Search

Major Depressive Disorder (MDD) is a heterogenous and etiologically complex disease often presenting with divergent appetitive phenotypes including Hyperphagic MDD (characterized by an increased appetite) and Hypophagic MDD (characterized by a decrease in appetite) which are closely related to comorbidities, including cardiometabolic disorders. Hyperphagia is associated with atypical depression, decreased stress-hormone signaling, a pro-inflammatory status, hypersomnia, and poorer clinical outcomes. Yet, our understanding of associated biological correlates of Hyperphagic and Hypophagic MDD remain fragmented. We performed an exploratory study on peripheral blood RNA profiling using bulk RNAseq in unmedicated individuals with Hyperphagic and Hypophagic MDD (n = 7 and n = 13, respectively). At baseline, we discovered an increased expression of TADA2B in hyperphagic MDD with the significant enrichment of 72 gene ontology pathways mainly related to inflammation. In addition, we used the Maastricht Acute Stress Task to uncover stress-related transcriptomic profiles in Hyper- and Hypophagic MDD and discovered the upregulation of CCDC196 and the downregulation of SPATA33 in hyperphagic MDD. Gene ontology enrichment analysis after stress exposure showed pathways related to ribosomal activity. Limitations: The present findings are tempered primarily by the limited sample size, which requires independent replication of this exploratory study. However, stringent methods controlling for false positive findings mitigate the risk associated with sample size limitations. Limitations notwithstanding, findings suggest that hyper- and hypophagic MDD is associated with divergent RNA expression profiles in peripheral blood that are amplified by exposure to a controlled stress test. Our findings in a well-controlled study provide evidence for peripheral markers of a relevant endophenotype of MDD. [ABSTRACT FROM AUTHOR]

Objective: Morbid hunger and hyperphagia (MHH) is a rare neurological disorder that can manifest following damage to the right frontal and temporal lobes. It can lead to detrimental short and long-term complications such as electrolyte imbalances, obesity, and cardiovascular diseases. This report details the case of a young male patient who developed MHH five months post-traumatic brain injury. Method: Single-case report. The patient exhibited colossal appetite, overeating, food-demanding behavior, and rapid weight gain. The prescription of quetiapine to manage his visual and auditory hallucinations was suspected of exacerbating the hyperphagia. A comprehensive, multidisciplinary rehabilitation approach was implemented, encompassing a meticulous dietary regime, environmental modifications, behavioral management, physical activities, therapeutic exercises, and pharmacological interventions, which included switching the anti-psychotics and introducing low-dose escitalopram. Results: Over the course of 6 months, the MHH gradually subsided, and the patient achieved the target bodyweight. The Glasgow Outcome Scale-Extended improved from 3 to 5. Conclusion: This is the first report on the use of escitalopram to manage secondary eating disorders. Our findings underscore the necessity to formally catalog and recognize disorders like MHH in diagnostic classifications to facilitate the systematic study of their pathophysiology, natural history, prognosis, and management strategies. [ABSTRACT FROM AUTHOR]

Feeding is regulated by energy homeostatic and pleasure-induced rewarding signals. Palatable food intake modifies serotonergic (5-HT) and dopaminergic (DA) pathways in nucleus accumbens, inducing neuronal maladaptations that favor hyperphagia for high-energy dense food and consequent obesity. Chronic stress is an environmental condition that increases the preference for palatable food by modulating brain DA and 5-HT metabolism. Objective: To evaluate the association between changes in accumbal 5-HT and DA metabolism and the effects of chronic stress, palatable food intake and their interaction with satiety/hunger condition. Methods: Wistar rats were housed in pairs (non-stressed) or individually (stressed), fed with chow or chocolate milk plus chow (Ch) for 2 weeks (4 groups); then 6 animals/group were 48 h fasted or maintained ad libitum; the rest were fasted and re-fed for 2 h either with chow or Ch. Results: Rats with prolonged high-energy density food intake and re-fed with chow showed reduced 5-HT metabolism, although there was no association with animals’ feeding behavior. In contrast, after re-fed with palatable food, stressed chow-fed rats had increased 5-HT turnover, which decreased in Ch re-fed rats, supporting that palatable food might induce positive mood changes related to high extracellular 5-HT in limbic regions. Discussion: Rats with prolonged palatable food intake exhibited high accumbal DA turnover independently of stress exposure, supporting its relation with the development of high-energy dense food hyperphagia. As accumbal 5-HT and DA metabolism changed due to fasting or re-feeding, alterations could represent the interaction of energy homeostatic and hedonic feeding signaling in animals. [ABSTRACT FROM AUTHOR]

Background and aims: Smokers typically have a lower body mass index (BMI) than non‐smokers, while smoking cessation is associated with weight gain. In pre‐clinical research, nicotine in tobacco smoking suppresses appetite and influences subsequent eating behaviour; however, this relationship is unclear in humans. This study measured the associations of smoking with different eating and dietary behaviours. Design: A cross‐sectional analysis of data from health assessments conducted between 2004 and 2022. Setting: An independent healthcare‐based charity within the United Kingdom. Participants: A total of 80 296 men and women (mean ± standard deviation [SD]: age, 43.0 ± 10.4 years; BMI, 25.7 ± 4.2 kg/m2; 62.5% male) stratified into two groups based on their status as a smoker (n = 6042; 7.5%) or non‐smoker (n = 74 254; 92.5%). Measurements Smoking status (self‐report) was the main exposure, while the primary outcomes were selected eating and dietary behaviours. Age, sex and socioeconomic status (index of multiple deprivation [IMD]) were included as covariates and interaction terms, while moderate‐to‐vigorous exercise and sleep quality were included as covariates only. Findings Smokers had lower odds of snacking between meals and eating food as a reward or out of boredom versus non‐smokers (all odds ratio [OR] ≤ 0.82; P < 0.001). Furthermore, smokers had higher odds of skipping meals, going more than 3 h without food, adding salt and sugar to their food, overeating and finding it hard to leave something on their plate versus non‐smokers (all OR ≥ 1.06; P ≤ 0.030). Additionally, compared with non‐smokers, smoking was associated with eating fried food more times per week (rate ratio [RR] = 1.08; P < 0.001), eating fewer meals per day, eating sweet foods between meals and eating dessert on fewer days per week (all RR ≤ 0.93; P < 0.001). Several of these relationships were modified by age, sex and IMD. Conclusions: Smoking appears to be associated with eating and dietary behaviours consistent with inhibited food intake, low diet quality and altered food preference. Several of these relationships are moderated by age, sex and socioeconomic status. [ABSTRACT FROM AUTHOR]

