% of cases). This disease induces various physiological alterations that concern neuroendocrine, metabolic and bone (osteopenia, osteoporosis) pathways, which have dramatic consequences on the patient’s health. Moreover, many arguments suggest that AN could be considered like an "addictiv" disorder supported by an addiction to weight loss and/or food restriction or physical activity. It thus suggests modifications of the central dopaminergic reward system. Furthermore, whatever the origins or the causes of this disorder, AN leads to peripheral and central alterations that might be involved in an "adaptation" phase allowing patients surviving to these drastic conditions. For some patients, a phase of "chronicity" is described in which these physiological changes may worsen the patient conditions and contribute, when exhaustion is amplifying, to death. Our study points out ghrelin, an orexigenic hormone whose plasma concentrations are significantly increased in AN patients. Mainly secreted by stomach cells, it targets multiple peripheral organs as well as numerous neuronal structures in the brain. At the peripheral level, this hormone acts among others in the liver whose main function is the maintenance of glucose homeostasis. It acts also on the adipose tissue to promote its growth that is associated with lipid storage and on muscle resulting in a reduction of triglycerides stock. At the central nervous system level, ghrelin have various targets like the structures involved in the homeostatic as well as hedonic (motivation/reward) control of food intake through the hypothalamus and the meso-cortico-limbic system respectively.To study the involvement of ghrelin in the potential adaptive mechanisms, and even in the worsening of the disease, we have developed an animal model of chronic food restriction associated or not with physical activity, mimicking the physiological symptoms of AN. Our first objective was to characterize and to phenotype the mouse model by evaluating various physiological (metabolic, endocrine) factors in order to study in our second objective the role of ghrelin as a potential predictor of disease progression.We showed that our mouse model constitutes a pertinent model to study on a long term duration the physiological and central altérations described in the restrictive type AN. Moreover, we showed that moderate physical activity associated with food restriction had stabilizing effects on numerous metabolic parameters that may reduce an early exhaustion of energy stocks. Concerning the role of ghrelin in such model, its plasma concentrations were increased like in AN patients and were suggested to contribute to the adaptive regulation of energy metabolism

Does playing O.zen improve our well-being?

Stress is considered to be an individual’s response to different pressures and demands in a particular environment (Pottier et al., 2011). In an ever more demanding and stressful world, many options for people to learn how to relax and how to deal with a challenging lifestyle are becoming available. O.zen is a great alternative, since it is a ludic and not expensive device, which goal is to help people to relax with the help of breathing games that can easily be accomplished no matter what time of the day or context. The goal of this study was to test O.zen’s efficiency. In order to do so, neuropsychological tests were held throughout the experiment to 28 participants that were divided in experimental (played O.zen) and control (watched videos equivalent to O.zen) groups. Also, cortisol levels and participants’ skin conductance was measured. Both groups showed overall improvements, with participants feeling significantly less anxious after playing O.zen, and showing a lower level of skin conductance. O.zen’s visuals and music seem to be beneficial on their own, with its biofeedback quality emphasizing the gains

Long-Term Energy Deficit in Mice Causes Long-Lasting Hypothalamic Alterations after Recovery

International audienceAlthough the short-term effects of fasting or energy deficit on hypothalamic neuropeptide circuitries are now better understood, the effects of long-term energy deficit and refeeding remain to be elucidated. We showed that after a long-term energy deficit, mice exhibited persistent hypoleptinemia following the refeeding period despite restoration of fat mass, ovarian activity, and feeding behavior. We aimed to examine the hypothalamic adaptations after 10 weeks of energy deficit and after 10 further weeks of nutritional recovery. To do so, we assessed the mRNA levels of the leptin receptor and the main orexigenic and anorexigenic peptides, and their receptors regulated by leptin. Markers of hypothalamic inflammation were assessed as leptin can also participate in this phenomenon. Long-term time-restricted feeding and separation induced significant increase in mRNA levels of hypothalamic orexigenic peptides, while both Y1 and Y5 receptor mRNAs were downregulated. No changes occurred in the mRNA levels of orexin (OX), melanin-concentrating hormone, pro-opiomelanocortin, 26RFa (26-amino acid RF-amide peptide), and their receptors despite an increase in the expression of melanocortin receptors (MC3-R and MC4-R) and OXR1 (OX receptor 1). The refeeding period induced an overexpression of leptin receptor mRNA in the hypothalamus. The other assessed mRNA levels were normalized except for Y2, Y5, MC3-R, and MC4-R, which remained upregulated. No convincing changes were observed in neuroinflammatory markers, even if interleukin-1β mRNA levels were increased in parallel with those of Iba1 (ionized calcium-binding adaptor molecule 1), a marker of microglial activation. Normalization of leptin-regulated functions and hypothalamic gene expressions in refed mice with low plasma leptin levels could be sustained by recalibration of hypothalamic sensitivity to leptin

Is there a role for ghrelin in central dopaminergic systems? Focus on nigrostriatal and mesocorticolimbic pathways.

