Search

Thyroid hormone excess secondary to global type 3 deiodinase (DIO3) deficiency leads to increased locomotor activity and reduced adiposity, but also to concurrent alterations in parameters of the leptin–melanocortin system that would predict obesity. To distinguish the underlying contributions to the energy balance phenotype of DIO3 deficiency, we generated mice with thyroid hormone excess targeted to pro-opiomelanocortin (POMC)-expressing cells via cell-specific DIO3 inactivation. These mice exhibit a male-specific phenotype of reduced hypothalamic Pomc expression, hyperphagia, and increased activity in brown adipose tissue, with adiposity and serum levels of leptin and thyroid hormones remained normal. These male mice also manifest a marked and widespread hypothalamic reduction in the expression of bone morphogenetic receptor 1a (BMPR1A), which has been shown to cause similar phenotypes when inactivated in POMC-expressing cells. Our results indicate that developmental overexposure to thyroid hormone in POMC-expressing cells programs energy balance mechanisms in a sexually dimorphic manner by suppressing adult hypothalamic BMPR1A expression. [ABSTRACT FROM AUTHOR]

Hyperphagia and subsequent obesity are important public health issues due to the associated risks of developing serious diseases. Certain stressors play a major role in the development of hyperphagia. In previous studies, we established a line of human growth hormone transgenic (TG) rats that exhibit hyperphagia and obesity from a young age. We recently demonstrated that voluntary running on a running wheel alleviates hyperphagia in TG rats. Wheel running provides environmental enrichment for rodents and plays a role in relieving stress. These results suggested that stress is the major factor inducing hyperphagia in TG rats. Thus, in the present study, we evaluated activation of the hypothalamus-pituitary-adrenal axis. TG rats showed bilateral enlargement of adrenal glands and hypercorticosteronemia, although their hypothalamic CRH level was comparable to that of wild-type (WT) rats. The ACTH-immunoreactive area was larger and the serum ACTH level in the dark phase was higher in TG rats than in WT rats. Adrenalectomy reduced the food intake of TG rats to a level comparable to that in WT rats, and supplying glucocorticoids recurred hyperphagia in TG rats. These treatments did not affect the food intake of WT rats. Rearing TG rats under group housing prevented hyperphagia and hypercorticosteronemia. These results suggest that glucocorticoids are appetite stimulants, and that TG rats exhibit increased sensitivity to the appetite-stimulating effect of glucocorticoids., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Binge eating disorder is the most prevalent eating disorder, affecting both sexes but more commonly found in women. Given the frequent co-occurrence of psychiatric disorders, this study aimed to establish a standardized experimental intermittent protocol to investigate overeating associated with depression. A 10-day protocol induced uncontrolled eating behavior in C57BL/6J female mice. The first experiment included the following groups: naive group (chow ad libitum), control group (chow and sucrose solution ad libitum), and fasting groups (16 and 20 h) exposed to an intermittent sucrose solution (10 %) and chow regimen. Subsequently, the feeding test, open field test, elevated plus maze test, tail suspension test, and light/dark conflict test were conducted. Furthermore, monoamine oxidase (MAO) A and B activities in brain structures and plasma corticosterone levels were assessed. Food overconsumption and depressive-like behavior were observed in both sucrose fasting groups, while risk-taking behaviors were specifically observed in the 20-hour fasting sucrose group. While both fasting sucrose groups caused reduced hippocampal MAO-A activity, only the F20 sucrose group inhibited MAO-B in the cortex and hypothalamus. Moreover, both fasting sucrose groups exhibited elevated corticosterone levels. In a separate design (Experiment 2), groups with 16 and 20 h of fasting alone (without sucrose) did not show the same behavioral results as the intermittent fasting sucrose groups, thus avoiding fasting bias. Based on these results, the 20-hour sucrose fasting group was chosen as the ideal protocol for mimicking overeating behavior associated with depression to investigate future therapeutic approaches for this comorbidity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 International Brain Research Organization (IBRO). Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: The authors have no conflicts of interest to declare., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Background: Overeating and inactivity are associated with type 2 diabetes. This study aimed to investigate its pathological basis using integrated omics and db/db/mice, a model representing this condition., Methods: The study involved housing 8-week-old db/m and db/db mice for 8 weeks. Various analyses were conducted, including gene expression in skeletal muscle and small intestine using next-generation sequencing; cytokine arrays of serum; assessment of metabolites in skeletal muscle, stool, and serum; and analysis of the gut microbiota. Histone modifications in small intestinal epithelial cells were profiled using CUT&Tag., Results: Compared with db/m mice, db/db mice had 22.4% lower grip strength and approximately five times the visceral fat weight (P < 0.0001). Serum cytokine arrays showed a 2.8-fold relative concentration of VEGF-A in db/db mice (P < 0.0001) and lower concentrations of several other cytokines. mRNA sequencing revealed downregulation of Myh expression in skeletal muscle, upregulation of lipid and glucose transporters, and downregulation of amino acid transporters in the small intestine of db/db/mice. The concentrations of saturated fatty acids in skeletal muscle were significantly higher, and the levels of essential amino acids were lower in db/db mice. Analysis of the gut microbiota, 16S rRNA sequencing, revealed lower levels of the phylum Bacteroidetes (59.7% vs. 44.9%) and higher levels of the phylum Firmicutes (20.9% vs. 31.4%) in db/db mice (P = 0.003). The integrated signal of histone modifications of lipid and glucose transporters was higher, while the integrated signal of histone modifications of amino acid transporters was lower in the db/db mice., Conclusions: The multi-omics approach provided insights into the epigenomic alterations in the small intestine, suggesting their involvement in the pathogenesis of inactivity-induced muscle atrophy in obese mice., (© 2024 The Author(s). Journal of Cachexia, Sarcopenia and Muscle published by Wiley Periodicals LLC.)