Abnormal reward sensitivity is a risk factor for psychiatric disorders, including eating disorders such as overeating and binge-eating disorder, but the brain structural mechanisms that underlie it are not completely understood. Here, we sought to investigate the relationship between multimodal whole-brain structural features and reward sensitivity in nonhuman primates. Reward sensitivity was evaluated through behavioral economic analysis in which monkeys (adult rhesus macaques; 7 female, 5 male) responded for sweetened condensed milk (10%, 30%, 56%), Gatorade, or water using an operant procedure in which the response requirement increased incrementally across sessions (i.e., fixed ratio 1, 3, 10). Animals were divided into high (n = 6) or low (n = 6) reward sensitivity groups based on essential value for 30% milk. Multimodal magnetic resonance imaging was used to measure gray matter volume and white matter microstructure. Brain structural features were compared between groups, and their correlations with reward sensitivity for various stimuli was investigated. Animals in the high sensitivity group had greater dorsolateral prefrontal cortex, centromedial amygdaloid complex, and middle cingulate cortex volumes than animals in the low sensitivity group. Furthermore, compared with monkeys in the low sensitivity group, high sensitivity monkeys had lower fractional anisotropy in the left dorsal cingulate bundle connecting the centromedial amygdaloid complex and middle cingulate cortex to the dorsolateral prefrontal cortex, and in the left superior longitudinal fasciculus 1 connecting the middle cingulate cortex to the dorsolateral prefrontal cortex. These results suggest that neuroanatomical variation in prefrontal-limbic circuitry is associated with reward sensitivity. These brain structural features may serve as predictive biomarkers for vulnerability to food-based and other reward-related disorders. [ABSTRACT FROM AUTHOR]

Narcolepsy type-1 is a rare chronic sleep disorder that has negative effects on quality of life if left untreated. Symptoms such as excessive daytime sleepiness, cataplexy, sleep paralysis, disrupted night sleep, vivid dreams, psychosomatic complaints, and decreased sexual desire are also observed. Diagnosis will be made according to the criteria in the international classification of sleep disorders 3rd edition 2023 revision (ICSD-3-TR-2023). In our case, there was excessive daytime sleepiness, disrupted night sleep, cataplexy, overeating, and increased sexual desire. As a result of clinical data, polysomnography, and multiple sleep latency tests, she was diagnosed with narcolepsy type-1 according to the ICSD-3-TR-2023 guidelines. In the differential diagnosis of excessive sexual desire, it was planned to distinguish "persistent genital arousal", "restless genital syndrome", "sexomnia", and "hypersexuality" diseases. According to the diagnostic and statistical manual of mental disorders fifth edition criteria, "hypersexuality" accompanying narcolepsy type-1 was diagnosed in the patient. To date, no increase in sexual desire has been reported in the literature regarding the diagnosis of narcolepsy type-1. In this case, it is aimed to discuss a case of hypersexuality that has not been observed to date, together with a diagnosis of narcolepsy type-1, in the light of the literature. [ABSTRACT FROM AUTHOR]

Research shows that features of food packaging can help to promote healthy food choices. Laboratory‐based studies demonstrate that smart design of packaging facilitates portion control. However, the extent to which consumers notice packaging features for portion control is not known. Therefore, this study investigated how individuals interact with food packaging, how they utilise the on‐pack serving‐size guidelines and how they make portion decisions. To do this, 25 adult participants were recruited to participate in an online semi‐structured interview. Data were analysed using thematic analysis until saturation was achieved. Participants reported that they rarely attend to on‐pack serving recommendations and indicated some resistance to them. Some structural features (small/single serving, pre‐portioned and resealable packaging) were identified as facilitators of portion control. In contrast, the healthiness evaluation of the product from packaging cues was described as a permissive cue to eat more of the product. Participants in this study value their autonomy and control, preferring convenient behavioural choices over recommended portion servings. They also reported future concerns about the effects of their diet on health, but that current context (hunger, convenience) sometimes presented a barrier to healthy eating. Packaging does more than protect its contents, packaging can affect eating decisions to support portion control, and for some, offers permission to overconsume. This study identified ways that participants use packaging to make portion decisions, revealing the role of habits, current context and future health considerations. The interviews revealed the importance of consumer values on food choice in general and portion control in particular. In conclusion, smart food packaging design could use these findings to nudge healthy portion decisions by incorporating consumer values and by recognising consumer needs for habitual, current and future concerns. [ABSTRACT FROM AUTHOR]

