A paraventricular thalamus to insular cortex glutamatergic projection gates "emotional" stress-induced binge eating in females.

It is well-established that stress and negative affect trigger eating disorder symptoms and that the brains of men and women respond to stress in different ways. Indeed, women suffer disproportionately from emotional or stress-related eating, as well as associated eating disorders such as binge eating disorder. Nevertheless, our understanding of the precise neural circuits driving this maladaptive eating behavior, particularly in women, remains limited. We recently established a clinically relevant model of 'emotional' stress-induced binge eating whereby only female mice display binge eating in response to an acute "emotional" stressor. Here, we combined neuroanatomic, transgenic, immunohistochemical and pathway-specific chemogenetic approaches to investigate whole brain functional architecture associated with stress-induced binge eating in females, focusing on the role of Vglut2 projections from the paraventricular thalamus (PVTVglut2+) to the medial insular cortex in this behavior. Whole brain activation mapping and hierarchical clustering of Euclidean distances revealed distinct patterns of coactivation unique to stress-induced binge eating. At a pathway-specific level, PVTVglut2+ cells projecting to the medial insular cortex were specifically activated in response to stress-induced binge eating. Subsequent chemogenetic inhibition of this pathway suppressed stress-induced binge eating. We have identified a distinct PVTVglut2+ to insular cortex projection as a key driver of "emotional" stress-induced binge eating in female mice, highlighting a novel circuit underpinning this sex-specific behavior.

Piracetam attenuates binge eating disorder related symptoms in rats.

Binge eating disorder (BED) is a stress-related disorder characterized by acute episodes of excessive food intake. Piracetam, a nootropic agent has been reported to show several other neuropharmacological properties. The present study, evaluated the pharmacological effect of piracetam (200 mg/kg i.p.) on BED in female rats, induced by free access to palatable cookies for 2 h on alternate days. BED was confirmed by an increase in binge eating behavior and weight gain. BED leads to anxiety, cognitive and memory deficits, as evaluated by EPM (Elevated plus maze), OFT (open field test), and Y-maze tests. Increased levels of plasma corticosterone (CORT), glutamate in nucleus accumbens (NAC), hypothalamus (HYP) and prefrontal cortex (PFC) indicate stress and excitotoxicity. Moreover, it was observed that the levels of dopamine were higher in NAC and PFC, and less in HYP which may be responsible for motivational behavior for palatable feeding and cognitive deficits. More surprisingly, feeding behaviour regulating hormones namelyleptin was increased and ghrelin level was decreased in BED. Further, level of acetylcholine which regulates cognitive behaviour was compromised in BED. Piracetam significantly decreased binge eating behavior and associated body weight and regulated the levels of concerned neurotransmitters in respective regions. However, piracetam did not alter normal feeding behavior in the fast-refed model. Further, piracetam showed brain region-specific decrease in vascular endothelial growth factor expression. Piracetam showed anxiolytic activity and also alleviated cognitive deficit observed in BED. Hence, preclinical evidence indicates the potential use of piracetam for the treatment of BED.

Role of relaxin-3/RXFP3 system in stress-induced binge-like eating in female rats.

Binge eating is frequently stimulated by stress. The neuropeptide relaxin-3 (RLN3) and its native receptor RXFP3 are implicated in stress and appetitive behaviors. We investigated the dynamics of the central RLN3/RXFP3 system in a newly established model of stress-induced binge eating. Female Sprague-Dawley rats were subjected to unpredictable intermittent 1-h access to 10% sucrose. When sucrose intake stabilized, rats were assessed for consistency of higher or lower sucrose intake in response to three unpredictable episodes of foot-shock stress; and assigned as binge-like eating prone (BEP) or binge-like eating resistant (BER). BEP rats displayed elevated consumption of sucrose under non-stressful conditions (30% > BER) and an additional marked increase in sucrose intake (60% > BER) in response to stress. Conversely, sucrose intake in BER rats was unaltered by stress. Chow intake was similar in both phenotypes on 'non-stress' days, but was significantly reduced by stress in BER, but not BEP, rats. After stress, BEP, but not BER, rats displayed a significant increase in RLN3 mRNA levels in the nucleus incertus. In addition, in response to stress, BEP, but not BER, rats had increased RXFP3 mRNA levels in the paraventricular and supraoptic nuclei of the hypothalamus. Intracerebroventricular administration of a selective RXFP3 antagonist, R3(B1-22)R, blocked the stress-induced increase in sucrose intake in BEP rats and had no effect on sucrose intake in BER rats. These results provide important evidence for a role of the central RLN3/RXFP3 system in the regulation of stress-induced binge eating in rats, and have therapeutic implications for eating disorders.