Background: Subjective socioeconomic status (SSES) and objective socioeconomic status (OSES) have been independently associated with body composition and eating behavior in children. While low OSES may constrain access to healthier foods, low SSES has been associated with increased preference for and motivation to consume higher energy foods and portions independent of OSES. Despite these distinct ways that OSES and SSES may affect children's eating behavior and adiposity, their joint contributions remain unclear. We investigated the independent and interactive associations of SSES and OSES with children's BMI, fat mass index (FMI), and caregiver-reported hyperphagia. Methods: Data were derived from the Children's Growth and Behavior Study, an ongoing observational study. Multiple linear regressions used child's SSES and OSES of the family as independent factors and modeled the statistical interaction of SSES and OSES with BMI ( n  = 128), FMI ( n  = 122), and hyperphagia and its subscales ( n  = 76) as dependent variables. Results: SSES was independently and negatively associated with hyperphagia severity and OSES was independently and negatively associated with both FMI and hyperphagia severity. There was a statistical interaction effect of SSES and OSES on hyperphagia severity-lower SSES was associated with greater hyperphagia severity only at lower levels of OSES. Conclusions: These findings demonstrate a relationship between low OSES and child adiposity and that the relationship between child SSES and hyperphagia severity may be most relevant for children from households with lower family OSES. Future research on socioeconomic disparities in children's body composition and eating behaviors should examine the interaction of SSES and OSES. Clinical Trial Registration: NCT02390765.

Prader-Willi syndrome (PWS) is characterized by hypotonia, distinctive facial features, hyperphagia, obesity, short stature, hypogonadism, intellectual disability, and behavior problems. Uncontrolled hyperphagia can lead to dangerous food-seeking behavior and with life-threatening obesity. Severe obesity is prone to obstructive sleep apnea (OSA) and can lead to cor pulmonale. This study reports on a case involving a 21-year-old man with PWS who developed OSA due to severe obesity, which led to cor pulmonale, a life-threatening complication. Multidisciplinary care provided in the intensive care unit included weight reduction, ventilation support, antipsychotics, sedative drugs, rehabilitation, and meticulous skin care. The patient did recover. To prevent severe obesity in adults with PWS, hyperphagia must be controlled, and the patient must also be managed by an endocrinologist throughout childhood.

Obesity is a serious public health concern. It significantly affects an individual’s quality of life and is associated with an increased risk of developing other conditions, including diabetes, hypertension, and cardiovascular complications. The increasing health, social, and economic impacts of this chronic disease means there is an urgent need for effective pharmacological treatment to achieve relevant weight loss. Defects in the hypothalamic leptin/melanocortin pathway contribute to a variety of rare forms of obesity. Insufficient efficacy of lifestyle intervention or bariatric surgery in individuals with mutations in genes encoding melanocortin 4 receptor (MC4R) pathway components demonstrates the dominance of this pathway in body weight homeostasis. Loss of function mutations in the MC4R pathway including mutations in the pro-opiomelanocortin (POMC), prohormone convertase subtilisin/kexin type 1 (PCSK1), leptin receptor (LEPR), or the MC4R genes have been shown to be causative of early-onset severe obesity. MC4R is the key regulator in the appetite-controlling pathway within the hypothalamus. Its activation stimulates energy expenditure and inhibits food intake, resulting in a negative energy balance and potentially reducing obesity. The most common cause of monogenic obesity are mutations in the gene encoding the MC4R protein. Managing patients with monogenic non-syndromic obesity is clinically challenging since they display complex phenotypes and the obesity is often refractory to classical treatments. Until recent years, there has been a lack of targeted and effective pharmacological therapies except for leptin (LEP) therapy that was available for leptin deficiency. Fortunately, the picture has changed and promising molecules acting on the leptin/melanocortin pathway such as setmelanotide are now emerging as targeted therapeutic opportunities. Setmelanotide is a synthetic, cyclic, 8-amino acid, peptide, potent and selective second generation MC4R agonist, an analog of the naturally occurring alpha melanocyte stimulating hormone (alfa-MSH). It restores the activity of the MC4 receptor pathway to reduce hunger and promote weight loss. Setmelanotide appears to be the most promising for patients with POMC or LEPR deficiency. Unfortunately, obesity is highly prevalent worldwide, and the percentage of affected individuals is rising year by year, making this is a disease that needs to be treated more often. Keywords: setmelanotide, obesity, hyperphagia, leptin, MC4R.

Current dietary guidelines recommend avoiding foods and beverages with added sugars and higher sodium before age 2 years. The aim was to describe daily snack food intake (frequency and total energy) and the associations with overconsumed nutrients (added sugars, sodium, and saturated fats) and child weight-for-length z scores. A cross-sectional, secondary analysis of baseline data from an ongoing longitudinal intervention was conducted. A sample of 141 caregivers with infants (aged 9 to 11 months) and toddlers (aged 12 to 15 months) was recruited in Buffalo, NY, between 2017 and 2019. Three 24-hour dietary recalls were used to categorize 'sweet and salty snack foods' or 'commercial baby snack foods' based on the US Department of Agriculture What We Eat in America food group classifications and estimate nutrient intakes. Child recumbent length and weight were measured by trained researchers. Daily frequency (times/day), energy (kcal/day), and overconsumed nutrients from snack food intake were calculated. Multivariable regression models examined associations between the frequency of and energy from snack food intake with overconsumed nutrients and child weight-for-length z scores. Infants consumed snack foods on average 1.2 times/day contributing 5.6% of total daily energy, 19.6% of added sugars, and 6.8% of sodium. Toddlers consumed snack foods on average 1.4 times/day contributing 8.9% of total daily energy, 40.0% of added sugars, and 7.2% of sodium. In adjusted models including all children, greater frequency of sweet and salty snack food intake, but not commercial baby snack foods, was associated with higher weight-for-length z scores. Snack foods are frequently consumed by infants and toddlers and contribute to the intake of overconsumed nutrients such as added sugars and sodium. Given the current guidelines to avoid added sugars and higher sodium before age 2 years, additional recommendations related to nutrient-dense snack intake may be beneficial. [ABSTRACT FROM AUTHOR]