Kleine-Levin syndrome (KLS) is a rare sleep disorder characterized by recurrent episodes of severe hypersomnolence in association with various degrees of cognitive impairment, perceptive abnormalities, apathy, behavioral disturbances. Some of these symptoms, hypersomnolence, compulsive eating and increased sexual drive may be replaced by their opposites or alternate with them. Remarkably enough, these « atypical symptoms » have never been enlighted nor compared in frequency with corresponding typical symptoms. Besides, KLS is more frequent in males than in females but no review has ever compared the frequency of precipitating factors and symptoms in males and females. To uncover these as yet uninvestigated aspects of KLS, a predesigned template was used to extract precipitating factors and symptoms, in 475 case reports of KLS, comprising 364 males and 111 females. Precipitating factors were more frequently recorded in males (67.31 %) than in females (49.55 %). Recurrent episodes of hypersomnolencee were present in 94.32 % of cases, recurrent insomnia in 1.05 % and alternation of hypersomnolence and insomnia in 4.63 %. Cognitive impairment was present in 67.37 % of cases and absent in 6.95 %. Derealization/altered perception was present in 38.32 % of cases and absent in 1.68 %. Severe apathy was present in 44.63 % of cases. Compulsive eating was present in 59.58 % of cases, absent in 13.26 %, replaced by anorexia in 9.05 %, alternation of compulsive eating and anorexia in 5.68 % and alternation of compulsive eating and no compulsive eating in 8.42 %. Increased sexual drive was present in 33.68 % of cases, absent in 22.74 %, replaced by decreased sexual drive in 1.47 %, alternation of increased sexual drive and no increased sexual drive in 2.95 %. Odd behaviors were present in 45.05 % of cases. Psychiatric features were present in 71.58 % of cases, absent in 2.95 %. Finally, the percentages of precipitating factors and of sleep disorder, apathy, sexual disorder, irritability/agressivity, were higher in males than in females. The frequency of the opposites of hypersomnolence, compulsive eating and increased sexual drive appears to be quite significant. In addition, a systematic comparison of precipitating factors and symptoms in males and females has shown limited differences between sexes. • Naming of Kleine-Levin symptoms must be standardized. • A review of KLS symptoms must include presence, absence and absence of data. • Hypersomnolence, hyperphagia, hypersexuality may be replaced by their opposite or alternate with it. • Comparison of precipitating factors and symptoms between sexes has shown minor differences. • Diagnostic criteria of Kleine-Levin syndrome should be updated. [ABSTRACT FROM AUTHOR]

Introduction: Herpes simplex virus type 1 (HSV-1) is the leading cause of sporadic fatal encephalitis, typically presenting with temporal lobe abnormalities. It usually manifests as fever, headache, seizure, altered sensorium, and focal neurological deficit. Hyperphagia as a sole complication of HSV-1 encephalitis is a rare presentation. Case Presentation: We report a 25-year-old woman with a 10-day history of fever, headache, and vomiting, progressing to confusion, visual hallucinations, and drowsiness. She had a history of meningoencephalitis at age 8 and well-controlled focal seizures. Upon admission, magnetic resonance imaging showed T2/fluid-attenuated inversion recovery hyperintensities in both temporal lobes with diffusion restriction. Electroencephalography indicated generalized slowing and cerebrospinal fluid (CSF) analysis revealed lymphocytic pleocytosis with elevated protein levels. Viral encephalitis was suspected, and intravenous acyclovir was initiated. CSF polymerase chain reaction (PCR) confirmed HSV-1. With treatment, she gradually improved but developed hyperphagia during hospital stay. Hyperphagia, a rare complication of herpes simplex virus (HSV) encephalitis, is a part of Kluver-Bucy syndrome typically associated with other cognitive dysfunctions. Despite early treatment, voracious appetite remained partially, emphasizing the need for rapid diagnosis and treatment to prevent severe outcomes. Conclusion: The case highlights that acute onset hyperphagia can be an isolated complication of HSV encephalitis, requiring tailored therapeutic strategies. Follow-up showed significant weight gain with partial improvement in hyperphagia, underscoring the challenges in managing this condition.

BACKGROUND: Psychotic disorders are a leading cause of disability in young adults. Antipsychotics have been the primary intervention for psychosis for over 60 years, and yet, we have made little progress in treating negative symptoms, neurocognition, and functional disability. There is growing evidence that cannabidiol (CBD) is effective in treating positive psychotic symptoms, possibly also negative and neurocognitive symptoms, and moreover is well tolerated compared to other psychotropic medications. Anecdotally, patients participating in the Cognitive Assessment and Risk Evaluation (CARE) Early Psychosis Treatment Program at the University of California, San Diego, are self-administering CBD and report subjective improvement in stress, anxiety, and ability to cope with symptoms. The overarching aim of the trial is to explore the effectiveness of CBD augmentation on symptoms and neurocognition in early psychosis while also exploring the mechanism of action of CBD and predictors of response to treatment. The mechanism by which cannabidiol has a therapeutic effect on psychosis is poorly understood. Recent evidence has suggested that CBD may reduce stress and pro-inflammatory biomarker levels. Endocannabinoids also have powerful roles in eating behavior, reward, and mood, indicating these neurotransmitters may play a role in reducing hyperphagia and metabolic abnormalities that are present early in the course of psychotic illness and exacerbated by antipsychotic medication. The neurophysiological effects of CBD have been studied in animal models of psychosis that show improvements in information processing in response to CBD, but there are no studies in individuals with early psychosis. METHOD: A total of 120 individuals in the early stages of psychosis will be randomized to 1000 mg of CBD versus placebo as an adjunct to existing treatment in a 8-week, double-blind superiority randomized control trial. The primary outcome measures are symptoms and neurocognition. DISCUSSION: We hypothesized that CBD will improve symptoms and neurocognition as well as secondary outcome measures of neurohormones, inflammation, eating behaviors, and information processing. Importantly, predictors, moderators, and mediators of the CBD effects will be examined. A better understanding of which individuals are likely to respond to CBD can inform treatment planning and personalize treatment. TRIAL REGISTRATION: ClinicalTrials.gov NCT04411225. Registered on June 2, 2020.

