Le système relaxine-3/RXFP3 dans la régulation de la prise alimentaire : effet de la diète, du stress et du facteur sexe

L’hyperphagie et l’obésité sont devenues des problèmes majeurs de notre société et touchent de manière différente les hommes et les femmes. Dès lors, il apparaît nécessaire de rechercher les bases physiologiques de ces troubles chez des modèles animaux, comme les rats développant l’hyperphagie induite par le stress et l’obésité induite par la diète (DIO). Dans ces modèles, l’étude du neuropeptide orexigène relaxine-3 semble être une piste prometteuse du fait de son implication dans la régulation du stress et de la prise alimentaire. Dans un premier temps, nous avons étudié ce neuropeptide chez un modèle animal de rat DIO. Ces rats sont hyperphagiques et défendent leur gain de poids corporel contre la restriction calorique. Nos résultats montrent une expression plus élevée de la relaxine-3 chez les rats DIO lorsqu’ils ont accès à la nourriture à volonté et une expression augmentée de son récepteur RXFP3 induite par la réalimentation suivant le jeûne, suggérant que la relaxine-3 serait impliquée dans le maintien du gain de poids corporel chez le phénotype DIO. Dans une deuxième étude, des rats mâles et femelles étaient soumis à un stress et une restriction alimentaire chronique. Nous avons observé que seules les femelles connaissaient des épisodes d’hyperphagie associés à un gain de poids corporel et une augmentation de l’expression de relaxine-3 qui pourrait être à la base de ce comportement sexuellement spécifique. Dans une troisième étude, par l’injection de relaxine-3 dans le cerveau des rats mâles et femelles, nous avons montré que ce neuropeptide avait un effet orexigène plus élevé chez les femelles que chez les mâles. Nous avons également observé une stimulation plus importante de l’axe corticotrope chez les mâles qui pourrait atténuer l’effet orexigène de la relaxine-3 tandis que, chez les femelles, la stimulation de l’expression de corticolibérine dans le noyau du lit de la strie terminale pourrait renforcer la motivation liée à la recherche de nourriture. En résumé, nos travaux démontrent le rôle du système relaxine-3/RXFP3 dans l’hyperphagie et le gain de poids corporel et montrent son rôle sexuellement spécifique dans la régulation de la prise alimentaire et de la réponse au stress.Hyperphagia and obesity are major problems in our society that affect differentially men and women. Therefore, it is necessary to seek the physiological basis of these health problems using animal models such as stress-induced hyperphagia and diet-induced obesity (DIO) in rats, taking into account diet, stress and sex factors. Investigating the role of the orexigenic neuropeptide relaxin-3 appears to be promising because of its involvement in the regulation of stress and food intake. First, we studied the role of relaxin–3 system in DIO rat model. These rats are hyperphagic and defend their elevated body weight against caloric restriction. The results of this study showed higher expression of relaxin-3 in the DIO rats in free feeding conditions, and, in addition, refeeding after food deprivation led to increased expression of the cognate receptor of relaxin-3 RXFP3 in DIO rats suggesting that relaxin-3 is involved in the defense of elevated body weight in the DIO phenotype. In the second study, hyperphagia was developed in female but not male rats submitted to repeated episodes of food restriction and stress. We observed that female hyperphagic rats showed increased expression of relaxin-3 which could be a cause of this sexually specific behavior. In the third study, by the central injection of relaxin-3 in male and female rats, we showed that female rats were more sensitive to lower doses of relaxin-3 and demonstrated higher increase in food intake compared to male rats. We also observed a greater stimulation of the hypothalamic pituitary adrenal (HPA) axis in male rats that may limit the orexigenic effect of relaxin-3. Conversely, in female rats, stimulation of corticotropin-releasing factor expression in the bed nucleus of the stria terminalis may enhance feeding behavior. In summary, our work demonstrates the role of relaxin-3/RXFP3 system in hyperphagia and body weight gain and shows its sex-specific effects in food intake regulation and stress response

The role of relaxin-3 and its receptor RXFP3 in defense of elevated body weight in diet-induced obesity

