Learning and the motivation to eat: forebrain circuitry

Appetite and eating are not only controlled by energy needs, but also by extrinsic factors that are not directly related to energy balance. Environmental signals that acquire motivational properties through associative learning—learned cues—can override homeostatic signals and stimulate eating in sated states, or inhibit eating in states of hunger. Such influences are important, as environmental factors are believed to contribute to the increased susceptibility to overeating and the rise in obesity in the developed world. Similarly, environmental and social factors contribute to the onset and maintenance of anorexia nervosa and other eating disorders through interactions with the individual genetic background. Nevertheless, how learning enables environmental signals to control feeding, and the underlying brain mechanisms are poorly understood. We developed two rodent models to study how learned cues are integrated with homeostatic signals within functional forebrain networks, and how these networks are modulated by experience. In one model, a cue previously paired with food when an animal was hungry induces eating in sated rats. In the other model, food-deprived rats inhibit feeding when presented with a cue that signals danger, a tone previously paired with footshocks. Here evidence will be reviewed that the forebrain network formed by the amygdala, lateral hypothalamus and medial prefrontal cortex mediates cue-driven feeding, while a parallel amygdalar circuitry mediates suppression of eating by the fear cue. Findings from the animal models may be relevant for understanding aspects of human appetite and eating, and maladaptive mechanisms that could lead to overeating and anorexia.     

To eat or not to eat: type 2 immunity controls food avoidance behavior

Growing evidence suggests that food allergies are regulated by neuroimmune interactions. However, the underlying molecular mechanisms remain unclear. Plum et al. and Florsheim et al. identify IgE-mediated mast cell activation, leukotrienes, and growth differentiating factor 15 (GDF15) as key regulators of the avoidance response to food allergens in mice.     

To eat or not to eat: neuronal metabolism, mitophagy, and Parkinson's disease

Neurons are exquisitely dependent upon mitochondrial respiration to support energy-demanding functions. Mechanisms that regulate mitochondrial quality control have recently taken center stage in Parkinson's disease research, particularly the selective degradation of mitochondria by autophagy (mitophagy). Unlike other cells, neurons show limited glycolytic potential, and both insufficient and excessive mitophagy have been linked to neurodegeneration. Kinases implicated in regulating mammalian mitophagy include extracellular signal-regulated protein kinases (ERK1/2) and PTEN-induced kinase 1 (PINK1). Increased expression of full-length PINK1 enhances recruitment of parkin to chemically depolarized mitochondria, resulting in rapid mitochondrial clearance in transformed cell lines. As parkin and PINK1 mutations cause autosomal recessive parkinsonism, potential defects in clearing dysfunctional mitochondria may contribute to mitochondrial abnormalities in disease. Given the unique features of metabolic regulation in neurons, however, mechanisms regulating mitochondrial network stability and the threshold for mitophagy are likely to vary from cells that preferentially utilize aerobic glycolysis. Moreover, removal of the entire mitochondrial complement may represent part of a neuronal cell death pathway. Future work utilizing physiological injuries that affect only a subset of mitochondria would help to elucidate whether defective recognition of damaged mitochondria, or alternatively, inability to maintain or generate healthy mitochondria, play the major roles in parkinsonian neurodegeneration.     

Body mass index and the risk of infection - from underweight to obesity

BackgroundNutritional status is a well-known risk factor for metabolic and endocrine disorders. Recent studies suggest that dietary intake also affects immune function and as a consequence infection risk.AimsThis reviews aims to give an overview on the effect of body weight on infection rate at different periods of life.SourcesClinically relevant prospective, cross-sectional and case–control community-based studies are summarized.ContentIn children and adolescents underweight is a significant risk factor for infection especially in developing countries, probably reflecting malnutrition and poor hygienic standards. Data from industrialized countries suggest that infection rate is also increased in obese children and adolescents. Similarly, several studies suggest a U-shaped increased infection rate in both underweight and obese adults. In the latter, infections of the skin and respiratory tract as well as surgical-site infections have consistently been reported to be more common than in normal-weight participants. Paradoxically, mortality of critically ill patients was reduced in obesity in some studies.ImplicationsSeveral studies in children or adults suggest that both underweight and obesity are associated with increased infection risk. However, confounding factors such as malnutrition, hygienic status and underlying disease or co-morbidities might aggravate accurate assessment of the impact of body weight on infection risk.     