ObjectiveDespite great advances in obesity therapeutics in recent years, there is still a need to identify additional therapeutic targets for the treatment of this disease. We previously discovered a signature of genes, including Chloride intracellular channel 1 (Clic1), whose expression was associated with drug-induced weight gain, and in these studies, we assess the effect of Clic1 inhibition on food intake and body weight in mice.MethodsWe studied the impact of Clic1 inhibition in mouse models of binge-eating, diet-induced obese mice and genetic models of obesity (Magel2 KO mice).ResultsClic1 knockout (KO) mice ate significantly less and had a lower body weight than WT littermates when either fed chow or high fat diet. Furthermore, pharmacological inhibition of Clic1 in diet-induced obese mice resulted in suppression of food intake and promoted highly efficacious weight loss. Clic1 inhibition also reduced food intake in binge-eating models and hyperphagic Magel2 KO mice. We observed that chronic obesity resulted in a significant change in subcellular localization of Clic1 with an increased ratio of Clic1 in the membrane in the obese state. These observations provide a novel therapeutic strategy to block Clic1 translocation as a potential mechanism to reduce food intake and lower body weight.ConclusionsThese studies attribute a novel role of Clic1 as a driver of food intake and overconsumption. In summary, we have identified hypothalamic expression of Clic1 plays a key role in food intake, providing a novel therapeutic target to treat overconsumption that is the root cause of modern obesity.

Kleine Levin syndrome (KLS) is a rare entity. It presents with subacute onset episodic hypersomnia, cognitive decline, altered perception, and occasional hyperphagia and hypersexuality with full recovery during the interepisodic period. Five cases presented with episodic hypersomnia and met the diagnostic criteria of KLS. The majority of the cases were females (3/5) in whom KLS is even rarer. The initial presentation was in the age range of 10–25 years. Cognitive dysfunction (5/5), derealization (4/5), viral prodrome (3/5), hyperphagia (3/5), and hypersexuality (2/5) were other clinical presentations. A differential diagnosis of atypical depression is the major challenge, and thorough history taking would help in differentiation. Treatment with stimulants (modafinil) and mood stabilizers (lithium) proved effective. A high degree of suspicion should be kept for cases of episodic hypersomnolence for early diagnosis and management of KLS.

Daily‐life stressors and food cravings are dynamic and vary within and across persons. Some evidence suggests interpersonal stressors increase appetite. However, little is known about the association of food craving with different types of stressors at the momentary level in the general population. We aimed to explore the momentary relationships between daily‐life stressful events and food craving in a non‐clinical community sample, and to compare the associations with food craving when the most stressful event was perceived as interpersonal versus non‐interpersonal. We used ecological momentary assessment (EMA) to collect reports on the most stressful event, perceived stressor type, stressor appraisal, and food craving from 123 adults three times a day scheduled at fixed intervals over 10 days. Mixed effects random intercepts and slopes models examined the within‐ and between‐person associations. Experiencing a stressor was significantly positively associated with within‐person food craving at the same measurement. No differences in momentary food craving were found when the most stressful event was perceived as interpersonal or non‐interpersonal (within‐person level). However, frequently reporting the most stressful event as interpersonal (vs. non‐interpersonal) was positively associated with food craving across the study (between‐person level), particularly when the stressor was appraised as more unpleasant. Daily‐life stressors were associated with momentary food craving. Individuals who generally perceived interpersonal stressors as their most stressful event tended to experience food cravings. Future research could further investigate the role of interpersonal stressors as a factor for overeating in daily life and the potential benefits of stress management in interventions. [ABSTRACT FROM AUTHOR]

Summary: Most patients with GNB1 encephalopathy have developmental delay and/or intellectual disability, brain anomalies and seizures. Recently, two cases with GNB1 encephalopathy caused by haploinsufficiency have been reported that also show a Prader–Willi‐like phenotype of childhood hypotonia and severe obesity. Here we present three new cases from our expert centre for genetic obesity in which GNB1 truncating and splice variants, probably leading to haploinsufficiency, were identified. They all have obesity, hyperphagia and intellectual deficit. The clinical cases and their weight courses are presented, together with a review of all 68 published cases with GNB1 encephalopathy. Information on weight was not mentioned in most of these articles, so we contacted authors for additional clinical information on weight status and hyperphagia. Of the 42 patients whose weight status we could determine, obesity was present in 8 patients (19%). Obesity is significantly over‐represented in the group with truncating and splicing variants. In this group, we see an obesity prevalence of 75%. Since GNB1 has been linked to several key genes in the hypothalamic leptin‐melanocortin pathway, which regulates satiety and energy expenditure, our data support the potential association between GNB1 haploinsufficiency and genetic obesity. We also suggest GNB1 is a candidate gene for the known obesity phenotype of the 1p36 microdeletion syndrome given this chromosomal region includes the GNB1 gene. Knowledge of an additional obesity phenotype is important for prognosis, early interventions against obesity and awareness when prescribing weight‐inducing medication. [ABSTRACT FROM AUTHOR]

In wild brown bears, likely factors triggering hibernation response to harsh environmental conditions are temperature, photoperiod, and food resources availability. In fact, constantly fed captive brown bears are described as skipping hibernation being active all year-round. Is the hibernation response so flexible and subordinate to contingencies, or else is an adaptation that, if dismissed, may negatively impact on bear well-being? This study investigates the potential hibernation response in captive brown bears under unvaried management conditions using an integrative approach simultaneously analyzing multiple animal-based variables together with environmental covariates. Data from a mid-latitude zoo revealed distinct behavioral, fecal glucocorticoids, and body condition score seasonal fluctuations, resembling natural hibernation cycles, despite constant food access. Environmental variables like photoperiod and visitor numbers significantly influenced activity levels. Bears exhibited behaviors indicative of hyperphagia and fall transition, such as appetitive feeding and denning behaviors. Hormonal analyses revealed high fecal cortisol metabolites levels during hyperphagia, suggesting physiological responses to seasonal changes. Findings underscore the importance of environmental cues and food availability in shaping zoo bear behavior and physiology. Considering that the hibernating vs. non-hibernating description might represent an oversimplification, management strategies should deal with captive bear potential need to freely express their adaptive predispositions by accommodating their natural behaviors, such as providing denning spots and adjusting diet composition as soon as typical hyperphagic and predenning behaviors emerge, ultimately enhancing their well-being. [ABSTRACT FROM AUTHOR]