Incidence of overweight and obesity has dramatically increased during the past three decades. Treatment of this serious clinical problem is hindered by the fact that once obesity has developed, the elevated body weight is defended against weight-decreasing treatment strategies by mechanisms that are not yet fully understood. This review focuses on the neuronal mechanisms that contribute to the maintenance of obesity after it develops in the DIO rat model. Among the neuronal factors regulating energy intake, orexigenic neuropeptide relaxin-3 and its cognate receptor RXFP3 may play an important role in the defense of elevated body weight in DIO. The levels of expression of relaxin-3 mRNA in the brainstem nucleus incertus (NI) were significantly increased in the ad libitum feeding state in DIO rats compared to DR rats. However, the effects of relaxin-3 in the DIO ad libitum-fed rats may be compensated by a significant decrease in the levels of expression of RXFP3 mRNA in the food intake-regulating brain regions of DIO rats including the paraventricular hypothalamic nucleus (PVN), central amygdala (CeA), NI, and nucleus of the solitary tract (NTS). Remarkably, the DIO rats showed an immediate rebound in food intake at refeeding and regained all body weight lost during starvation. This significant increase in food intake during refeeding was accompanied by an increase in the levels of expression of RXFP3 in the parvocellular PVN, CeA, NI, and NTS in the DIO rats to the levels of the DR rats. Moreover, the expression of RXFP3 in the paraventricular thalamic nucleus was significantly higher in the refed DIO rats compared to the DR counterparts. A constitutive increase in the expression of relaxin-3 accompanied by a relative increase in the expression of RXFP3 in food intake-regulating brain regions during refeeding after food deprivation may contribute to the mechanisms of defense of elevated body weight in the DIO phenotype

The role of relaxin-3 and its receptor RXFP3 in defense of elevated body weight in diet-induced obesity

Incidence of overweight and obesity has dramatically increased during the past three decades. Treatment of this serious clinical problem is hindered by the fact that once obesity has developed, the elevated body weight is defended against weight-decreasing treatment strategies by mechanisms that are not yet fully understood. This review focuses on the neuronal mechanisms that contribute to the maintenance of obesity after it develops in the DIO rat model. Among the neuronal factors regulating energy intake, orexigenic neuropeptide relaxin-3 and its cognate receptor RXFP3 may play an important role in the defense of elevated body weight in DIO. The levels of expression of relaxin-3 mRNA in the brainstem nucleus incertus (NI) were significantly increased in the ad libitum feeding state in DIO rats compared to DR rats. However, the effects of relaxin-3 in the DIO ad libitum-fed rats may be compensated by a significant decrease in the levels of expression of RXFP3 mRNA in the food intake-regulating brain regions of DIO rats including the paraventricular hypothalamic nucleus (PVN), central amygdala (CeA), NI, and nucleus of the solitary tract (NTS). Remarkably, the DIO rats showed an immediate rebound in food intake at refeeding and regained all body weight lost during starvation. This significant increase in food intake during refeeding was accompanied by an increase in the levels of expression of RXFP3 in the parvocellular PVN, CeA, NI, and NTS in the DIO rats to the levels of the DR rats. Moreover, the expression of RXFP3 in the paraventricular thalamic nucleus was significantly higher in the refed DIO rats compared to the DR counterparts. A constitutive increase in the expression of relaxin-3 accompanied by a relative increase in the expression of RXFP3 in food intake-regulating brain regions during refeeding after food deprivation may contribute to the mechanisms of defense of elevated body weight in the DIO phenotype

The role of relaxin-3 and its receptor RXFP3 in defense of elevated body weight in diet-induced obesity

Incidence of overweight and obesity has dramatically increased during the past three decades. Treatment of this serious clinical problem is hindered by the fact that once obesity has developed, the elevated body weight is defended against weight-decreasing treatment strategies by mechanisms that are not yet fully understood. This review focuses on the neuronal mechanisms that contribute to the maintenance of obesity after it develops in the DIO rat model. Among the neuronal factors regulating energy intake, orexigenic neuropeptide relaxin-3 and its cognate receptor RXFP3 may play an important role in the defense of elevated body weight in DIO. The levels of expression of relaxin-3 mRNA in the brainstem nucleus incertus (NI) were significantly increased in the ad libitum feeding state in DIO rats compared to DR rats. However, the effects of relaxin-3 in the DIO ad libitum-fed rats may be compensated by a significant decrease in the levels of expression of RXFP3 mRNA in the food intake-regulating brain regions of DIO rats including the paraventricular hypothalamic nucleus (PVN), central amygdala (CeA), NI, and nucleus of the solitary tract (NTS). Remarkably, the DIO rats showed an immediate rebound in food intake at refeeding and regained all body weight lost during starvation. This significant increase in food intake during refeeding was accompanied by an increase in the levels of expression of RXFP3 in the parvocellular PVN, CeA, NI, and NTS in the DIO rats to the levels of the DR rats. Moreover, the expression of RXFP3 in the paraventricular thalamic nucleus was significantly higher in the refed DIO rats compared to the DR counterparts. A constitutive increase in the expression of relaxin-3 accompanied by a relative increase in the expression of RXFP3 in food intake-regulating brain regions during refeeding after food deprivation may contribute to the mechanisms of defense of elevated body weight in the DIO phenotype