No association of the Arg51Gln and Leu72Met polymorphisms of the ghrelin gene with anorexia nervosa or bulimia nervosa

Genetic factors likely contribute to the biological vulnerability to anorexia nervosa (AN) and bulimia nervosa (BN). We investigated whether the Arg51Gln and/or the Leu72Met gene polymorphisms of the human ghrelin, a peptide involved in the regulation of eating behavior, were associated to AN and/or BN. Two-hundred-ninety-two Caucasian women (114 with BN, 59 with AN and 119 healthy controls) participated into the study. No significant differences were found in the frequencies of the Arg51Gln and the Leu72Met ghrelin gene variants among patients with AN or BN and healthy controls. Moreover, no significant differences emerged in eating-related phenotypic variables between patients carrying the Leu72Met genotype as compared to those with the Leu72Leu genotype. These results suggest that the Arg51Gln and the Leu72Met polymorphisms of the human ghrelin gene do not contribute to the genetic susceptibility to AN and BN.     

First Account of Psychological Changes Perceived by a Female with Congenital Leptin Deficiency upon Treatment with Metreleptin

Two psychiatric interviews of a 39-year old female with congenital leptin deficiency were conducted to define psychological changes 14 and 165 days after initiation of treatment with human recombinant leptin (metreleptin). The most pronounced initial experience related to the reduced preoccupation with food. An improved mood was reported by the patient, which she associated with this reduced preoccupation. Her mood remained elevated upon recontact, whereas she was no longer preoccupied with food. Overall, the interviews provide a vivid account of the subjective experiences upon the initiation of treatment. Some of the findings bear a resemblance to those reported recently in patients with anorexia nervosa who were treated with metreleptin for 1–3 weeks. This case report provides further evidence that metreleptin has strong psychopharmacological effects in patients with absolute or relative leptin deficiency. We strongly recommend profound psychological examinations of patients with congenital leptin deficiency at baseline and after intitiation of treatment with human recombinant leptin to gain further insight into the functions affected by this hormone.     

A systematic review of the literature on family functioning across all eating disorder diagnoses in comparison to control families

The objectives of this review were to systematically identify and evaluate quantitative research comparing family functioning (a) in eating disorder families with control families, (b) in families with different eating disorder diagnoses (c) perceptions of different family members and (d) the relationship between family functioning and recovery. This adds to the findings of previous reviews of family functioning by including data from control families, the range of diagnoses, and focusing on recovery. Findings were considered in relation to models of family functioning.     

“Glass fairies” and “bone children”: Adolescents and young adults with anorexia nervosa show positive reactions towards extremely emaciated body pictures measured by the startle reflex paradigm

In this study, we investigated the emotional processing of extremely emaciated body cues in adolescents and young adults with (n = 36) and without (n = 36) anorexia nervosa (AN), introducing a new picture type, which was taken from websites that promote extreme thinness and is targeted specifically at adolescents interested in extreme thinness. A startle reflex paradigm was used for implicit reactions, while a self‐assessment instrument was used for subjective responses. We found a significant group difference with a startle inhibition (appetitive response) among the patients and a startle potentiation (aversive response) among the controls, whereas no such difference for subjective measures was found. The results are in contrast to previous studies, which proposed a general failure to activate the appetitive motivational system in AN, but in keeping with findings from other addictions, where the same response pattern has been found. Implications for prevention and therapy are discussed.     

Quantity not composition of dietary fats represents the dominant contributor to experimental obesity: Relevance to human pathophysiology

Plant fats are low in saturated fats but high in unsaturated fats compared to animal fats, and are supposedly less obesogenic. This study compared the obesogenic effects of plant and animal derived fatty diets in Wistar rats. Rats of each gender were divided into three dietary (standard chow (SC), high fat diet rich in animal fat (HFDaf) and a high fat diet rich in plant fat (HFDpf)) groups of ten each and fed for 17 weeks. Anthropometric, Adiposity and nutritive variables were assessed using standard methods. Comparing HFDpf to HFDaf: Abdominal circumference (AC),initial feed intaken (IFI), final feed intake(FFI), final body weight (FBW), white adipose tissue (WAT) were increased but brown adipose tissue (BAT) decreased in male rats fed with HFDpf; also, there were increased body length, IFI, FFI but decreased AC, FBW, BAT in female rats fed with HFDpf. Comparing male to female rats: Thoracic circumference, IFI, FFI, energy intake were increased while Adiposity index decreased across diet groups in male rats; the AC, FBW increased while WAT, BAT decreased in HFDpf fed group, also, BAT was increased but AC, FBW decreased in HFDaf fed group in male rats. Palatability and high feed efficiency of consumed diets were more associated with obesogenic risk than just the level of saturation. Therefore, Obesogenic effects of fatty diets in both genders is more dependent on the quantity (amount) of fatty diet consumed than the dietary fat composition alone.     