Daily experiences of mothers caring for children with Prader-Willi syndrome (PWS) are largely unknown and unvoiced. Knowledge of PWS has generally focused on pathology of the disorder. This emphasis overlooks the challenging moments of everyday life caring for children with PWS. Storied accounts of mothers caring for children with PWS offer expanded narratives to medicalized descriptions of experience. An understanding of everyday challenges in managing physical and mental health issues of PWS including hyperphagia and anxiety may create shifts in social and clinical perspectives. This understanding could improve practices in health and social care for families with PWS. This narrative inquiry studied everyday experience using storied accounts. Participants were mothers caring for children aged 3–17 years with genetically confirmed PWS who were experiencing hyperphagia. Four participants were recruited, and each interviewed 8–12 times over 12 months. Field texts and narrative accounts were co-composed through a collaborative process of analysis. Engaging with participants' day-to-day experiences offered insights into their work of nurturing, caring, and contributing to the care of a child with PWS. Narrative threads focused on complexity and rarity and include the desire to be normal, how ordinary becomes extraordinary, isolation, behaviors and normative standards, and alternative stories of mothering. Recommendations for practice and policy include (a) challenges of mothering a child with complexity, (b) moving beyond functionality and impairment to participation and quality of life, (c) re-storying narratives and supports for families, and (d) engaging with mothers to determine care priorities. [ABSTRACT FROM AUTHOR]

Smith Magenis Syndrome (SMS) is a rare genetic disorder caused by RAI1 haploinsufficiency. Obesity in people with SMS is believed partially due to dysfunction of the proximal melanocortin 4 receptor (MC4R) pathway. We therefore studied effects of treatment with the MC4R agonist setmelanotide on obesity and hunger, as well as metabolic, cardiac and safety, in individuals with SMS. People with SMS received once-daily setmelanotide injections, with the dose titrated bi-weekly to a maximum of 3 mg over ∼1 month; and a full-dose treatment duration of 3mo. The primary outcome was percent change in body weight. Secondary outcomes included hunger, waist circumference, body composition, and safety. 12 individuals, ages 11–39 y, enrolled and 10 completed the full-dose treatment phase. Mean percent change in body weight at end-treatment was − 0.28 % [(95 % CI, −2.1 % to 1.5 %; n = 12; P = 0.66]. Participants experienced a significant decrease in total cholesterol associated with a significant decrease in HDL-cholesterol and a trend for lower LDL-cholesterol. Self-reported hunger was reduced at end-treatment (p = 0.011). All participants reported adverse events (AEs), most commonly injection-site reactions and skin hyperpigmentation. No AEs led to withdrawal or death. In this trial, setmelanotide did not significantly reduce body weight in participants with SMS. Participants reported significant differences in hunger, but such self-reports are difficult to interpret without a placebo-treated group. The changes in lipid profiles require further investigation. Results of this study do not suggest that dysfunction of the proximal MC4R pathway is the main etiology for obesity in people with SMS. • Nonsignificant weight changes in individuals with SMS after setmelanotide treatment. • Lipid profiles changed in response to setmelanotide treatment for obesity in SMS. • SMS-related obesity may not be primarily caused by proximal MC4R pathway insufficiency. [ABSTRACT FROM AUTHOR]

The serotonin 2C receptor (5-HT2CR)-melanocortin pathway plays well-established roles in the regulation of feeding behavior and body weight homeostasis. Dysfunctions in this system, such as loss-of-function mutations in the Htr2c gene, can lead to hyperphagia and obesity. In this study, we aimed to investigate the potential therapeutic strategies for ameliorating hyperphagia, hyperglycemia, and obesity associated with a loss-of-function mutation in the Htr2c gene (Htr2c F327L/Y). We demonstrated that reexpressing functional 5-HT2CR solely in hypothalamic pro-opiomelanocortin (POMC) neurons is sufficient to reduce food intake and body weight in Htr2c F327L/Y mice subjected to a high-fat diet (HFD). In addition, 5-HT2CR expression restores the responsiveness of POMC neurons to lorcaserin, a selective agonist for 5-HT2CR. Similarly, administration of melanotan II, an agonist of the melanocortin receptor 4 (MC4R), effectively suppresses feeding and weight gain in Htr2c F327L/Y mice. Strikingly, promoting wheel-running activity in Htr2c F327L/Y mice results in a decrease in HFD consumption and improved glucose homeostasis. Together, our findings underscore the crucial role of the melanocortin system in alleviating hyperphagia and obesity related to dysfunctions of the 5-HT2CR, and further suggest that MC4R agonists and lifestyle interventions might hold promise in counteracting hyperphagia, hyperglycemia, and obesity in individuals carrying rare variants of the Htr2c gene. [ABSTRACT FROM AUTHOR]

