Neural Food Reward Processing in Successful and Unsuccessful Weight Maintenance.

OBJECTIVE: Weight loss maintenance is one of the biggest challenges in behavioral weight loss programs. The present study aimed to examine metabolic influences on the mesolimbic reward system in people with successful and unsuccessful long-term weight loss maintenance. METHODS: Thirty-three women with obesity at least 6 months after the completion of a diet were recruited: seventeen women were able to maintain their weight loss, whereas sixteen showed weight regain. Using functional magnetic resonance imaging in combination with the assessment of appetite-regulating hormones, neural reward processing during hunger and satiety was investigated. An incentive delay task was employed to investigate the expectation and receipt of both food-related and monetary reward. RESULTS: Only participants with successful weight loss maintenance showed a satiety-induced attenuation of brain activation during the receipt of a food-related reward. Furthermore, in successful weight loss maintenance, the attenuation of active ghrelin levels was related to brain activation in response to food-related reward anticipation during satiety. CONCLUSIONS: The findings suggest that an attenuated influence of satiety signaling on the neural processing of food-related reward contributes to unsuccessful weight loss maintenance. Thus, intact satiety signaling to the mesolimbic reward system may serve as a promising target for tackling weight cycling.

Integration of homeostatic signaling and food reward processing in the human brain.

BACKGROUND: Food intake is guided by homeostatic needs and by the reward value of food, yet the exact relation between the two remains unclear. The aim of this study was to investigate the influence of different metabolic states and hormonal satiety signaling on responses in neural reward networks. METHODS: Twenty-three healthy participants underwent functional magnetic resonance imaging while performing a task distinguishing between the anticipation and the receipt of either food- or monetary-related reward. Every participant was scanned twice in a counterbalanced fashion, both during a fasted state (after 24 hours fasting) and satiety. A functional connectivity analysis was performed to investigate the influence of satiety signaling on activation in neural reward networks. Blood samples were collected to assess hormonal satiety signaling. RESULTS: Fasting was associated with sensitization of the striatal reward system to the anticipation of food reward irrespective of reward magnitude. Furthermore, during satiety, individual ghrelin levels were associated with increased neural processing during the expectation of food-related reward. CONCLUSIONS: Our findings show that physiological hunger stimulates food consumption by specifically increasing neural processing during the expectation (i.e., incentive salience) but not the receipt of food-related reward. In addition, these findings suggest that ghrelin signaling influences hedonic-driven food intake by increasing neural reactivity during the expectation of food-related reward. These results provide insights into the neurobiological underpinnings of motivational processing and hedonic evaluation of food reward. TRIAL REGISTRATION: ClinicalTrials.gov NCT03081585. FUNDING: This work was supported by the German Competence Network on Obesity, which is funded by the German Federal Ministry of Education and Research (FKZ 01GI1122E).

Intestinal inflammation influences α-MSH reactive autoantibodies: relevance to food intake and body weight.

Autoantibodies reacting with alpha-melanocyte-stimulating hormone (α-MSH), an anorexigenic neuropeptide, are involved in regulation of feeding. In this work we studied if intestinal inflammation (mucositis) may influence α-MSH autoantibodies production relevant to food intake and body weight. Mucositis and anorexia were produced in Sprague-Dawley rats by methotrexate (MTX, 2.5mg/kg/day, for three days, subcutaneously). Plasma levels of total IgG and of α-MSH autoantibodies were measured during and after MTX-induced mucositis and were compared with pair-fed and ad libitum-fed controls. Effects of intraperitoneal injections of rabbit anti-α-MSH IgG (3 or 10 µg/day/rat) on MTX-induced anorexia and on plasma α-MSH peptide concentration were separately studied. Here we show that in MTX rats, intestinal mucositis and anorexia were accompanied by decreased plasma levels of both total IgG and of α-MSH autoantibodies while refeeding was characterized by their elevated levels. In spite of similar food intake in MTX and pair-fed rats, recovery of body weight was delayed by at least 1 week in the MTX group. During refeeding and body weight deficit in MTX rats, α-MSH IgG autoantibody levels correlated negatively with food to water intake ratios. Injections of anti-α-MSH IgG induced a dose-dependent attenuation of food intake and body weight regain in MTX-treated rats accompanied by increased concentrations of α-MSH peptide which correlated positively with plasma levels of α-MSH autoantibodies. These data show that intestinal inflammation, independently from food restriction, affects general humoral immune response which may influence food intake and body weight control via modulation of α-MSH plasma concentration by α-MSH reactive autoantibodies.

Ghrelin reactive autoantibodies in restrictive anorexia nervosa.

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.

Gastric electrical stimulation increases ghrelin production and inhibits catecholaminergic brainstem neurons in rats.

Gastric electrical stimulation (GES) is a new therapeutic option for functional dyspepsia and gastroparesis. In addition to ameliorating nausea and vomiting, GES results in improved appetite which is not always associated with accelerated gastric emptying. To explore the central and peripheral factors underlying GES-associated improvement of appetite we developed a GES model in anaesthetized Wistar rats. During laparotomy, two electrodes were implanted into the stomach and high-frequency low-energy GES (14 Hz, 5 mA) was applied. The effects of 1 h GES were compared with sham stimulation. After GES, c-Fos expression was increased in the mucosal and submucosal layers of the stimulated area (174%). In the stomach, GES increased ghrelin mRNA (178%) and doubled the number of ghrelin-positive cells, resulting in elevated plasma levels of ghrelin (2.3 ± 0.2 vs. 1.6 ± 0.2 ng/mL). In the arcuate nucleus of the hypothalamus, GES increased c-Fos (277%) and agouti-related protein (AgRP) mRNA expression (135%). GES reduced the number of c-Fos-positive cells throughout the nucleus of the solitary tract (between 93 and 75% from rostral to caudal levels) including catecholaminergic neurons (81% at caudal level). Gastric emptying, plasma glucose and heart rate variability were not affected by GES. This study shows that GES may improve appetite via stimulation of main orexigenic pathways, including ghrelin production in the stomach and AgRP in the hypothalamus, as well as by reducing the activity of catecholaminergic brainstem neurons.