Background A possible driver of obesity is insensitivity (passive overconsumption) to food energy density (ED, kcal/g); however, it is unclear whether this insensitivity applies to all meals. Objectives We assessed the influence of ED on energy intake (kcal) across a broad and continuous range of EDs comprised of noncovertly manipulated, real-world meals. We also allowed for the possibility that the association between energy intake and ED is nonlinear. Methods We completed a secondary analysis of 1519 meals which occurred in a controlled environment as part of a study conducted by Hall and colleagues to assess the effects of food ultra-processing on energy intake. To establish the generalizability of the findings, the analyses were repeated in 32,162 meals collected from free-living humans using data from the UK National Diet and Nutrition Survey (NDNS). Segmented regressions were performed to establish ED "breakpoints" at which the association between consumed meal ED and mean centered meal caloric intake (kcal) changed. Results Significant breakpoints were found in both the Hall et al. data set (1.41 kcal/g) and the NDNS data set (1.75 and 2.94 kcal/g). Centered meal caloric intake did not increase linearly with consumed meal ED, and this pattern was captured by a 2-component ("volume" and "calorie content" [biologically derived from the sensing of fat, carbohydrate, and protein]) model of physical meal size (g), in which volume is the dominant signal with lower energy-dense foods and calorie content is the dominant signal with higher energy-dense foods. Conclusions These analyses reveal that, on some level, humans are sensitive to the energy content of meals and adjust meal size to minimize the acute aversive effects of overconsumption. Future research should consider the relative importance of volume and calorie-content signals, and how individual differences impact everyday dietary behavior and energy balance. [ABSTRACT FROM AUTHOR]

This study investigates the function of Elp1 and Elongator in the pituitary gland. Two conditional knockout models were generated where Elp1 was selectively deleted in either somatotropes of the anterior pituitary or Pomc -expressing cells of the anterior and intermediate pituitary. Although loss of Elp1 in somatotropes did not significantly impact murine growth or development, its loss in Pomc- expressing cells resulted in dramatically reduced levels of α-MSH, hyperphagia and obesity. This report provides the first evidence that Elongator plays an essential role in regulating the melanocortin satiety pathway. • Elongator loss results in a drastic reduction of α-MSH. • Selective ablation of Elp1 in the pituitary results in obesity and hyperphagia. • Elp1 is expressed in the anterior and intermediate pituitary. • Elp1 ablation results in altered levels of POMC, ACTH, PC1 and PC2. [ABSTRACT FROM AUTHOR]

Kleine–Levin syndrome (KLS) is a rare central disorder of daytime hypersomnolence and is often characterized by a relapsing and remitting course, recurrent episodes of excessive sleep lasting from 12 to 20 hours a day, and symptoms including hyperphagia, hallucinations, derealization, disorientation, and hypersexuality. There are numerous perioperative considerations in dealing with KLS that include challenges during induction of anesthesia, delayed emergence, postoperative sleep disorders, and delirium. However, due to its rare occurrence, the anesthetic considerations of KLS remain poorly described. This case report outlines the anesthetic considerations and management of a young female patient with KLS who underwent transnasal excision of a trigeminal schwannoma under general anesthesia. [ABSTRACT FROM AUTHOR]

Aim: The prevalence of childhood and adolescent obesity is increasing worldwide as well as in India. Prader--Willi syndrome (PWS) is one of the most common causes of syndromic obesity with varied clinical manifestations across different lifespan. Herewith, we describe clinical and molecular characteristics of eight PWS who were diagnosed in an obesity clinic of tertiary care hospital. Materials and Methods: Clinically suspected cases of PWS were screened between January 2014 and January 2022. Detailed history and clinical examination were done to look for typical features of PWS like characteristic facial appearance, short stature, obesity, hyperphagia, delayed puberty or hypogonadism, diabetes mellitus, developmental delay, cognitive dysfunction, learning disabilities or abnormal behavior. All were evaluated, with 75 g oral glucose tolerance tests (GTT), HbA1c, Free T4, TSH, LH, FSH, testosterone, and growth hormone level. Intelligent quotient (IQ) of each patient was assessed by a psychiatrist using Binet-Kamat test. Molecular confirmation of clinically suspected PWS was done by either Methylation-specific polymerase chain reaction (MS-PCR) or Fluorescence in situ Hybridization (FISH) methods. Results: Based on clinical and molecular characteristics, eight were diagnosed as PWS. Except one, all were male with characteristic facies, mean age of study cohort was 12 years and mean BMI of 44.58. Obesity, short stature, hyperphagia, hypotonia, and mild to moderate mental retardation were noted in entire (100%) PWS study population. All male PWS patients had cryptorchidism, which was bilateral in six patients and unilateral (right undescended testes) in one. Apart from obesity, short stature, other endocrine associations noted were diabetes mellitus in 50% and subclinical hypothyroidism in 37% of PWS. Molecular characteristics of PWS were confirmed by Methylation-specific PCR in seven and by FISH method in one. Conclusion: Prader-Willi syndrome should be kept in mind in case of childhood or adolescent obesity with short stature, hypotonia, cryptorchidism, and developmental delay or cognitive dysfunction. Judicious use of molecular diagnostic testing should be made in all clinically suspected cases. Early diagnosis and appropriate management of this complex disorder by a multidisciplinary team will improve the quality of life and treatment outcome. [ABSTRACT FROM AUTHOR]

Phytophagous insects are organisms that use a part of a plant as a food resource. Within this group, we focused on the pest insect Anastrepha obliqua, a fly that feeds on fruits of plants of different species and causes economic losses on the American continent. The ability of the larvae of this species to feed on various fruits (polyphagia) has been studied from different perspectives but never at the level of microRNAs. These interfering RNAs can regulate gene expression in tissues and organs of an organism. The objective of this work was to obtain the first micro‐transcriptome and to determine its expression levels and possible target mRNAs when the third instar larvae of the species A. obliqua feed on fruits of plants of three different species: Spondias purpurea, Mangifera indica and Averrhoa star fruit. A total of 116 microRNAs were identified in the study, of which 37 were completely new. Fifty‐four microRNAs were expressed in all larvae, regardless of the fruit, while 44 were detected in larvae that fed on a specific fruit. Twenty‐one microRNAs showed differential expression, and the annotation of the targets showed that these interfering RNAs have important genes that play roles in the development, feeding and detoxification of the larvae as possible targets. The construction of the first micro‐transcriptome and the identification of possible targets for A. obliqua provide new information for understanding the mechanisms that control gene expression in this species of dipteran. [ABSTRACT FROM AUTHOR]

Copyright of Gaceta Médica de Caracas is the property of Academia Nacional de Medicina and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The article reports that fasting has a significant effect on human gut microbiota with important allies in immune defense with its effects on inflammation and immune cell rejuvenation. Topics include microbiota is helpful in preventing overgrowth and enhancing the dominance of beneficial symbiotic strains over pathogenic ones; and reduce symptoms of the autoimmune condition multiple sclerosis in individuals who are severely affected by relapses.