The growth hormone secretagogue receptor (GHSR), primarily known as the receptor for the hunger hormone ghrelin, potently controls food intake, yet the specific Ghsr-expressing cells mediating the orexigenic effects of this receptor remain incompletely characterized. Since Ghsr is expressed in gamma-aminobutyric acid (GABA)–producing neurons, we sought to investigate whether the selective expression of Ghsr in a subset of GABA neurons is sufficient to mediate GHSR's effects on feeding. First, we crossed mice that express a tamoxifen-dependent Cre recombinase in the subset of GABA neurons that express glutamic acid decarboxylase 2 (Gad2) enzyme (Gad2-CreER mice) with reporter mice, and found that ghrelin mainly targets a subset of Gad2 -expressing neurons located in the hypothalamic arcuate nucleus (ARH) and that is predominantly segregated from Agouti-related protein (AgRP)–expressing neurons. Analysis of various single-cell RNA-sequencing datasets further corroborated that the primary subset of cells coexpressing Gad2 and Ghsr in the mouse brain are non-AgRP ARH neurons. Next, we crossed Gad2-CreER mice with reactivable GHSR-deficient mice to generate mice expressing Ghsr only in Gad2 -expressing neurons (Gad2-GHSR mice). We found that ghrelin treatment induced the expression of the marker of transcriptional activation c-Fos in the ARH of Gad2-GHSR mice, yet failed to induce food intake. In contrast, food deprivation–induced refeeding was higher in Gad2-GHSR mice than in GHSR-deficient mice and similar to wild-type mice, suggesting that ghrelin-independent roles of GHSR in a subset of GABA neurons is sufficient for eliciting full compensatory hyperphagia in mice. [ABSTRACT FROM AUTHOR]

Background: We explored change in child appetitive traits from 5 to 9–11 years old and examined associations between appetitive traits at both timepoints and child diet quality. Methods: This is secondary analyses of the ROLO longitudinal birth cohort study, including mother-child dyads from the 5 and 9–11-year old follow-up. The Children's Eating Behaviour Questionnaire measured child appetitive traits, with 167 children having matched data for both timepoints. The Healthy Eating Index (HEI) measured diet quality. Linear mixed models and multiple linear regression were completed. Results: Mean (SD) score for 'Emotional Overeating' (1.63 (0.51) vs. 1.99 (0.57), p = <0.001) and 'Enjoyment of Food' (3.79 (0.72) vs. 3.98 (0.66), p = <0.001) increased from 5 to 9–11 years. Mean score for 'Desire to Drink' (2.63 (0.94) vs. 2.45 (0.85), p = 0.01), 'Satiety Responsiveness (3.07 (0.66) vs. 2.71 (0.66), p = <0.001), 'Slowness Eating' (3.02 (0.77) vs. 2.64 (0.78), p = <0.001), and 'Food Fussiness' (3.00 (1.04) vs. 2.81 (0.96), p = 0.001) decreased. At 5-years-old, 'Food Responsiveness' and 'Enjoyment of Food' were positively associated with HEI and 'Desire to Drink', 'Satiety Responsiveness' and 'Food Fussiness' were negatively associated with HEI. At 9–11-years, 'Enjoyment of Food' was positively and 'Desire to Drink' and 'Food 'Fussiness' were negatively associated with HEI. Conclusions: Food approach appetitive traits increased over time, whereas food avoidant appetitive traits tended to decrease. At both time points 'Food Fussiness' and 'Desire to Drink" were inversely associated with HEI. Further research on how appetitive traits track over childhood and how this relates to dietary quality and weight is warranted. [ABSTRACT FROM AUTHOR]

Kleine Levin syndrome (KLS) is a rare entity. It presents with subacute onset episodic hypersomnia, cognitive decline, altered perception, and occasional hyperphagia and hypersexuality with full recovery during the interepisodic period. Five cases presented with episodic hypersomnia and met the diagnostic criteria of KLS. The majority of the cases were females (3/5) in whom KLS is even rarer. The initial presentation was in the age range of 10--25 years. Cognitive dysfunction (5/5), derealization (4/5), viral prodrome (3/5), hyperphagia (3/5), and hypersexuality (2/5) were other clinical presentations. A differential diagnosis of atypical depression is the major challenge, and thorough history taking would help in differentiation. Treatment with stimulants (modafinil) and mood stabilizers (lithium) proved effective. A high degree of suspicion should be kept for cases of episodic hypersomnolence for early diagnosis and management of KLS. [ABSTRACT FROM AUTHOR]

This study examined the effects of exercise and detraining at a young age on fat accumulation in various organs. Four‐week‐old male Otsuka Long‐Evans Tokushima Fatty (OLETF) rats were assigned to either the non‐exercise sedentary (OLETF Sed) or exercise groups. The exercise group was subdivided into two groups: exercise between 4 and 12 weeks of age (OLETF Ex) and exercise between 4 and 6 weeks of age followed by non‐exercise between 6 and 12 weeks of age (OLETF DT). Body weight was significantly lower in the OLETF Ex group than in the OLETF Sed group at 12 weeks of age. Fat accumulation in the epididymal white adipose tissue, liver, and brown adipose tissue was suppressed in the OLETF Ex group. During the exercise period, body weight and food intake in the OLETF DT group were significantly lower than those in the OLETF Sed group. However, food intake was significantly higher in the OLETF DT group than in the OLETF Sed group after exercise cessation, resulting in extreme obesity with fatty liver and brown adipose tissue whitening. Detraining after early‐onset exercise promotes hyperphagia, causing extreme obesity. Overeating should be avoided during detraining periods in cases of exercise cessation at a young age. [ABSTRACT FROM AUTHOR]

