An orexigenic subnetwork within the human hippocampus.

Only recently have more specific circuit-probing techniques become available to inform previous reports implicating the rodent hippocampus in orexigenic appetitive processing1-4. This function has been reported to be mediated at least in part by lateral hypothalamic inputs, including those involving orexigenic lateral hypothalamic neuropeptides, such as melanin-concentrating hormone5,6. This circuit, however, remains elusive in humans. Here we combine tractography, intracranial electrophysiology, cortico-subcortical evoked potentials, and brain-clearing 3D histology to identify an orexigenic circuit involving the lateral hypothalamus and converging in a hippocampal subregion. We found that low-frequency power is modulated by sweet-fat food cues, and this modulation was specific to the dorsolateral hippocampus. Structural and functional analyses of this circuit in a human cohort exhibiting dysregulated eating behaviour revealed connectivity that was inversely related to body mass index. Collectively, this multimodal approach describes an orexigenic subnetwork within the human hippocampus implicated in obesity and related eating disorders.

Human habit neural circuitry may be perturbed in eating disorders.

Circuit-based mechanisms mediating the development and execution of habitual behaviors involve complex cortical-striatal interactions that have been investigated in animal models and more recently in humans. However, how human brain circuits implicated in habit formation may be perturbed in psychiatric disorders remains unclear. First, we identified the locations of the sensorimotor putamen and associative caudate in the human brain using probabilistic tractography from Human Connectome Project data. We found that multivariate connectivity of the sensorimotor putamen was altered in humans with binge eating disorder and bulimia nervosa and that the degree of alteration correlated with severity of disordered eating behavior. Furthermore, the extent of this circuit aberration correlated with mean diffusivity in the sensorimotor putamen and decreased basal dopamine D2/3 receptor binding potential in the striatum, consistent with previously reported microstructural changes and dopamine signaling mediating habit learning in animal models. Our findings suggest a neural circuit that links habit learning and binge eating behavior in humans, which could, in part, explain the treatment-resistant behavior common to eating disorders and other psychiatric conditions.

Involvement of Ghrelin Dynamics in Stress-Induced Eating Disorder: Effects of Sex and Aging.

Stress, a factor that affects appetite in our daily lives, enhances or suppresses appetite and changes palatability. However, so far, the mechanisms underlying the link between stress and eating have not been fully elucidated. Among the peripherally produced appetite-related peptides, ghrelin is the only orexigenic peptide, and abnormalities in the dynamics and reactivity of this peptide are involved in appetite abnormalities in various diseases and psychological states. This review presents an overview of the research results of studies evaluating the effects of various stresses on appetite. The first half of this review describes the relationship between appetite and stress, and the second half describes the relationship between the appetite-promoting peptide ghrelin and stress. The effects of sex differences and aging under stress on appetite are also described.

Roles for the gut microbiota in regulating neuronal feeding circuits.

The gut microbiota has the capacity to affect host appetite via intestinal satiety pathways, as well as complex feeding behaviors. In this Review, we highlight recent evidence that the gut microbiota can modulate food preference across model organisms. We discuss effects of the gut microbiota on the vagus nerve and brain regions including the hypothalamus, mesolimbic system, and prefrontal cortex, which play key roles in regulating feeding behavior. Crosstalk between commensal bacteria and the central and peripheral nervous systems is associated with alterations in signaling of neurotransmitters and neuropeptides such as dopamine, brain-derived neurotrophic factor (BDNF), and glucagon-like peptide-1 (GLP-1). We further consider areas for future research on mechanisms by which gut microbes may influence feeding behavior involving these neural pathways. Understanding roles for the gut microbiota in feeding regulation will be important for informing therapeutic strategies to treat metabolic and eating disorders.

Relationship between Orexigenic Peptide Ghrelin Signal, Gender Difference and Disease.

Growth hormone secretagogue receptor 1a (GHS-R1a), which is one of the G protein-coupled receptors (GPCRs), is involved in various physiological actions such as energy consumption, growth hormone secretion promoting action, and cardiovascular protective action. The ligand was searched for as an orphan receptor for a while, but the ligand was found to be acylated ghrelin (ghrelin) discovered by Kangawa and Kojima et al. in 1999. Recently, it has also been reported that dysregulation of GHS-R1a mediates reduced feeding in various diseases. On the other hand, since the physiological effects of ghrelin have been studied exclusively in male mice, few studies have been conducted on gender differences in ghrelin reactivity. In this review, we describe (1) the characteristics of GHS-R1a, (2) the role of ghrelin in hypophagia due to stress or anticancer drugs, and (3) the gender differences in the physiological effects of GHS-R1a and the influence of stress on it.