Prader-Willi syndrome (PWS) is characterized by hypotonia, distinctive facial features, hyperphagia, obesity, short stature, hypogonadism, intellectual disability, and behavior problems. Uncontrolled hyperphagia can lead to dangerous foodseeking behavior and with life-threatening obesity. Severe obesity is prone to obstructive sleep apnea (OSA) and can lead to cor pulmonale. This study reports on a case involving a 21-year-old man with PWS who developed OSA due to severe obesity, which led to cor pulmonale, a life-threatening complication. Multidisciplinary care provided in the intensive care unit included weight reduction, ventilation support, antipsychotics, sedative drugs, rehabilitation, and meticulous skin care. The patient did recover. To prevent severe obesity in adults with PWS, hyperphagia must be controlled, and the patient must also be managed by an endocrinologist throughout childhood. [ABSTRACT FROM AUTHOR]

Copyright of Iranian Journal of Veterinary Science & Technology is the property of Ferdowsi University of Mashhad Press and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The type of parenting style influences the way children cope with problems and can create states of anxiety that can even alter their eating habits, which can cause problems in their oral health. The present study aimed to find out which parenting style is more favorable for the oral health of their children. In this cross-sectional study, 186 children (aged 8–15 years) were examined to assess the mean Decayed/Missing/Filled teeth (DMFT + dmft) index, and they were asked to complete the State–Trait Anxiety Inventory, the Parenting Style Scale, and questions about their oral hygiene habits. On the other hand, their parents answered the Parental Feeding Style Questionnaire and the Children's Eating Behavior Questionnaire. Results showed that a worse oral health status was associated with a higher state of anxiety, more overeating, more emotional eating, and higher psychological control. A higher rate of missing teeth was associated with increased undereating and overeating. Emotional eating was positively related to psychological control. State of anxiety, overeating, and parental psychological control predicted 24.6% of DMFT + dmft. In addition, emotional eating had a moderating effect in DMFT + dfmt only in those with low levels of affection and communication. In conclusion, high psychological control and low levels of parental affection and communication will increase the state of anxiety in children, influencing their caries rate. [ABSTRACT FROM AUTHOR]

Recurrent episodes of hypersomnia, hypersexuality, compulsive eating, behavioral and cognitive disturbances, are the basic clinical features of Kleine-Levin syndrome (KLS). Our case report describes a patient who was diagnosed with KLS at the age of 20. With appropriate therapy, the disease had a satisfactory course until patient had a moderate form of SARS-CoV-2 infection, which led to a significant exacerbation of all symptoms. SARS-CoV-2 virus can cause almost any neurological disease, and relapse of KLS is another evidence of neurotropicity of the virus.

Abstract Prader-Willi syndrome (PWS) is a rare neurodevelopmental genetic disorder associated with a characteristic behavioral phenotype that includes severe hyperphagia and a variety of other behavioral challenges such as temper outbursts and anxiety. These behaviors have a significant and dramatic impact on the daily functioning and quality of life for the person with PWS and their families. To date, effective therapies addressing these behavioral challenges have proven elusive, but several potential treatments are on the horizon. However, a limiting factor for treatment studies in PWS is the lack of consensus in the field regarding how to best define and measure the complex and interrelated behavioral features of this syndrome. The International PWS Clinical Trials Consortium (PWS-CTC, www.pwsctc.org ) includes expert PWS scientists, clinicians, and patient advocacy organization representatives focused on facilitating clinical trials in this rare disease. To address the above gap in the field, members of the PWS-CTC “Behavior Outcomes Working Group” sought to develop a unified understanding of the key behavioral features in PWS and build a consensus regarding their definition and description. The primary focus of this paper is to present consensus definitions and descriptions of key phenotypic PWS behaviors including hyperphagia, temper outbursts, anxiety, obsessive–compulsive behaviors, rigidity, and social cognition deficits. Patient vignettes are provided to illustrate the interrelatedness and impact of these behaviors. We also review some available assessment tools as well as new instruments in development which may be useful in measuring these behavioral features in PWS.

ObjectiveThe hippocampus is a key structure implicated in food motivation and intake. Research has shown that the hippocampus is vulnerable to the consumption of a western diet (i.e., high saturated fat and simple carbohydrates). Studies of patients with obesity (OB), compared with healthy weight (HW), show changes in hippocampal volume and response to food cues. Moreover, evidence suggests that OB children, relative to HW, have greater hippocampal response to taste. However, no study has examined the association of hippocampal volume with taste functioning in children. We hypothesized that OB children, relative to HW, would show a significant reduction in hippocampal volume and that decreased volume would be significantly associated with greater activation to taste. Finally, we explored whether hippocampal activation would be associated with measures on eating and eating habits.SubjectsTwenty-five 8-12-year-old children (i.e., 13 HW, 12 OB) completed a magnetic resonance imaging scan while participating in a taste paradigm (i.e., 1 ml of 10% sucrose or ionic water delivered pseudorandomly every 20 s).ResultsChildren with OB, relative to HW, showed reduced left hippocampal volume (t=1.994, P=0.03, 95% confidence interval (CI)=-40.23,  755.42), and greater response to taste in three clusters within the left hippocampus (z=3.3, P=0.001, 95% CI=-0.241, -0.041; z=3.3, P=0.001, 95% CI=-0.2711, -0.0469; z=2.7, P=0.007, 95% CI=-0.6032, -0.0268). Activation within the hippocampus was associated with eating in the absence of hunger (EAH%; t=2.408, P=0.025, 95% CI= 1.751708, 23.94109) and two subscales on a measure of eating behaviors (Food responsiveness, t=2.572, P=0.017, 95% CI= 0.9565195, 9.043440; Food enjoyment, t=2.298, P=0.032, 95% CI=0.2256749, 4.531298).ConclusionAs hypothesized, OB children, relative to HW, had significantly reduced hippocampal volume, and greater hippocampal activation to taste. Moreover, hippocampal activation was associated with measures of eating. These results contribute to research on the relationship between OB, overeating and cognitive impairment.