2-Hydroxyestradiol enhances binge onset in female rats and reduces prefrontal cortical dopamine in male rats.

Women are more likely to suffer from a bingeing-related eating disorder, which is surprising, since estradiol reduces meal size and is associated with reduced binge frequency. This apparent contradiction may involve the estradiol metabolite, 2-hydroxyestradiol. We previously reported that female rats had faster escalations in shortening intake during the development of bingeing than did males, but acute administration of 2-hydroxyestradiol increased the intake of vegetable shortening to a greater extent in male rats once bingeing was established. Here, we report two separate studies that follow up these previous findings. In the first, we hypothesized that chronic exposure to 2-hydroxyestradiol would promote escalation of bingeing during binge development in ovariectomized female rats. In the second, we hypothesized that acute exposure to 2-hydroxyestradiol would enhance dopamine signaling in the prefrontal cortex after bingeing was established in male rats. In study 1, non-food-deprived female rats were separated into 3 groups: ovariectomized (OVX) with chronic 2-hydroxyestradiol supplementation (E), OVX with vehicle supplementation (O), and intact with vehicle (I). Each group was given access to an optional source of dietary fat (shortening) on Mon, Wed, and Fri for 4 weeks. 2-hydroxyestradiol supplementation prevented OVX-induced weight gain and enhanced escalation of shortening intake over the four-week period (ps<0.05). Additionally, in week 4, rats in the E group ate significantly more shortening than I controls, less chow than either the O or I group, and had a higher shortening to chow ratio than O or I (ps<0.05). Study 2 indicated that acute injection of 2-hydroxyestradiol abolished shortening-evoked dopamine efflux in the prefrontal cortex of bingeing male rats (p<0.05). Together, these studies indicate that 2-hydroxyestradiol can exacerbate bingeing as it develops and can suppress dopamine signaling in the prefrontal cortex once bingeing is established.

Prenatal choline supplementation mitigates behavioral alterations associated with prenatal alcohol exposure in rats.

BACKGROUND: Prenatal alcohol exposure can alter physical and behavioral development, leading to a range of fetal alcohol spectrum disorders. Despite warning labels, pregnant women continue to drink alcohol, creating a need to identify effective interventions to reduce the severity of alcohol's teratogenic effects. Choline is an essential nutrient that influences brain and behavioral development. Recent studies indicate that choline supplementation can reduce the teratogenic effects of developmental alcohol exposure. The present study examined whether choline supplementation during prenatal ethanol treatment could mitigate the adverse effects of ethanol on behavioral development. METHODS: Pregnant Sprague-Dawley rats were intubated with 6 g/kg/day ethanol in a binge-like manner from gestational days 5-20; pair-fed and ad libitum chow controls were included. During treatment, subjects from each group were intubated with either 250 mg/kg/day choline chloride or vehicle. Spontaneous alternation, parallel bar motor coordination, Morris water maze, and spatial working memory were assessed in male and female offspring. RESULTS: Subjects prenatally exposed to alcohol exhibited delayed development of spontaneous alternation behavior and deficits on the working memory version of the Morris water maze during adulthood, effects that were mitigated with prenatal choline supplementation. Neither alcohol nor choline influenced performance on the motor coordination task. CONCLUSIONS: These data indicate that choline supplementation during prenatal alcohol exposure may reduce the severity of fetal alcohol effects, particularly on alterations in tasks that require behavioral flexibility. These findings have important implications for children of women who drink alcohol during pregnancy.

Disorders of fuel metabolism: medical complications associated with starvation, eating disorders, dietary fads, and supplements.

Disorders of fuel metabolism as they relate to abnormal fuel intake,abnormal fuel expenditure, and dietary supplements are the focus of this article. The emergency physician should be aware of the medical complications that can occur as a result of starvation states,eating disorders, fad diets, hypermetabolic states, and ergogenic aids. Knowledge and understanding of the complications associated with these disorders will facilitate the diagnosis and management of patients who present to the emergency department with any of the disorders reviewed.

Hypothalamic digoxin, hemispheric chemical dominance, and eating behavior.