Persistent level of mental distress in PTSD patients is not reflected in cytokine levels 1 year after the treatment.

OBJECTIVE: Cross-sectional data show that post-traumatic stress disorder (PTSD) patients often have increased levels of circulating inflammatory markers. There is, however, still a paucity of longitudinal studies with long follow-up times on levels of cytokines in such patients. The current study assesses patients with and without PTSD diagnosis 1 year after discharge from inpatient treatment. METHODS: Patients in treatment for serious non-psychotic mental disorders were recruited at the beginning of their treatment stay at a psychiatric centre in Norway. Ninety patients submitted serum samples and filled out the Hopkins Symptom Checklist-90 Revised Global Severity Index (HSCL-90R GSI) questionnaire during their mainstay and at a follow-up stay 1 year after discharge. Of these patients, 33 were diagnosed with PTSD, 48 with anxiety, depression, or eating disorder, while 9 patients had missing data. The patients were diagnosed using the Mini-International Neuropsychiatric Interview (MINI). RESULTS: At the follow-up stay (T3), PTSD patients had higher levels of GSI scores than non-PTSD patients (p = 0.048). These levels were unchanged from the year before (T2) in both groups. The levels of circulating cytokines/chemokine did not differ between the PTSD and non-PTSD patients at T3. At T2, however, the PTSD and non-PTSD groups exhibited different levels of interleukin 1ß (IL-1ß) (p = 0.053), IL-1RA (p = 0.042), and TNF-α (p = 0.037), with the PTSD patients having the higher levels. CONCLUSION: Despite exhibiting different mental distress scores, the PTSD and non-PTSD patients did not differ regarding levels of circulating inflammatory markers at 1-year follow-up.

Gender-specific approach in psychiatric diseases: Because sex matters.

In both animals and human beings, males and females differ in their genetic background and hormonally driven behaviour and show sex-related differences in brain activity and response to internal and external stimuli. Gender-specific medicine has been a neglected dimension of medicine for long time, and only in the last three decades it is receiving the due scientific and clinical attention. Research has recently begun to identify factors that could provide a neurobiological basis for gender-based differences in health and disease and to point to gonadal hormones as important determinants of male-female differences. Animal studies have been of great help in understanding factors contributing to sex-dependent differences and sex hormones action. Here we review and discuss evidence provided by clinical and animal studies in the last two decades showing gender (in humans) and sex (in animals) differences in selected psychiatric disorders, namely eating disorders (anorexia nervosa, bulimia nervosa, binge eating disorder), schizophrenia, mood disorders (anxiety, depression, obsessive-compulsive disorder) and neurodevelopmental disorders (autism spectrum disorders, attention-deficit/hyperactivity disorder).

A Narrative Review of Sex Differences in Eating Disorders: Is There a Biological Basis?

PURPOSE: Eating disorders and their core symptoms (eg, binge eating, body weight/shape concerns) disproportionately affect females, and these sex-differentiated effects become prominent during and after puberty. Although psychosocial influences such as heightened sociocultural pressures for thinness in girls and women contribute to this sex imbalance, biological factors could also play an important role. METHODS: This narrative review summarizes evidence of biological factors underlying the sex-differentiated prevalence of eating pathology as well as within-sex variability in risk. FINDINGS: There are sex differences in the pubertal emergence of genetic effects on eating pathology (adrenarche in males; gonadarche in females), and at least some genetic contributions to eating pathology seem to vary between the sexes. Furthermore, sex steroid hormones (eg, testosterone, estradiol, progesterone) are leading contributors to differential risk for eating pathology in males and females across the life span. Emerging data suggest that between-sex and within-sex variability in risk might occur via hormone-driven modulation (activation/deactivation) of genetic influences and neural responsiveness to food-related cues. IMPLICATIONS: There is a biological basis to heightened risk for eating pathology in females, relative to males, as well as unique biological influences within each sex. Findings from this review highlight the importance of studying both sexes and considering sex-specific biological mechanisms that may underlie differential risk for eating pathology.

Disordered eating in women with type 1 diabetes: Continuous glucose monitoring reveals the complex interactions of glycaemia, self-care behaviour and emotion.