Dietary excess triggers accumulation of pro-inflammatory microglia in the mediobasal hypothalamus (MBH), but the components of this microgliosis and its metabolic consequences remain uncertain. Here, we show that microglial inflammatory signaling determines the immunologic response of the MBH to dietary excess and regulates hypothalamic control of energy homeostasis in mice. Either pharmacologically depleting microglia or selectively restraining microglial NF-κB-dependent signaling sharply reduced microgliosis, an effect that includes prevention of MBH entry by bone-marrow-derived myeloid cells, and greatly limited diet-induced hyperphagia and weight gain. Conversely, forcing microglial activation through cell-specific deletion of the negative NF-κB regulator A20 induced spontaneous MBH microgliosis and cellular infiltration, reduced energy expenditure, and increased both food intake and weight gain even in absence of a dietary challenge. Thus, microglial inflammatory activation, stimulated by dietary excess, orchestrates a multicellular hypothalamic response that mediates obesity susceptibility, providing a mechanistic rationale for non-neuronal approaches to treat metabolic diseases.

Current management for hyperphagia and consequent obesity in Prader-Willi syndrome (PWS) remains challenging and largely unsuccessful. Current and emerging therapies for managing hyperphagia and obesity in Prader-Willi syndrome: A narrative review. Treatment with lisdexamphetamine substantially reduced hyperphagia and body mass index for a single patient with PWS over a 6-month period. [Extracted from the article]

Prader-Willi syndrome (PWS) is a rare, complex multisystem genetic disorder which includes hypothalamic dysfunction, hyperphagia, cognitive and behavioral problems, increased anxiety, and compulsive behaviors. Individuals with PWS have a deficit of oxytocin producing neurons in the paraventricular nucleus of the hypothalamus. Oxytocin plays a role in regulation of feeding behaviors, social interactions, and emotional reactivity, which are all issues that significantly affect the quality of life for individuals with this syndrome. We performed a double-blind, placebo-controlled, crossover study in 24 children with PWS at three academic institutions using 5 days of intranasal oxytocin (IN-OT) or 5 days of intranasal placebo spray, followed by a 4 week washout period, and then patients returned for 5 days of treatment with the alternate source. Questionnaires, including the Aberrant Behavior Checklist, Social Responsiveness Scale, Repetitive Behavior Scale - Revised, and the Hyperphagia Questionnaire, as well as Clinical Global Impression scales were administered. Blood testing for sodium, potassium, and glucose levels on days 2, 4, and 6, and a 24 hr diet recall. All scales factor improvement from Day 3 to Day 6 favored oxytocin over placebo. No single factor showed a statistically significant difference (P

The endocannabinoid system in the brain and periphery plays a major role in controlling food intake and energy balance. We reported that tasting dietary fats was met with increased levels of the endocannabinoids, 2-arachidonoyl-sn-glycerol (2-AG) and anandamide, in the rat upper small intestine, and pharmacological inhibition of this local signaling event dose-dependently blocked sham feeding of fats. We now investigated the contribution of peripheral endocannabinoid signaling in hyperphagia associated with chronic consumption of a western-style diet in mice ([WD] i.e., high fat and sucrose). Feeding patterns were assessed in male C57BL/6Tac mice maintained for 60days on WD or a standard rodent chow (SD), and the role for peripheral endocannabinoid signaling at CB1Rs in controlling food intake was investigated via pharmacological interventions. In addition, levels of the endocannabinoids, 2-AG and anandamide, in the upper small intestine and circulation of mice were analyzed via liquid chromatography coupled to tandem mass spectrometry to evaluate diet-related changes in endocannabinoid signaling and the potential impact on food intake. Mice fed WD for 60days exhibited large increases in body weight, daily caloric intake, average meal size, and rate of feeding when compared to control mice fed SD. Inhibiting peripheral CB1Rs with the peripherally-restricted neutral cannabinoid CB1 receptor antagonist, AM6545 (10mg/kg), significantly reduced intake of WD during a 6h test, but failed to modify intake of SD in mice. AM6545 normalized intake of WD, average meal size, and rate of feeding to levels found in SD control mice. These results suggest that endogenous activity at peripheral CB1Rs in WD mice is critical for driving hyperphagia. In support of this hypothesis, levels of 2-AG and anandamide in both, jejunum mucosa and plasma, of ad-libitum fed WD mice increased when compared to SC mice. Furthermore, expression of genes for primary components of the endocannabinoid system (i.e., cannabinoid receptors, and endocannabinoid biosynthetic and degradative enzymes) was dysregulated in WD mice when compared to SC mice. Our results suggest that hyperphagia associated with WD-induced obesity is driven by enhanced endocannabinoid signaling at peripheral CB1Rs.

Prader-Willi syndrome (PWS), the leading genetic cause of obesity, is characterized by a striking hyperphagic behavior that can lead to obesity, type-2 diabetes, cardiovascular disease and death. The molecular mechanism underlying impaired satiety in PWS is unknown. Oleoylethanolamide (OEA) is a lipid mediator involved in the control of feeding, body weight and energy metabolism. OEA produced by small-intestinal enterocytes during dietary fat digestion activates type-α peroxisome proliferator-activated receptors (PPAR-α) to trigger an afferent signal that causes satiety. Emerging evidence from genetic and human laboratory studies suggests that deficits in OEA-mediated signaling might be implicated in human obesity. In the present study, we investigated whether OEA contributes to feeding dysregulation in Magel2m+/p- (Magel2 KO) mice, an animal model of PWS. Fasted/refed male Magel2 KO mice eat more than do their wild-type littermates and become overweight with age. Meal pattern analyses show that hyperphagia in Magel2 KO is due to increased meal size and meal duration rather than to lengthening of the intermeal interval, which is suggestive of a defect in mechanisms underlying satiation. Food-dependent OEA accumulation in jejunum and fasting OEA levels in plasma are significantly greater in Magel2 KO mice than in wild-type controls. Together, these findings indicate that deletion of the Magel2 gene is accompanied by marked changes in OEA signaling. Importantly, intraperitoneal administration of OEA (10mg/kg) significantly reduces food intake in fasted/refed Magel2 KO mice, pointing to a possible use of this natural compound to control hunger in PWS.

Triphenyl phosphate (TPhP) is a flame retardant additive frequently found in consumer products and household dust. We administered 170μg of TPhP in maternal food from gestational day 8.5 to weaning and evaluated metabolic phenotypes of 3.5 month old male and female rats, and weight-matched males up to 6 months, to assess the development of obesity and type 2 diabetes mellitus (T2DM), respectively. Perinatal TPhP exposure increased body and fat mass in 3.5 month old male and female rats, while leptin and cumulative energy intake were elevated in males and females, respectively. Independent of body mass, perinatal TPhP exposure accelerated T2DM onset in males and increased plasma non-esterified- fasting fatty acids. These observations suggest that perinatal exposure to TPhP exacerbates the development of obesity in male and female UCDavis-T2DM rats and accelerates T2DM onset in male UCD-T2DM rats.