Effects of diet and obesity on body weight regulation during pregnancy and lactation in the rat

The effects of obesity level and cafeteria feeding were studied in rats during pregnancy and lactation. The non-fetal weight gain in pregnancy was three times greater with the cafeteria diet than with chow, indicating that fat deposition is not regulated at an optimal level during pregnancy. There was a strong negative correlation between postpartum weight and weight change during lactation. Obese rats were finicky in that their weight changes in lactation were exaggerated when the diet was changed between pregnancy and lactation. Pup growth rate was proportional to maternal energy intake but in this experiment not related to maternal protein, fat or carbohydrate intake. In obese rats switched to chow, intake was inadequate for normal pup growth. Thus, the weight gains in pregnancy are not regulated at a set level, and the weight change in lactation appears to compensate for the weight gain in pregnancy.     

Perifornical fiber system mediates VMH electrically-induced suppression of feeding

Fiber pathways mediating the cessation of food ingestion during continuous low-level electrical stimulation of the ventromedial region of the hypothalamus (VMH) were appraised in food-deprived male rats using knife cuts. Parasagittal knife cuts in the medial perifornical area of the hypothalamus produced much larger increases in threshold current intensities for the inhibition of feeding than did cuts in the lateral perifornical hypothalamus. These findings indicate that fiber pathways critical to the inhibitory feeding effect of continuous VMH electrical stimulation traverse the perifornical hypothalamus but not the lateral hypothalamus. A comparison of these and other results demonstrates an anatomical similarity between the fiber pathways mediating VMH electrically-induced inhibition of feeding and hypothalamic hyperphagia following lesions or knife cuts. The nature of the inhibitory feeding effect of VMH electrical stimulation is also addressed and behavioral observations strongly supportive of a specific anorectic effect produced by the stimulation are reported.     

Brief daily postpartum separations from the litter alter dam response to psychostimulants and to stress

Neonatal handling induces several behavioral and neurochemical alterations in pups, including decreased responses to stress and reduced fear in new environments. However, there are few reports in the literature concerning the behavioral effects of this neonatal intervention on the dams during the postpartum period. Therefore, the aim of the current study was to determine if brief postpartum separation from pups has a persistent impact on the dam''s stress response and behavior. Litters were divided into two neonatal groups: 1) non-handled and 2) handled [10 min/day, from postnatal day (PND) 1 to 10]. Weaning occurred at PND 21 when behavioral tasks started to be applied to the dams, including sweet food ingestion (PND 21), forced swimming test (PND 28), and locomotor response to a psychostimulant (PND 28). On postpartum day 40, plasma was collected at baseline for leptin assays and after 1 h of restraint for corticosterone assay. Regarding sweet food consumption, behavior during the forced swimming test or plasma leptin levels did not differ between dams briefly separated and non-separated from their pups during the postpartum period. On the other hand, both increased locomotion in response to diethylpropion and increased corticosterone secretion in response to acute stress were detected in dams briefly separated from their pups during the first 10 postnatal days. Taken together, these findings suggest that brief, repeated separations from the pups during the neonatal period persistently impact the behavior and induce signs of dopaminergic sensitization in the dam.     

Intact regulation of protein intake during the development of hypothalamic or genetic obesity in rats

Adult female rats made hyperphagic with bilateral lesions of the medial hypothalamus as well as spontaneously hyperphagic adult female rats of the Zucker strain were studied for their abilities to regulate dietary protein and energy intakes. This was accomplished by permitting both models of animal obesity to select freely between two isocaloric diets containing 10% vs 60% by weight casein (protein) for at least one month. Compared to appropriate control groups, both experimental groups became obese by consuming more of the low protein diet and less of the high protein diet. The overall effect of this selection pattern was an excessive intake of energy in the form of carbohydrate and fat while maintaining control levels of protein intake. These data imply that the stimulus for hyperphagia in both animal models of obesity is some physiological and/or behavioral error in energy regulation but not protein regulation.     