Chemotherapy-induced anorexia is accompanied by activation of brain pathways signaling dehydration.

BACKGROUND AND AIMS: Cancer chemotherapy is accompanied by anorexia and mucositis. To clarify the mechanisms of chemotherapy-induced anorexia, we studied the expression of c-fos and appetite-regulating neuropeptidergic and inflammatory mediators in the hypothalamus of rats treated with methotrexate (MTX). METHODS: Sprague-Dawley rats received MTX (2.5mg/kg, subcutaneously) on three consecutive days and were compared with ad libitum- and pair-fed control rats five days after the first injection. RESULTS: MTX administration inhibited food and water intake and induced lean and fat mass losses. MTX also induced mucositis and diarrhea without changes in plasma osmolality. Pair-fed rats lost a similar amount of body weight but had no mucositis or diarrhea. Increased number of c-fos positive hypothalamic vasopressin neurosecretory neurons as well as numerous c-fos positive cells in the subfornical organ and in the organum vasculosum of the lamina terminalis were found in MTX-treated as compared to control or pair-fed rats. In both MTX and pair-fed rats, a decrease of hypothalamic proopiomelanocortin mRNA expression and low plasma levels of interleukin-1ß (IL-1ß) were found reflecting probably the energy deficit. No significant changes of IL-1ß mRNA expression and intensity of microglial staining in the hypothalamus were found in MTX-treated rats. CONCLUSION: The pattern of c-fos expression in the hypothalamus during MTX treatment is similar to that seen with systemic dehydration, which is known to cause anorexia. No evidence of inflammatory origin of anorexia was found, suggesting that chemotherapy accompanied by mucositis and diarrhea may cause anorexia associated with systemic dehydration.

Psychopathological and personality features in primary Sjogren's syndrome--associations with autoantibodies to neuropeptides.

OBJECTIVES: To determine the spectrum of personality and psychopathology features of patients with primary SS (pSS) and explore whether they are linked to disease characteristics as well as the presence of autoantibodies (autoAbs) against neuropeptides. METHODS: Personality and psychopathological variables were determined in 103 pSS patients and 110 healthy controls (HCs). AutoAbs against hypothalamic and pituitary neuropeptides were measured by ELISA in 25 pSS patients and 25 HCs. Data analysis was performed by univariate and multivariate logistic regression models and by comparison with regression models. RESULTS: A higher number of pSS patients reported distinct personality traits (neuroticism, psychoticism and obsessiveness) and psychological distress compared with HCs. After adjustment for personality characteristics and demographics, only hypochondriasis was the main psychopathology feature associated with pSS, suggesting that psychopathological manifestations in the setting of pSS are primarily dependent on premorbid personality characteristics. Although no differences were detected between serum levels of neuropeptide autoAbs in pSS cases and controls, levels of autoAbs against alpha-melanocyte-stimulating hormone (alpha-MSH) correlated with anxiety scores in both groups examined but with higher intercept in pSS subjects. Significant correlations between anxiety score and autoAbs directed against oxytocin and vasopressin were also detected in the pSS patients. CONCLUSIONS: pSS patients exhibit a distinct pattern of personality traits and high levels of psychological distress compared with HCs, which seems to be determined by premorbid personality characteristics. Correlations between anxiety and alpha-MSH autoAbs suggest their potential involvement in anxiety development in both pSS and HCs.

Regulation of feeding and anxiety by alpha-MSH reactive autoantibodies.

alpha-Melanocyte-stimulating hormone (alpha-MSH) is a stress-related neuropeptide involved in the regulation of motivated behavior, appetite and emotion including stimulation of satiety and anxiety. Although autoantibodies (autoAbs) reactive with alpha-MSH have been identified in human subjects and in rats, it remained unknown if these autoAbs are involved in the regulation of feeding and anxiety and if their production is related to stress. Here we show that repeated exposure of rats to anxiolytic mild stress by handling increases the levels and affinity of alpha-MSH reactive IgG autoAbs and that these changes are associated with adaptive feeding and anxiety responses during exposure of rats to a strong stress by food restriction. Importantly, an increase in affinity of alpha-MSH reactive autoAbs was associated with changes of their functional roles from stimulation to inhibition of alpha-MSH-mediated behavioural responses, suggesting that these autoAbs can be a carrier or a neutralizing molecule of alpha-MSH peptide, respectively. Using a model of passive transfer into the brain, we show that alpha-MSH autoAbs affinity purified from blood of rats exposed to repeated mild stress, but not from control rats, are able to increase acutely food intake, suppress anxiety and modify gene expression of hypothalamic neuropeptides in naïve rats. These data provide the first evidence that autoAbs reactive with alpha-MSH are involved in the physiological regulation of feeding and mood, supporting a further role of the immune system in the control of motivated behavior and adaptation to stress.