Although loss of control (LOC) while eating is a core construct of bulimia nervosa (BN), questions remain regarding its validity and prognostic significance independent of overeating. We examined trajectories of objective and subjective binge eating (OBE and SBE, respectively; i.e., LOC eating episodes involving an objectively or subjectively large amount of food) among adults participating in psychological treatments for BN-spectrum disorders (n = 80). We also explored whether changes in the frequency of these eating episodes differentially predicted changes in eating-related and general psychopathology and, conversely, whether changes in eating-related and general psychopathology predicted differential changes in the frequency of these eating episodes. Linear mixed models with repeated measures revealed that OBE decreased twice as rapidly as SBE throughout treatment and 4-month follow-up. Generalized linear models revealed that baseline to end-of-treatment reductions in SBE frequency predicted baseline to 4-month follow-up changes in eating-related psychopathology, depression, and anxiety, while changes in OBE frequency were not predictive of psychopathology at 4-month follow-up. Zero-inflation models indicated that baseline to end-of-treatment changes in eating-related psychopathology and depression symptoms predicted baseline to 4-month follow-up changes in OBE frequency, while changes in anxiety and self-esteem did not. Baseline to end-of-treatment changes in eating-related psychopathology, self-esteem, and anxiety predicted baseline to 4-month follow-up changes in SBE frequency, while baseline to end-of-treatment changes in depression did not. Based on these findings, LOC accompanied by objective overeating may reflect distress at having consumed an objectively large amount of food, whereas LOC accompanied by subjective overeating may reflect more generalized distress related to one's eating- and mood-related psychopathology. BN treatments should comprehensively target LOC eating and related psychopathology, particularly in the context of subjectively large episodes, to improve global outcomes.

The transcripts for Bdnf (brain-derived neurotrophic factor), driven by different promoters, are expressed in different brain regions to control different body functions. Specific promoter(s) that regulates energy balance remain unclear. We show that disruption of Bdnf promoters I and II but not IV and VI in mice (Bdnf-e1−/−, Bdnf-e2−/−) results in obesity. Whereas Bdnf-e1−/− exhibited impaired thermogenesis, Bdnf-e2−/− showed hyperphagia and reduced satiety before the onset of obesity. The Bdnf-e2 transcripts were primarily expressed in ventromedial hypothalamus (VMH), a nucleus known to regulate satiety. Re-expressing Bdnf-e2 transcript in VMH or chemogenetic activation of VMH neurons rescued the hyperphagia and obesity of Bdnf-e2−/− mice. Deletion of BDNF receptor TrkB in VMH neurons in wildtype mice resulted in hyperphagia and obesity, and infusion of TrkB agonistic antibody into VMH of Bdnf-e2−/− mice alleviated these phenotypes. Thus, Bdnf-e2-transcripts in VMH neurons play a key role in regulating energy intake and satiety through TrkB pathway.

• GLP-1R agonists decrease nicotine withdrawal-induced hyperphagia and body weight gain. • In animal models, GLP-1R agonists decrease voluntary nicotine taking and seeking. • The effects of GLP-1R agonists on smoking behavior in clinical studies are less clear. • GLP-1R agonists may ameliorate nicotine withdrawal-induced cognitive deficits and mood disorders. Nicotine use disorder (NUD) remains a leading cause of preventable death in the U.S. Unfortunately, current FDA-approved pharmacotherapies for smoking cessation have limited efficacy and are associated with high rates of relapse. One major barrier to long-term smoking abstinence is body weight gain during withdrawal. Nicotine withdrawal-induced body weight gain can also lead to development of chronic disease states like obesity and type II diabetes mellitus. Therefore, it is critical to identify novel pharmacotherapies for NUD that decrease relapse and nicotine withdrawal symptoms including body weight gain. Recent studies demonstrate that glucagon-like peptide-1 receptor (GLP-1R) agonists attenuate voluntary nicotine taking and seeking and prevent withdrawal-induced hyperphagia and body weight gain. Emerging evidence also suggests that GLP-1R agonists improve cognitive deficits, as well as depressive- and anxiety-like behaviors, which contribute to smoking relapse during withdrawal. While further studies are necessary to fully characterize the effects of GLP-1R agonists on NUD and understand the mechanisms by which GLP-1R agonists decrease nicotine withdrawal-mediated behaviors, the current literature supports GLP-1R-based approaches to treating NUD. [ABSTRACT FROM AUTHOR]

Loss of prolyl endopeptidase-like (PREPL) encoding a serine hydrolase with (thio)esterase activity leads to the recessive metabolic disorder Congenital Myasthenic Syndrome-22 (CMS22). It is characterized by severe neonatal hypotonia, feeding problems, growth retardation, and hyperphagia leading to rapid weight gain later in childhood. The phenotypic similarities with Prader-Willi syndrome (PWS) are striking, suggesting that similar pathways are affected. The aim of this study was to identify changes in the hypothalamic-pituitary axis in mouse models for both disorders and to examine mitochondrial function in skin fibroblasts of patients and knockout cell lines. We have demonstrated that Prepl is downregulated in the brains of neonatal PWS-IC-p/+m mice. In addition, the hypothalamic-pituitary axis is similarly affected in both Prepl −/− and PWS-IC-p/+m mice resulting in defective orexigenic signaling and growth retardation. Furthermore, we demonstrated that mitochondrial function is altered in PREPL knockout HEK293T cells and can be rescued with the supplementation of coenzyme Q10. Finally, PREPL-deficient and PWS patient skin fibroblasts display defective mitochondrial bioenergetics. The mitochondrial dysfunction in PWS fibroblasts can be rescued by overexpression of PREPL. In conclusion, we provide the first molecular parallels between CMS22 and PWS, raising the possibility that PREPL substrates might become therapeutic targets for treating both disorders. [Display omitted] • Prepl is reduced in neonatal brains of the mouse model for PWS • The hypothalamic-pituitary axis is altered in Prepl knockout and PWS mice • Mitochondrial dysfunction is observed in skin fibroblasts of PREPL and PWS patients • CoenzymeQ10 rescues mitochondrial dysfunction in PREPL-deficient cells • Overexpression of PREPL rescues mitochondrial dysfunction in PWS patient cells [ABSTRACT FROM AUTHOR]