Summary: Nearly 90 clinicians and researchers from around the world attended the first IMPROVE 2022 International Meeting on Pathway‐Related Obesity. Delegates attended in person or online from across Europe, Argentina and Israel to hear the latest scientific and clinical developments in hyperphagia and severe, early‐onset obesity, and set out a vision of excellence for the future for improving the diagnosis, treatment, and care of patients with melanocortin‐4 receptor (MC4R) pathway‐related obesity. The meeting co‐chair Peter Kühnen, Charité Universitätsmedizin Berlin, Germany, indicated that change was needed with the rapidly increasing prevalence of obesity and the associated complications to improve the understanding of the underlying mechanisms and acknowledge that monogenic forms of obesity can play an important role, providing insights that can be applied to a wider group of patients with obesity. World‐leading experts presented the latest research and led discussions on the underlying science of obesity, diagnosis (including clinical and genetic approaches such as the role of defective MC4R signalling), and emerging clinical data and research with targeted pharmacological approaches. The aim of the meeting was to agree on the questions that needed to be addressed in future research and to ensure that optimised diagnostic work‐up was used with new genetic testing tools becoming available. This should aid the planning of new evidence‐based treatment strategies for the future, as explained by co‐chair Martin Wabitsch, Ulm University Medical Center, Germany. [ABSTRACT FROM AUTHOR]

A 9‐year‐old, entire, female, soft‐coated Wheaten terrier and a 7‐year‐old, male, neutered greyhound were presented for clinical signs suggestive of hyperadrenocorticism (polyuria, polydipsia, and in the first case, polyphagia and weight gain). Adrenocorticotrophic hormone stimulation test and low‐dose dexamethasone suppression test ruled out excessive production of cortisol. Imaging (abdominal ultrasound and computed tomography) revealed an adrenal mass in both cases. Further hormonal testing revealed hyperprogesteronism. In the first case, surgical treatment was not considered due to vascular invasion of the mass, the patient was treated successfully with trilostane and was still stable 18 months later. In the second case, adrenalectomy was performed, and the clinical signs resolved, the dog was stable 10 months later. We report two clinical cases of progesterone‐secreting adrenocortical tumours and their management. [ABSTRACT FROM AUTHOR]

Introduction: Prader-Willi Syndrome (PWS) is a genetic disorder marked by hyperphagia, obesity, developmental delays, and behavioral challenges. Traditional treatments like dietary control and growth hormone therapy often fail to effectively manage these symptoms. Recently, glucagon-like peptide-1 (GLP-1) analogs have shown potential in treating PWS. This review assesses the efficacy, safety and mechanisms of GLP-1 analogs in PWS treatment. They improve glycemic control, cardiovascular health, and appetite regulation, contributing to better weight management and overall health in PWS patients. These analogs enhance insulin secretion, inhibit glucagon release, and slow gastric emptying, helping to reduce postprandial glucose spikes and caloric intake. Results: Several small-scale studies and case reports have shown mixed results regarding the effectiveness of GLP-1 analogs in reducing BMI and hyperphagia in PWS patients. Although the studies demonstrated varied outcomes in terms of BMI reduction, all of them reported improvement in satiety or appetite levels. Conclusions: Overall, GLP-1 analogs hold promise for addressing hyperphagia, obesity, and glycemic control in PWS patients, improving their overall health and quality of life. Continued research and long-term studies are essential to establish these benefits and optimize treatment strategies.

Background: Obesity is a multifactorial neurohormonal disease that results from dysfunction within energy regulation pathways and is associated with increased morbidity, mortality, and reduced quality of life. The most common form is polygenic obesity, which results from interactions between multiple gene variants and environmental factors. Highly penetrant monogenic and syndromic obesities result from rare genetic variants with minimal environmental influence and can be differentiated from polygenic obesity depending on key symptoms, including hyperphagia; early-onset, severe obesity; and suboptimal responses to nontargeted therapies. Timely diagnosis of monogenic or syndromic obesity is critical to inform management strategies and reduce disease burden. We outline the physiology of weight regulation, role of genetics in obesity, and differentiating characteristics between polygenic and rare genetic obesity to facilitate diagnosis and transition toward targeted therapies. Methods: In this narrative review, we focused on case reports, case studies, and natural history studies of patients with monogenic and syndromic obesities and clinical trials examining the efficacy, safety, and quality of life impact of nontargeted and targeted therapies in these populations. We also provide comprehensive algorithms for diagnosis of patients with suspected rare genetic causes of obesity. Results: Patients with monogenic and syndromic obesities commonly present with hyperphagia (ie, pathologic, insatiable hunger) and early-onset, severe obesity, and the presence of hallmark characteristics can inform genetic testing and diagnostic approach. Following diagnosis, specialized care teams can address complex symptoms, and hyperphagia is managed behaviorally. Various pharmacotherapies show promise in these patient populations, including setmelanotide and glucagon-like peptide-1 receptor agonists. Conclusion: Understanding the pathophysiology and differentiating characteristics of monogenic and syndromic obesities can facilitate diagnosis and management and has led to development of targeted pharmacotherapies with demonstrated efficacy for reducing body weight and hunger in the affected populations.

Antipsychotic (AP) drugs are efficacious treatments for various psychiatric disorders, but excessive weight gain and subsequent development of metabolic disease remain serious side effects of their use. Increased food intake leads to AP-induced weight gain, but the underlying molecular mechanisms remain unknown. In previous studies, we identified the neuropeptide Agrp and the transcription factor nuclear receptor subfamily 5 group A member 2 (Nr5a2) as significantly upregulated genes in the hypothalamus following AP-induced hyperphagia. While Agrp is expressed specifically in the arcuate nucleus of the hypothalamus and plays a critical role in appetite stimulation, Nr5a2 is expressed in both the CNS and periphery, but its role in food intake behaviors remains unknown. In this study, we investigated the role of hypothalamic Nr5a2 in AP-induced hyperphagia and weight gain. In hypothalamic cell lines, olanzapine treatment resulted in a dose-dependent increase in gene expression of Nr5a2 and Agrp. In mice, the pharmacological inhibition of NR5A2 decreased olanzapine-induced hyperphagia and weight gain, while the knockdown of Nr5a2 in the arcuate nucleus partially reversed olanzapine-induced hyperphagia. Chromatin-immunoprecipitation studies showed for the first time that NR5A2 directly binds to the Agrp promoter region. Lastly, the analysis of single-cell RNA seq data confirms that Nr5a2 and Agrp are co-expressed in a subset of neurons in the arcuate nucleus. In summary, we identify Nr5a2 as a key mechanistic driver of AP-induced food intake. These findings can inform future clinical development of APs that do not activate hyperphagia and weight gain.