Involvement of orexin in the sex-specific effect of relaxin-3 on food intake in rats

Involvement of orexin in the sex-specific effect of relaxin-3 on food intake in rats. 24. Annual Meeting of the International Behavioral Neuroscience Society (IBNS

Eye tracking of smoking-related stimuli in tobacco use disorder: A proof-of-concept study combining attention bias modification with alpha-transcranial alternating current stimulation

International audienceBackground: Tobacco use disorder (TUD) is characterized by the presence of an attentional bias (AB) towards smoking-related stimuli. We investigated whether combining an AB modification paradigm (ABM) with transcranial alternating current stimulation (tACS) applied over the dorsolateral prefrontal cortex (DLPFC) reduces the AB towards smoking-related stimuli, as well as craving level and impulsive choices. Methods: In a sham-controlled, crossover preliminary study, 19 subjects with TUD received two stimulation arms: 1) active tACS (10 Hz, 2 mA, 30 min) combined with ABM and 2) sham tACS combined with ABM, in a randomized order, separated by one week. AB towards smoking cues during passive observation of smoking and neutral cues was assessed with an eye-tracking device and reactions times at a visual-probe task. Craving level was measured with the Questionnaire of Smoking Urges. Impulsive choices were assessed with the delay discounting task. Results: Active tACS combined with ABM reduced the amount of time spent looking at smoking-related pictures (p = 0.03), prevented the increase of self-reported desire to smoke (p = 0.026), and reduced the proportion of impulsive choices (p = 0.049), compared to sham tACS combined with ABM. No significant effects were reported on other craving dimensions and on AB based on reaction times. Conclusions: These preliminary findings suggest that combining tACS with ABM may help smokers who wish to quit by reducing the desire to smoke, attention to smoking-cues, and impulsive decision-making

Differential effects of central administration of relaxin-3 on food intake and hypothalamic neuropeptides in male and female rats

Relaxin-3 (RLN3) is an orexigenic neuropeptide that produces sex-specific effects on food intake by stronger stimulation of feeding in female compared with male rats. This study determined which hypothalamic nuclei and associated neuropeptides may be involved in the sex-specific orexigenic effects of RLN3. Relaxin-3 (800 pmol) or vehicle was injected into the lateral ventricle of female and male rats. Food and water intake were measured after the first injection, and rats were euthanized after the second injection to determine the mRNA expression of the hypothalamic neuropeptides. Food but not water intake showed sex-specific effects of RLN3. Stimulation of food intake by RLN3 was significantly higher in female than in male rats. No effect of RLN3 injection was found on c-fos mRNA expression in the arcuate, dorsomedial and ventromedial hypothalamic nuclei. Increased c-fos mRNA expression was observed in the paraventricular hypothalamic nucleus (PVN) in both sexes and in the lateral hypothalamic area (LHA) in female rats. Relaxin-3 injections led to a sex-nonspecific increase in the expression of oxytocin mRNA in the magnocellular PVN. Conversely, RLN3-induced expression of anorexigenic neuropeptide arginine vasopressin (AVP) was significantly higher in the parvocellular PVN in male compared with female rats. Finally, RLN3 administration significantly increased the expression of orexin (ORX) mRNA in the LHA in female but not in male rats. Stronger expression of anorexigenic AVP in the PVN in male rats and increased expression of ORX in the LHA in female rats may contribute to stronger orexigenic effects of RLN3 in female rats compared with male rats