Obesity is a global medical problem; its common form is known as diet-induced obesity (DIO); however, there are several rare genetic disorders, such as Prader–Willi syndrome (PWS), that are also associated with obesity (genetic-induced obesity, GIO). The currently available therapeutics for treating DIO and GIO are very limited, and they result in only a partial improvement. Cannabidiolic acid (CBDA), a constituent of Cannabis sativa, gradually decarboxylates to cannabidiol (CBD). Whereas the anti-obesity properties of CBD have been reasonably identified, our knowledge of the pharmacology of CBDA is more limited due to its instability. To stabilize CBDA, a new derivative, CBDA-O-methyl ester (HU-580, EPM301), was synthesized. The therapeutic potential of EPM301 in appetite reduction, weight loss, and metabolic improvements in DIO and GIO was tested in vivo. EPM301 (40 mg/kg/d, i.p.) successfully resulted in weight loss, increased ambulation, as well as improved glycemic and lipid profiles in DIO mice. Additionally, EPM301 ameliorated DIO-induced hepatic dysfunction and steatosis. Importantly, EPM301 (20 and 40 mg/kg/d, i.p.) effectively reduced body weight and hyperphagia in a high-fat diet-fed Magel2null mouse model for PWS. In addition, when given to standard-diet-fed Magel2null mice as a preventive treatment, EPM301 completely inhibited weight gain and adiposity. Lastly, EPM301 increased the oxidation of different nutrients in each strain. All together, EPM301 ameliorated obesity and its metabolic abnormalities in both DIO and GIO. These results support the idea to further promote this synthetic CBDA derivative toward clinical evaluation in humans. [ABSTRACT FROM AUTHOR]

Background and aims: Non‐invasive brain stimulation has shown potential in clinical applications aiming at reducing craving and consumption levels in individuals with drug addiction or overeating behaviour. However, it is unclear whether these intervention effects are maintained over time. This study aimed to measure the immediate, short‐ and long‐term effects of excitatory transcranial direct current stimulation (tDCS) and high‐frequency repetitive transcranial magnetic stimulation (rTMS) targeting at dorsolateral prefrontal cortex (dlPFC) in people with drug addiction or overeating. Methods: A systematic review and random effects meta‐analysis. We included 20 articles (total of 22 studies using randomized controlled trials: 3 alcohol dependence, 3 drug dependence, 12 smoking, 4 overeating; total: 720 participants) from January 2000 to June 2020, which reported at least one follow‐up assessment of craving, consumption or abstinence levels after the intervention. We compared effects of active versus sham stimulation immediately after the intervention and at the last follow‐up assessment, as compared with baseline. Results: Excitatory neuromodulation of dlPFC activity reduced craving and consumption immediately after the intervention (craving: g = 0.734, CI = 0.447–1.021, P < 0.001; consumption: g = 0.527, CI = 0.309–0.745; P < 0.001), as well as during short‐, mid‐ and long‐term abstinence (craving: g = 0.677, CI = 0.440–0.914, P < 0.001; consumption: g = 0.445, CI = 0.245–0.645, P < 0.001; abstinence levels: g = 0.698, CI = 0.433–0.963, P < 0.001; average time of follow‐up: 84 ± 83 days after last stimulation). Additional analysis demonstrated that the intervention effects were sustained in all populations studied (food, nicotine, alcohol or drug abuse) and with both stimulation techniques used (rTMS, tDCS). Interventions targeting at the left (vs right) hemisphere may be more effective. Conclusions: Excitatory neuromodulation targeting the dorsolateral prefrontal cortex appears to lead to a sustained reduction of craving and consumption in individuals with addiction or overeating behaviour. [ABSTRACT FROM AUTHOR]

Although the importance of diet quality was identified more than 120 years ago, it was nearly 60 years before the specific quantitative nutrient needs for humans were determined. Dr Doris Howes Calloway, a nutrition professor at the University of California in Berkeley, established a metabolic unit for studying human nutrient requirements. This article reviews the early origins of human nutrition research and the unique contributions of Dr Calloway worldwide. [ABSTRACT FROM AUTHOR]

Background and Objectives A strong correlation exists between Type 2 diabetes mellitus and adverse childhood experiences. How adverse childhood experiences inform later-life diabetes management is less understood. This article examines diabetes management from the perspective of affective practice to explore the lingering impact of trauma biographies in diabetes management. Research Design and Methods This secondary narrative analysis of 15 in-depth interviews with community-dwelling older adults with diabetes (subsample of the Subjective Experiences of Diabetes Study) focuses on the ways their reported childhood adversity affects perceptions of and responses to diabetes self-management. Results The experiences of adversity in childhood accumulate, throughout the life course, in the affective practices informing diabetes self-management, from blood glucose testing, to food consumption, to the emotions invested in body size. We identify 3 thematic areas that emerged across participants: (a) undermining self-worth, (b) (over)eating and food as comfort, and (c) weight and body size. Discussion and Implications Our findings highlight affective practices as a mechanism through which adverse events accumulate and shape well-being over the life course. This analysis also suggests the potential for (de)accumulation of affective practices to improve diabetes management. The findings support recent calls for trauma-informed clinical care. [ABSTRACT FROM AUTHOR]

Monogenic obesity is a severe, genetically determined disorder that affects up to 1/1000 newborns. Recent reports on potential new therapeutics and innovative clinical approaches have highlighted the need for early identification of individuals with rare genetic variants that can alter the functioning of the leptin-melanocortin signalling pathway, in order to speed up clinical intervention and reduce the risk of chronic complications. Therefore, next-generation DNA sequencing of central genes in the leptin-melanocortin pathway was performed in 1508 children and adolescents with and without obesity, aged 2-19 years. The recruited cohort comprised approximately 5% of the national paediatric population with obesity. The model-estimated effect size of rare variants in the leptin-melanocortin signalling pathway on longitudinal weight gain between carriers and non-carriers was derived. In total, 21 (1.4%) participants had known disease-causing heterozygous variants (DCVs) in the genes under investigation, and 62 (4.1%) participants were carriers of rare variants of unknown clinical significance (VUS). The estimated frequency of potential genetic variants associated with obesity (including rare VUS) ranged between 1/150 (VUS and DCV) and 1/850 (DCV) and differed significantly between participants with and without obesity. On average, the variants identified would result in approximately 7.6 kg (7.0-12.9 kg at the 95th percentile of body weight) (girls) and 8.4 kg (8.2-14.4 kg) (boys) of additional weight gain in carriers at age 18 years compared with subjects without obesity. In conclusion, children with a genetic predisposition to obesity can be promptly identified and may account for more than 6% of obesity cases. Early identification of genetic variants in the LEPR , PCSK1 , POMC , MC3R and MC4R genes could reduce the societal burden and improve the clinical management of early severe childhood obesity and its implementation should be further investigated. [ABSTRACT FROM AUTHOR]