Abstract Background Prader-Willi syndrome (PWS) is a rare neurobehavioral-metabolic disease caused by the lack of paternally expressed genes in the chromosome 15q11-q13 region, characterized by hypotonia, neurocognitive problems, behavioral difficulties, endocrinopathies, and hyperphagia resulting in severe obesity if energy intake is not controlled. Diazoxide choline extended-release (DCCR) tablets have previously been evaluated for their effects on hyperphagia and other behavioral complications of people with PWS in a Phase 3 placebo-controlled study of participants with PWS, age 4 and older with hyperphagia (C601) and in an open label extension study, C602. Methods To better understand the longer-term impact of DCCR, a cohort from PATH for PWS, a natural history study that enrolled participants with PWS age 5 and older, who met the C601 age, weight and baseline hyperphagia inclusion criteria and had 2 hyperphagia assessments ≥ 6 months apart, were compared to the C601/C602 cohort. Hyperphagia was measured using the Hyperphagia Questionnaire for Clinical Trials (HQ-CT, range 0–36). The primary analysis used observed values with no explicit imputation of missing data. A sensitivity analysis was conducted in which all missing HQ-CT assessments in the C601/C602 cohort were assigned the highest possible value (36), representing the worst-case scenario. Other behavioral changes were assessed using the Prader-Willi Syndrome Profile questionnaire (PWSP). Results Relative to the PATH for PWS natural history study cohort, the DCCR-treated C601/C602 cohort showed significant improvements in HQ-CT score at 26 weeks (LSmean [SE] -8.3 [0.75] vs. -2.5 [0.43], p

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are genetic imprinting disorders resulting from absent or reduced expression of paternal or maternal genes in chromosome 15q11q13 region, respectively. The most common etiology is deletion of the maternal or paternal 15q11q13 region. Methylation is the first line for molecular diagnostic testing; MS-MLPA is the most sensitive test. The molecular subtype of PWS/AS provides more accurate recurrence risk information for parents and for the individual affected with the condition. Management should include a multidisciplinary team by various medical subspecialists and therapists. Developmental and behavioral management of PWS and AS in infancy and early childhood includes early intervention services and individualized education programs for school-aged children. Here, we compare and discuss the mechanisms, pathophysiology, clinical features, and management of the two imprinting disorders, PWS and AS.

BackgroundEarly childhood is a pivotal period for the development of healthy eating practices. One way to promote child health is to identify early modifiable factors that affect child eating and weight. Given the intergenerational transmission of eating behaviors, this study examined how mothers' eating behaviors were associated with child feeding practices, and whether child weight-for-length (z-WFL) moderated this relation, in a community sample.MethodsParticipants were 72 mother-child dyads. Maternal eating behaviors-emotional, external and restrained-were assessed 9-months postpartum, using the Dutch Eating Behavior Questionnaire. Child feeding-restrictive, pressure, and concern about overeating/overweight or undereating/underweight-was measured using the Infant Feeding Questionnaire, and child z-WFL were assessed 18-months postpartum. Linear regressions were used to test the main effect of maternal eating and the interaction effect of maternal eating and child z-WFL, on child feeding practices.ResultsMaternal restrained eating was associated with child pressure feeding, and contrarily with concerns about overeating/overweight. However, a significant interaction between child z-WFL and both maternal emotional and external eating were found with regard to concern about child undereating/underweight. Paradoxically, among children who weighed more, greater maternal emotional and greater external eating were associated with greater concern about child undereating/underweight.ConclusionsIn this community sample, mothers were more likely to report contradictory feeding practices and concerns, suggesting complicated relations among a mother's own eating behavior, her child's weight, and her perceptions of child eating and weight. This may indicate a need for better communication and support of infant feeding practices.Trial registrationData was collected as part of two grants (MAMAS Grant ID: HL097973-01; SEED Grant ID: HL116511-02) conducted at the University of California, San Francisco (UCSF). All subjects gave their informed consent for inclusion before they participated in the study. The study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by institutional review board at UCSF.

Prader-Willi syndrome (PWS) is a complex, genetic, neurodevelopmental disorder. PWS has three molecular genetic classes. The most common defect is due to a paternal 15q11-q13 deletion observed in about 60% of individuals. This is followed by maternal disomy 15 (both 15 s from the mother), found in approximately 35% of cases. the remaining individuals have a defect of the imprinting center that controls the activity of imprinted genes on chromosome 15. Mild cognitive impairment and behavior problems in PWS include self-injury, anxiety, compulsions, and outbursts in childhood, impacted by genetic subtypes. Food seeking and hyperphagia can lead to morbid obesity and contribute to diabetes and cardiovascular or orthopedic problems. The control of hyperphagia and improving food-related behaviors are the most important unmet needs in PWS and could be addressed with the development of a new therapeutic agent, as currently no approved therapeutics exist for PWS treatment. The status of clinical trials with existing results for the management of obesity and hyperphagia in PWS will be discussed in this review, including treatments such as beloranib, setmelanotide, a diazoxide choline controlled-release tablet (DCCR), an unacylated ghrelin analogue, oxytocin and related compounds, glucagon-like peptide 1 receptor agonists, surgical intervention, and transcranial direct-current stimulation.