OBJECTIVES: Glycaemia in people with type 1 diabetes and disordered eating is not well characterised. We explored the glycaemia, self-care behaviour and emotional state of women with type 1 diabetes and disordered eating. RESEARCH DESIGN AND METHODS: In all, 13 women with and 10 without disordered eating and type 1 diabetes participated in this case-control study. We used a mixed-methods approach with a 7-day blinded continuous glucose monitoring and real-time record of non-prompted capillary glucose (CG), emotion, activity and physical symptoms on a diabetes diary using a smartphone application (mySugr®). We compared groups using Mann-Whitney U test or Fisher's exact test. We conducted thematic analyses of free-text diary entries (NVivo®) and quantitative analysis of emotion/symptom tags. RESULTS: People with type 1 diabetes and disordered eating spent longer time above range in level 2 hyperglycaemia (>13.9 mmol/L, Median [interquartile range]: 21% [16,60] vs 5% [2,17], p = 0.015). They had lower time in range and similar time below range compared to those without disordered eating. The standard deviation of CG was significantly higher in the disordered eating group (4.7 mmol/L [4.5, 6.1] vs 3 [2.8, 3.2], p = 0.018). The median of the percentage of rising sensor glucose trends was three times higher in the disordered eating group. They also had higher negative emotional and physical symptoms associated with high blood glucose (>15 mmol/L). CONCLUSIONS: Disordered eating has a significant impact on the glycaemia and emotion of a person with type 1 diabetes.

Cholinergic dysfunction in the dorsal striatum promotes habit formation and maladaptive eating.

Dysregulation of habit formation has been recently proposed as pivotal to eating disorders. Here, we report that a subset of patients suffering from restrictive anorexia nervosa have enhanced habit formation compared with healthy controls. Habit formation is modulated by striatal cholinergic interneurons. These interneurons express vesicular transporters for acetylcholine (VAChT) and glutamate (VGLUT3) and use acetylcholine/glutamate cotransmission to regulate striatal functions. Using mice with genetically silenced VAChT (VAChT conditional KO, VAChTcKO) or VGLUT3 (VGLUT3cKO), we investigated the roles that acetylcholine and glutamate released by cholinergic interneurons play in habit formation and maladaptive eating. Silencing glutamate favored goal-directed behaviors and had no impact on eating behavior. In contrast, VAChTcKO mice were more prone to habits and maladaptive eating. Specific deletion of VAChT in the dorsomedial striatum of adult mice was sufficient to phenocopy maladaptive eating behaviors of VAChTcKO mice. Interestingly, VAChTcKO mice had reduced dopamine release in the dorsomedial striatum but not in the dorsolateral striatum. The dysfunctional eating behavior of VAChTcKO mice was alleviated by donepezil and by l-DOPA, confirming an acetylcholine/dopamine deficit. Our study reveals that loss of acetylcholine leads to a dopamine imbalance in striatal compartments, thereby promoting habits and vulnerability to maladaptive eating in mice.

Medical management of eating disorders: an update.

PURPOSE OF REVIEW: Eating disorders are associated with numerous medical complications. The aim of this study was to review recent progress in improving the medical management of patients with eating disorders. RECENT FINDINGS: With close medical monitoring and electrolyte supplementation, accelerated refeeding protocols improve weight restoration without increasing the risk of refeeding syndrome. Olanzapine improves weight restoration better than placebo, without leading to adverse metabolic effects seen in individuals not in starvation. Alterations of the gut microbiome in anorexia nervosa have been demonstrated, but their clinical relevance remains unclear. SUMMARY: Medical complications of eating disorders may facilitate the first contact with health professionals and treatment initiation. Medical complications of anorexia nervosa generally occur due to starvation, malnutrition and their associated physiological effects, whereas medical complications of bulimia nervosa are generally due to purging behaviors. Most medical complications in patients with binge eating disorder are secondary to obesity. Most medical complications of eating disorders can be effectively treated with nutritional management, weight normalization and the termination of purging behaviors. In summary, eating disorders are associated with many medical complications that have to be carefully assessed and managed as early as possible to improve long-term outcomes.

Nesfatin-1 in the neurochemistry of eating disorders. / Nesfatyna-1 w neurochemii zaburzen odzywiania.

The vast majority of new neuropeptides feature unique biochemical properties as well as awide spectrum of physiological activity applied in numerous neuronal pathways, including hypothalamus and the limbic system. Special interest should be paid to nesfatin-1 - the relatively recently discovered and still intensively studied regulatory factor and a potential modulator of eating behaviors. New information about it now allows to consider this neuropeptide as a potentially important factor involved in the pathogenesis of many different mental disorders. The considered pharmacomodulation of nesfatinergic signaling may be potentially helpful in the future treatment of some neuropsychiatric and metabolic disorders including anorexia nervosa. Although the results of some basic and clinical tests seem to be promising, all possible applications of the aforementioned neuropeptides, together with their agonists and antagonists still remain in the area of speculation. The intensive search of selective modulators of their known receptors may facilitate the opening of a promising chapter in the eating disorders therapy. This paper provides a review of recent scientific reports regarding the hypothetical role of nesfatin-1 in the neuronal pathways related to pathophysiology of anorexia nervosa.