Leptin is a pleiotropic hormone known for regulating appetite and metabolism. To characterize the role of leptin signaling in rainbow trout, we used CRISPR/Cas9 genome editing to disrupt the leptin receptor (LepR) genes, lepra1 and lepra2. We compared wildtype (WT) and mutant fish that were either fed to satiation or feed deprived for six weeks. The LepR mutants exhibited a hyperphagic phenotype, which led to heavier body weight, faster specific growth rate, increased viscero- and hepatosomatic indices, and greater condition factor. Muscle glycogen, plasma leptin, and leptin transcripts (lepa1) were also elevated in fed LepR mutant fish. Expression levels of several hypothalamic genes involved in feed regulation were analyzed (agrp, npy, orexin, cart-1, cart-2, pomc-a1, pomc-b). No differences were detected between fed WT and mutants except for pomc-b (proopiomelanocortin-b), where levels were 7.5-fold higher in LepR fed mutants, suggesting that pomc-b expression is regulated by leptin signaling. Fatty acid (FA) content did not statistically differ in muscle of fed mutant fish compared to WT. However, fasted mutants exhibited significantly lower muscle FA concentrations, suggesting that LepR mutants exhibit increased FA mobilization during fasting. These data demonstrate a key role for leptin signaling in lipid and energy mobilization in a teleost fish. [ABSTRACT FROM AUTHOR]

Brown bears are one of the few large carnivore species that survived the final Pleistocene wave of extinctions, perhaps in part owing to their wide ecological plasticity, variety of forms and polyphagia. Although the brown bear has become a well‐studied system, many questions remain regarding the ecological, trophic and genetic diversity throughout their distribution. For example, knowledge about Asiatic Russian brown bears from the Late Pleistocene arctic tundra steppe, an ecosystem with no analogue in modern times, is sparse. Here we compared diets, morphometry and genetic affinities of Late Pleistocene bears based on broadly sampled subfossil remains from Asiatic Russia. Collecting sites included the Ural Mountains, the lower reaches of the Irtysh River, the upper reaches of the Ob River, the Altai Mountains of western Siberia, the Indigirka–Kolyma Lowlands and northwestern Chukotka. An extremely large bear specimen from the middle Indigirka (41 090 14C a BP) that lived in landscapes of treeless shrubs and wet meadows had a diet composed principally of large herbivorous mammals. A bear from western Chukotka (25 880 14C a BP), much smaller in size, had a diet close to that of modern brown bears. These two Late Pleistocene NE Russian brown bears may comprise a previously undiscovered, but extinct, genetic lineage. At the end of the Pleistocene (MIS 3 and MIS 2), the brown bears from the Ob River Valley and Urals lived in periglacial forest‐steppes and those from the southern Urals in conditions of periglacial steppe. Brown bears from the Ob River valley and Urals, as well as ancient Altai bears, were characterized by a varied diet, from polyphagia to vegetarianism. In living brown bears, the proportions of different dietary foods are primarily related to food availability, which depends on the geographical zone and climatic conditions. We conclude that the same was true for Late Pleistocene brown bears of NE Siberia. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Prader-Willi syndrome (PWS) is a genomic imprinting disorder predominantly caused by the absence of paternally expressed imprinted genes at chromosome 15q11.2-q13. The PCSK1 gene is vital for the processing of hypothalamic POMC to ACTH and a-MSH, leading to food intake suppression and increased energy expenditure. The aim of this study was to investigate whether our PWS patient had a defect in genes involved in the hypothalamic melanocortin-4 receptor (MC4R) pathway. PATIENTS AND METHODS: A 27-year-old Greek man with PWS presented to the Adult Endocrine Clinic with morbid obesity and hyperphagia. He also had obstructive sleep apnea, growth hormone deficiency, gonadal failure and metabolic disturbances. At 6 years of age, chromosomal testing confirmed PWS with a deletion in the q11q13 region of the long arm of paternal chromosome 15. RESULTS: At the age of 27 years, further genetic testing was conducted, and next generation sequencing revealed a PCSK1_pN221D_ HET mutation which was confirmed by Sanger sequencing. CONCLUSIONS: Our findings suggest that different genetic abnormalities may be present in an individual with PWS and that patients with PWS may need to be investigated for PCSK1 mutations, as the finding may potentially offer a novel treatment perspective for them. [ABSTRACT FROM AUTHOR]

Introduction: In patients with pro-opiomelanocortin (POMC) or leptin receptor (LEPR) deficiency, managing obesity and hyperphagia can be burdensome for patients and caretakers. The impacts on health-related quality of life are under-recognized and are not well characterized. Methods: We conducted in-depth qualitative interviews in patients with POMC (n = 3) and LEPR (n = 2) deficiencies participating in an ongoing open-label extension of phase 3 clinical trials with the melanocortin receptor 4 agonist setmelanotide to describe the patient experience of hyperphagia and characterize changes following treatment with setmelanotide. Results: Prior to setmelanotide treatment, all five patients described abnormal sensations of hunger with none indicating feeling satiated after meals and also reported that the burden of hyperphagia impacted their families, emotions, and work and/or school functioning. Following setmelanotide treatment, all five patients reported consistent reductions in hunger and weight, decreased eating, and feeling satiated after meals in addition to substantial improvements in each area of functioning they had previously reported. All five patients indicated they were very satisfied with the impact of setmelanotide on their quality of life and would be upset if treatment was discontinued. Conclusions: In patients with POMC or LEPR deficiency, hyperphagia and the inability to feel satiety negatively impacted quality of life. By reducing hunger and improving satiety, setmelanotide facilitated important changes in the lives of these patients. This qualitative research study suggests that the impact of setmelanotide goes beyond favorable clinical changes (e.g., weight and hunger) to also include quality of life improvements that are highly meaningful to patients. [ABSTRACT FROM AUTHOR]