Understanding the reward system functioning in anorexia nervosa: Crucial role of physical activity

Hyperactivity is a potential neurobiological marker and a core psychopathological trait in anorexia nervosa (AN). We investigated the processing of hyperactivity-related information in fifteen AN patients, 15 athletes and 15 non-athletes to examine if they represent disorder-related reward information using eye tracking. We assessed the extent of individually performed physical activity, mood, trait reward sensitivity and serum leptin levels. Results revealed a pronounced bias in overall attentional engagement toward stimuli associated with physical activity in patients and athletes as compared to non-athletes. In patients, relevant correlations were found: trait reward sensitivity and attentional orienting were strongly correlated and amount of physical activity correlated with attentional orienting and engagement. Compared to non-athletes, patients and athletes rated exercise stimuli as more pleasant. Findings suggest that exercise-related stimuli are perceived as rewarding by AN patients. Positive motivational valence of physical activity might contribute to disorder development and maintenance.     

The rise, fall, and resurrection of the ventromedial hypothalamus in the regulation of feeding behavior and body weight

Early researchers found that lesions of the ventromedial hypothalamus (VMH) resulted in hyperphagia and obesity in a variety of species including humans, which led them to designate the VMH as the brain's "satiety center." Many researchers later dismissed a role for the VMH in feeding behavior when Gold claimed that lesions restricted to the VMH did not result in overeating and that obesity was observed only with lesions or knife cuts that extended beyond the borders of the VMH and damaged or severed the ventral noradrenergic bundle (VNAB) or paraventricular nucleus (PVN). However, anatomical studies done both before and after Gold's study did not replicate his results with lesions, and in nearly every published direct comparison of VMH lesions vs. PVN or VNAB lesions, the group with VMH lesions ate substantially more food and gained twice as much weight. Several other important differences have also been found between VMH and both PVN and VNAB lesion-induced obesity. Concerns regarding (a) motivation to work for food and (b) the effects of nonirritative lesions have also been addressed and answered in many studies. Lesion studies with weanling rats and adult pair-tube-fed rats, as well as recent studies of knockout mice deficient in the orphan nuclear receptor steroidogenic factor 1, indicate that VMH lesion-induced obesity is in large part a metabolic obesity (due to autonomic nervous system disorders) independent of hyperphagia. However, there is ample evidence that the VMH also plays a primary role in feeding behavior. Neuroimaging studies in humans have shown a marked increase in activity in the area of the VMH during feeding. The VMH has a large population of glucoresponsive neurons that dynamically respond to blood glucose levels and numerous histamine, dopamine, serotonin, and GABA neurons that respond to feeding-related stimuli. Recent studies have implicated melanocortins in the VMH regulation of feeding behavior: food intake decreases when arcuate nucleus pro-opiomelanocortin (POMC) neurons activate VMH brain-derived neurotrophic factor (BDNF) neurons. Moderate hyperphagia and obesity have also been observed in female rats with damage to the efferent projections from the posterodorsal amygdala to the VMH. Hypothalamic obesity can result from damage to either the POMC or BDNF neurons. The concept of hypothalamic feeding and satiety centers is outdated and unnecessary, and progress in understanding hypothalamic mechanisms of feeding behavior will be achieved only by appreciating the different types of neural and blood-borne information received by the various nuclei, and then attempting to determine how this information is integrated to obtain a balance between energy intake and energy output.     

To move or not to move: imperatives modulate action-related verb processing in the motor system

It has been suggested that the processing of action-related words involves activation of the motor circuitry. Using fMRI (functional magnetic resonance imaging), the current study further explored the interaction between action and language by investigating whether the linguistic context, in which an action word occurs, modulates motor circuitry activity related to the processing of action words. To this end, we examined whether the presentation of hand action-related verbs as positive or negative imperatives, for example, “Do grasp” or “Don't write,” modulates neural activity in the hand area of primary motor cortex (M1) or premotor cortex (Pm). Subjects (n = 19) were asked to read silently the imperative phrases, in which both meaningful action verbs and meaningless pseudo-verbs were presented, and to decide whether they made sense (lexical decision task). At the behavioral level, response times in the lexical decision task were significantly longer for negative, compared to positive, imperatives. At the neural level, activity was differentially decreased by action verbs presented as negative imperatives for the premotor and the primary motor cortex of both hemispheres. The data suggest that context (here: positive vs. negative imperatives), in which an action verb is encountered, modulates the neural activity within key areas of the motor system. The finding implies that motor simulation (or motor planning) rather than semantic processing per se may underlie previously observed motor system activation related to action verb processing. Furthermore, the current data suggest that negative imperatives may inhibit motor simulation or motor planning processes.