International audienceThe gastro-intestinal peptide ghrelin has been assigned many functions. These include appetite regulation, energy metabolism, glucose homeostasis, intestinal motility, anxiety, memory or neuroprotection. In the last decade, this pleiotropic peptide has been proposed as a therapeutic agent in gastroparesis for diabetes and in cachexia for cancer. Ghrelin and its receptor, which is expressed throughout the brain, play an important role in motivation and reward. Ghrelin finely modulates the mesencephalic dopaminergic signaling and is thus currently studied in pathological conditions including dopamine-related disorders. Dopamine regulates motivated behaviors, modulating reward processes, emotions and motor functions to enable the survival of individuals and species. Numerous dopamine-related disorders including Parkinson's disease or eating disorders like anorexia nervosa involve altered ghrelin levels. However, despite the growing interest for ghrelin in these pathological conditions, global integrative studies investigating its role in brain dopaminergic structures are still lacking. In this review, we discuss the role of ghrelin on dopaminergic neurons and its relevance in the search for new therapeutics for Parkinson's disease- and anorexia nervosa-related dopamine deficits

Long-Term Physiological Alterations and Recovery in a Mouse Model of Separation Associated with Time-Restricted Feeding: A Tool to Study Anorexia Nervosa Related Consequences

<div><p>Background</p><p>Anorexia nervosa is a primary psychiatric disorder, with non-negligible rates of mortality and morbidity. Some of the related alterations could participate in a vicious cycle limiting the recovery. Animal models mimicking various physiological alterations related to anorexia nervosa are necessary to provide better strategies of treatment.</p><p>Aim</p><p>To explore physiological alterations and recovery in a long-term mouse model mimicking numerous consequences of severe anorexia nervosa.</p><p>Methods</p><p>C57Bl/6 female mice were submitted to a separation-based anorexia protocol combining separation and time-restricted feeding for 10 weeks. Thereafter, mice were housed in standard conditions for 10 weeks. Body weight, food intake, body composition, plasma levels of leptin, adiponectin, IGF-1, blood levels of GH, reproductive function and glucose tolerance were followed. Gene expression of several markers of lipid and energy metabolism was assayed in adipose tissues.</p><p>Results</p><p>Mimicking what is observed in anorexia nervosa patients, and despite a food intake close to that of control mice, separation-based anorexia mice displayed marked alterations in body weight, fat mass, lean mass, bone mass acquisition, reproductive function, GH/IGF-1 axis, and leptinemia. mRNA levels of markers of lipogenesis, lipolysis, and the brown-like adipocyte lineage in subcutaneous adipose tissue were also changed. All these alterations were corrected during the recovery phase, except for the hypoleptinemia that persisted despite the full recovery of fat mass.</p><p>Conclusion</p><p>This study strongly supports the separation-based anorexia protocol as a valuable model of long-term negative energy balance state that closely mimics various symptoms observed in anorexia nervosa, including metabolic adaptations. Interestingly, during a recovery phase, mice showed a high capacity to normalize these parameters with the exception of plasma leptin levels. It will be interesting therefore to explore further the central and peripheral effects of the uncorrected hypoleptinemia during recovery from separation-based anorexia.</p></div

Expression analysis in adipose tissues of genes involved in lipid metabolism.

<p>Relative mRNA levels of Glut4, FASn, ABHD5 and ATGL were determined by real-time PCR experiments, in subcutaneous (SCAT) and visceral adipose tissues (VAT) of control □ and SBA ▪ mice. PPIA and HPRT were used as housekeeping genes. All results are expressed as fold-change compared to one SCAT of the control group after 10 weeks. Analyses were done after 10 weeks of SBA protocol and 10 additional weeks of REC protocol. Data represent mean ± SEM; n = 5–10/group. *<i>p</i><0.05 and **<i>p</i><0.005 when compared to CT group at the same duration; ^‡<i>p</i><0.05 and ^{‡ ‡}<i>p</i><0.005 when compared to the previous value of the same group.</p