The isoprenoid pathway produces an endogenous membrane Na+-K+ ATPase inhibitor, digoxin, which can regulate neurotransmitter and amino acid transport. Digoxin synthesis and neurotransmitter patterns were assessed in eating disorders. The patterns were compared in those with right hemispheric and left hemispheric dominance. The serum HMG CoA reductase activity, RBC membrane Na+-K+ ATPase activity, serum digoxin, magnesium, tryptophan catabolites (serotonin, quinolinic acid, strychnine, and nicotine), and tyrosine catabolites (morphine, dopamine, and noradrenaline) were measured in anorexia nervosa, bulimia nervosa, right hemispheric dominant, left hemispheric dominant, and bihemispheric dominant individuals. Digoxin synthesis was increased with upregulated tryptophan catabolism and downregulated tyrosine catabolism in those with anorexia nervosa and right hemispheric chemical dominance. Digoxin synthesis was reduced with downregulated tryptophan catabolism and upregulated tyrosine catabolism in those with bulimia nervosa and left hemispheric chemical dominance. The membrane Na+-K+ ATPase activity and serum magnesium were decreased in anorexia nervosa and right hemispheric chemical dominance while they were increased in bulimia nervosa and left hemispheric chemical dominance. Hypothalamic digoxin and hemispheric chemical dominance play a central role in the regulation of eating behavior. Anorexia nervosa represents the right hemispheric chemically dominant/hyperdigoxinemic state and bulimia nervosa the left hemispheric chemically dominant/hypodigoxinemic state.

Impact of anorexia, bulimia and obesity on the gynecologic health of adolescents.

Dieting behaviors and nutrition can have an enormous impact on the gynecologic health of adolescents. Teenaged patients with anorexia nervosa can have hypothalamic suppression and amenorrhea. In addition, these adolescents are at high risk of osteoporosis and fractures. Unfortunately, data suggest that estrogen replacement, even in combination with nutritional supplementation, does not appear to correct the loss of bone density in these patients. Approximately one half of adolescents with bulimia nervosa also have hypothalamic dysfunction and oligomenorrhea or irregular menses. Generally, these abnormalities do not impact bone density and can be regulated with interval dosing of progesterone or regular use of oral contraceptives. In contrast, the obese adolescent with menstrual irregularity frequently has anovulation and hyperandrogenism, commonly referred to as polycystic ovary syndrome. Insulin resistance is thought to play a role in the pathophysiology of this condition. While current management usually involves oral contraceptives, future treatment may include insulin-lowering medications, such as metformin, to improve symptoms. Because all of these patients are potentially sexually active, discussion about contraception is important.

Biological correlates of binge eating.

Eating disorders are associated with numerous biological perturbations; however, sorting out cause from effect is difficult. Neuroendocrine and metabolic abnormalities are seen in both anorexia nervosa and bulimia nervosa, but they have not been described in binge eating disorder, in which neither starvation nor compensatory behaviors are present. Although these findings may reflect biologic differences among subgroups of binge eaters, an alternative explanation is that many of the biological correlates of binge eating are the result of metabolic derangement secondary to starvation and/or purging. The identification of binge eating disorder provides an opportunity to study the causes and concomitants of binge eating in the absence of compensatory behaviors.

Bone metabolism and osteopenia in eating disorders.

Bone loss is a potentially debilitating condition in women with eating disorders. Complications may include failure to achieve peak bone mass, increased risk of premature fractures, and inability to reach the height potential. We therefore conducted a comprehensive evaluation of 58 women with anorexia nervosa (AN), bulimia (BUL) and anorexia/bulimia (AB), comparing bone mineral density (BMD) to physical parameters, biochemical indices, and markers for bone formation and resorption. BMDs were significantly lower in patients with AN than in those with AB and BUL, and overt osteopenia was uncommon in AB and BUL. Hypercortisolism was the best laboratory marker to assess the risk of osteopenia in patients with AN. However, there were no associated changes in bone formation or resorption parameters. No direct correlation was found between BMD and body mass index, estrogen deficiency, tubular reabsorption of phosphorus, serum vitamin D, PTH, BGP, or alkaline phosphatase levels. Although the prognosis for complete recovery to normal BMD is poor, treatment of the underlying depressive disorder, improvement in nutrition with increased weight, and spontaneous resumption of menses are associated with restoring bone health.

Neurochemistry of bulimia nervosa.