Association between eating behavior, anthropometric and biochemical measurements, and peptide YY (PYY) hormone levels in obese adolescents in outpatient care.

Objective To evaluate the eating behavior of obese adolescents and its association with biochemical, anthropometric and peptide YY (PYY) measures. Methods Fifty-one obese adolescents received counseling for weight management at 12 monthly appointments. Fasting serum PYY levels, total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), triglycerides (TG), low density lipoprotein cholesterol (LDL-C), insulin and glucose levels, waist circumference (WC) and results from the Three-Factor Eating Questionnaire (TFEQ-21) were assessed. Results Over one year there was a significant increase in PYY levels (p = 0.026), reduction in TC (p = 0.003), TG (p = 0.022), BMI (p = 0.002), BMI z-score (p < 0.001) and WC (p = 0.003). During this period there was a decrease in the uncontrolled eating score (UE), illustrating that adolescents displayed more self-control (p = 0.008) at the end of the study; however, this result was independent of BMI and BMI z-score (p = 0.407). The reduction in UE was associated with a significant improvement in insulin levels (rs = 0.326; p = 0.020). The reduction in UE was also associated with lower levels of blood glucose (r = 0.332; p = 0.017), and the increase of cognitive restriction, with the reduction of insulin insulin (rs = -0.294; p = 0.036) and TG (r = -0.368; p = 0.008) and an increase in Cognitive Restraint. Conclusions Our results show that after a year of monitoring weight loss, adolescents had more controlled eating behaviors, increased PYY levels, and reduced weights.

Eating behaviours related to psychological stress are associated with functional hypothalamic amenorrhoea in exercising women.

Functional hypothalamic amenorrhoea (FHA) can occur due to the independent or combined effects of psychogenic and energetic stressors. In exercising women, research has primarily focused on energy deficiency as the cause of FHA while psychological stressors have been ignored. To assess both psychological and metabolic factors associated with FHA in exercising women, we performed across-sectional comparison of 61 exercising women (≥2 hours/week, age 18-35 years, BMI 16-25kg/m2), who were eumenorrheic or amenorrhoeic confirmed by daily urine samples assayed for reproductive hormone metabolites. Psychological factors and eating behaviours were assessed by self-report questionnaires. Exercising women with FHA had lower resting metabolic rate (p=0.023), T3 (p<0.001), T4 (p=0.013), leptin (p=0.002), higher peptide YY (p<0.001), greater drive for thinness (p=0.017), greater dietary cognitive restraint (p<0.001), and displayed dysfunctional attitudes, i.e., need for social approval (p=0.047) compared to eumenorrheic women. Amenorrhoeic women displayed asignificant positive correlation between the need for social approval and drive for thinness with indicators of stress, depression, and mood, which was not apparent in eumenorrheic women. In exercising women with FHA, eating behaviours are positively related to indicators of psychological stress and depression.

Teenager With Abdominal Pain and Decreased Appetite.

A 16-year-old girl presented to her primary care physician with a one-month history of decreased appetite and abdominal pain. She had normal bowel movements and no vomiting, but her periumbilical pain limited her ability to finish most meals. She had gradual weight loss over the previous 2 years, and during the previous 4 years, she intermittently received counseling for depression after the loss of her mother. Her initial physical examination and laboratory evaluation were unremarkable. She was referred to a nutritionist, adolescent medicine, and pediatric gastroenterology. Her presentation evolved over time, which ultimately led to a definitive diagnosis.

The orbitofrontal cortex, food intake and obesity

Obesity is a major health challenge facing many people throughout the world. Increased consumption of palatable, high-caloric foods is one of the major drivers of obesity. Both orexigenic and anorexic states have been thoroughly reviewed elsewhere; here, we focus on the cognitive control of feeding in the context of obesity, and how the orbitofrontal cortex (OFC) is implicated, based on data from preclinical and clinical research. The OFC is important in decision-making and has been heavily researched in neuropsychiatric illnesses such as addiction and obsessive­compulsive disorder. However, activity in the OFC has only recently been described in research into food intake, obesity and eating disorders. The OFC integrates sensory modalities such as taste, smell and vision, and it has dense reciprocal projections into thalamic, midbrain and striatal regions to fine-tune decision-making. Thus, the OFC may be anatomically and functionally situated to play a critical role in the etiology and maintenance of excess feeding behaviour. We propose that the OFC serves as an integrative hub for orchestrating motivated feeding behaviour and suggest how its neurobiology and functional output might be altered in the obese state.