Normal weight bulimia nervosa, a disorder of unknown etiology, is characterized by bingeing and purging behavior, disturbances of mood, and neuroendocrine abnormalities. Bulimic women have alterations of neurotransmitter systems known to contribute to the modulation of feeding, mood, and neuroendocrine function. Bulimic patients have increased cerebrospinal fluid concentrations of peptide YY (PYY), a peptide which is a potent stimulant of feeding in experimental animals. It has been suggested that increased brain PYY activity could contribute to the powerful and uncontrollable drive of bulimic patients to binge. It also has been reported that bulimics have impaired satiety and secretion of cholecystokinin, a peptide known to induce satiety and reduce food intake in animals and humans. Most data show that bulimic women have alterations of serotonin and norepinephrine activity. In animals, serotonin appears to have effects on eating behavior (inhibition) that are opposite to the actions of endogenous norepinephrine (activation) at alpha 2 receptors in the hypothalamus. Bingeing behavior is consistent with an overactivity of the hypothalamic alpha-noradrenergic system, an underactivity of hypothalamic serotonergic systems, or a combination of both defects. In summary, it is possible that bulimic patients have a trait-related disturbance of one or more neurotransmitter systems that could cause their appetitive dysregulation. Alternatively, these neurotransmitter disturbances may be secondary to extremes of dietary intake. Nonetheless, such neurotransmitter disturbances may contribute to a high recidivism rate. That is, bulimic patients could enter a vicious cycle in which pathologic feeding sustains and provokes continued pathologic feeding behavior. Moreover, the self-reinforcing effects of bulimia, such as decreased anxiety or food craving, may be mediated through behavior-induced changes in neurotransmission.

[The role of serotonin in normal appetite regulation and in the pathogenesis of anorexia/bulimia]. / Serotonins rolle i normal appetittregulering og i patogenesen ved anorexi/bulimi.

Evidence accumulated over the past two decades indicates the existence of several neurochemical systems that influence feeding behavior. The central region regulating appetite is thought to be in the hypothalamus, where different monoaminergic systems are localized. It has been suggested that altered function in these systems is taking part in the pathogenesis of anorexia and bulimia nervosa. According to these theoretical principles and to the development of specific monoaminergic and anti-monoaminergic drugs, the pharmacological treatment of eating disorders can become more successful in the future. This article discusses the role of serotonin in appetite regulation and presents new evidence that a dysfunction in hypothalamic serotonergic pathways can be an important part of the pathogenesis of anorexia and bulimia nervosa.

The effect of bulimia upon diet, body fat, bone density, and blood components.

A study was conducted to determine baseline data for dietary intake, percent body fat, bone mineral density, and blood components in women with bulimia. Eight bulimic and 10 control subjects completed the study. Each subject was assessed for a 3-day diet, frequency of purge, menstrual history, percent body fat, bone mineral density, by dual photon absorptiometry, and blood components. Mean age, height, and weight of subjects were similar. Percent body fat was similar for both groups. Vomiting was the predominant method of purge. Folacin intake was found to be significantly (p less than .05) lower in bulimic subjects. Control subjects consumed greater quantities of vitamin/mineral supplements than the bulimic subjects. Bone mineral density (gm/cm2) was found to be lower in bulimic subjects. Mean hemoglobin (gm/L [gm/dL]) levels were found to be significantly (p less than .01) higher in control subject. The data indicate that the method and duration of purge behavior could influence bone mineral density and blood components.

[Bulimia, bulimia-anorexia and nocturnal secretion of melatonin and cortisol]. / Boulimie, boulimie-anorexie et sécrétion nocturne de mélatonine et de cortisol.

The authors compared nocturnal variations of melatonin (MT) and cortisol levels in subjects with bulimia (n = 12), 6 with a normal body weight and 6 with anorexia nervosa, as well as 6 control subjects. The hypothesis, formulated for anorexia nervosa, that a decrease of noradrenergic activity induces a decrease of pineal activity, therefore a decrease of melatonin secretion, was not confirmed by our study. Moreover, in subjects with bulimia in the absence of anorexia nervosa, no significant decrease of nocturnal melatonin secretion was reported. Significant differences were due to cortisol variations when comparing MTmax/Cmin ratios. Melatonin did not add any complementary biological cue for diagnostic assessment for subjects with eating disorder and depression. The results of this study suggest that melatonin does not appear to be a useful biological marker in bulimia.