A POMC-originated circuit regulates stress-induced hypophagia, depression, and anhedonia.

Chronic stress causes dysregulations of mood and energy homeostasis, but the neurocircuitry underlying these alterations remain to be fully elucidated. Here we demonstrate that chronic restraint stress in mice results in hyperactivity of pro-opiomelanocortin neurons in the arcuate nucleus of the hypothalamus (POMCARH neurons) associated with decreased neural activities of dopamine neurons in the ventral tegmental area (DAVTA neurons). We further revealed that POMCARH neurons project to the VTA and provide an inhibitory tone to DAVTA neurons via both direct and indirect neurotransmissions. Finally, we show that photoinhibition of the POMCARH→VTA circuit in mice increases body weight and food intake, and reduces depression-like behaviors and anhedonia in mice exposed to chronic restraint stress. Thus, our results identified a novel neurocircuitry regulating feeding and mood in response to stress.

Gender Dysphoria, Eating Disorders and Body Image: An Overview.

BACKGROUND: Gender dysphoria is a clinical condition in which a state of inner suffering, stress and anxiety is detected when biological sex and a person's gender identity do not coincide. People who identify themselves as transgender people are more vulnerable and may have higher rates of dissatisfaction with their bodies which are often associated with a disorderly diet in an attempt to change the bodily characteristics of the genus of birth and, conversely, to accentuate the characteristics of the desired sexual identity. AIM: The purpose of this work is to examine the association between dissatisfaction with one's own body and eating and weight disorders in people with gender dysphoria. RESULTS: Gender dysphoria and eating disorders are characterized by a serious discomfort to the body and the body suffers in both conditions. The results of our study suggest that rates of pathological eating behaviors and symptoms related to a disordered diet are high in patients with gender dysphoria and that standard screening for these symptoms must be considered in both populations at the time of evaluation and during the course of the treatment. CONCLUSION: In light of this evidence, clinicians should always investigate issues related to sexuality and gender identity in patients with eating disorders, to develop more effective prevention measures and better strategies for therapeutic intervention.

Higher body mass index is linked to altered hypothalamic microstructure.

Animal studies suggest that obesity-related diets induce structural changes in the hypothalamus, a key brain area involved in energy homeostasis. Whether this translates to humans is however largely unknown. Using a novel multimodal approach with manual segmentation, we here show that a higher body mass index (BMI) selectively predicted higher proton diffusivity within the hypothalamus, indicative of compromised microstructure in the underlying tissue, in a well-characterized population-based cohort (n1 = 338, 48% females, age 21-78 years, BMI 18-43 kg/m²). Results were independent from confounders and confirmed in another independent sample (n2 = 236). In addition, while hypothalamic volume was not associated with obesity, we identified a sexual dimorphism and larger hypothalamic volumes in the left compared to the right hemisphere. Using two large samples of the general population, we showed that a higher BMI specifically relates to altered microstructure in the hypothalamus, independent from confounders such as age, sex and obesity-associated co-morbidities. This points to persisting microstructural changes in a key regulatory area of energy homeostasis occurring with excessive weight. Our findings may help to better understand the pathomechanisms of obesity and other eating-related disorders.

Gastrointestinal Sensing of Meal-Related Signals in Humans, and Dysregulations in Eating-Related Disorders.

The upper gastrointestinal (GI) tract plays a critical role in sensing the arrival of a meal, including its volume as well as nutrient and non-nutrient contents. The presence of the meal in the stomach generates a mechanical distension signal, and, as gastric emptying progresses, nutrients increasingly interact with receptors on enteroendocrine cells, triggering the release of gut hormones, with lipid and protein being particularly potent. Collectively, these signals are transmitted to the brain to regulate appetite and energy intake, or in a feedback loop relayed back to the upper GI tract to further adjust GI functions, including gastric emptying. The research in this area to date has provided important insights into how sensing of intraluminal meal-related stimuli acutely regulates appetite and energy intake in humans. However, disturbances in the detection of these stimuli have been described in a number of eating-related disorders. This paper will review the GI sensing of meal-related stimuli and the relationship with appetite and energy intake, and examine changes in GI responses to luminal stimuli in obesity, functional dyspepsia and anorexia of ageing, as examples of eating-related disorders. A much better understanding of the mechanisms underlying these dysregulations is still required to assist in the development of effective management and treatment strategies in the future.