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American Journal of Physiology.... Jun 2011Given the unabated obesity problem, there is increasing appreciation of expressions like "my eyes are bigger than my stomach," and recent studies in rodents and humans... (Review)
Review
Given the unabated obesity problem, there is increasing appreciation of expressions like "my eyes are bigger than my stomach," and recent studies in rodents and humans suggest that dysregulated brain reward pathways may be contributing not only to drug addiction but also to increased intake of palatable foods and ultimately obesity. After describing recent progress in revealing the neural pathways and mechanisms underlying food reward and the attribution of incentive salience by internal state signals, we analyze the potentially circular relationship between palatable food intake, hyperphagia, and obesity. Are there preexisting individual differences in reward functions at an early age, and could they be responsible for development of obesity later in life? Does repeated exposure to palatable foods set off a cascade of sensitization as in drug and alcohol addiction? Are reward functions altered by secondary effects of the obese state, such as increased signaling through inflammatory, oxidative, and mitochondrial stress pathways? Answering these questions will significantly impact prevention and treatment of obesity and its ensuing comorbidities as well as eating disorders and drug and alcohol addiction.
Topics: Animals; Behavior, Addictive; Humans; Hyperphagia; Models, Animal; Neural Pathways; Obesity; Reward; Signal Transduction
PubMed: 21411768
DOI: 10.1152/ajpregu.00028.2011 -
The Journal of Clinical Endocrinology... Jun 2023Prader-Willi syndrome (PWS) is a rare genetic disorder characterized by endocrine and neuropsychiatric problems including hyperphagia, anxiousness, and distress.... (Randomized Controlled Trial)
Randomized Controlled Trial
CONTEXT
Prader-Willi syndrome (PWS) is a rare genetic disorder characterized by endocrine and neuropsychiatric problems including hyperphagia, anxiousness, and distress. Intranasal carbetocin, an oxytocin analog, was investigated as a selective oxytocin replacement therapy.
OBJECTIVE
To evaluate safety and efficacy of intranasal carbetocin in PWS.
DESIGN
Randomized, double-blind, placebo-controlled phase 3 trial with long-term follow-up.
SETTING
Twenty-four ambulatory clinics at academic medical centers.
PARTICIPANTS
A total of 130 participants with PWS aged 7 to 18 years.
INTERVENTIONS
Participants were randomized to 9.6 mg/dose carbetocin, 3.2 mg/dose carbetocin, or placebo 3 times daily during an 8-week placebo-controlled period (PCP). During a subsequent 56-week long-term follow-up period, placebo participants were randomly assigned to 9.6 mg or 3.2 mg carbetocin, with carbetocin participants continuing at their previous dose.
MAIN OUTCOME MEASURES
Primary endpoints assessed change in hyperphagia (Hyperphagia Questionnaire for Clinical Trials [HQ-CT]) and obsessive-compulsive symptoms (Children's Yale-Brown Obsessive-Compulsive Scale [CY-BOCS]) during the PCP for 9.6 mg vs placebo, and the first secondary endpoints assessed these same outcomes for 3.2 mg vs placebo. Additional secondary endpoints included assessments of anxiousness and distress behaviors (PWS Anxiousness and Distress Behaviors Questionnaire [PADQ]) and clinical global impression of change (CGI-C).
RESULTS
Because of onset of the COVID-19 pandemic, enrollment was stopped prematurely. The primary endpoints showed numeric improvements in both HQ-CT and CY-BOCS which were not statistically significant; however, the 3.2-mg arm showed nominally significant improvements in HQ-CT, PADQ, and CGI-C scores vs placebo. Improvements were sustained in the long-term follow-up period. The most common adverse event during the PCP was mild to moderate flushing.
CONCLUSIONS
Carbetocin was well tolerated, and the 3.2-mg dose was associated with clinically meaningful improvements in hyperphagia and anxiousness and distress behaviors in participants with PWS.
CLINICAL TRIALS REGISTRATION NUMBER
NCT03649477.
Topics: Child; Humans; Prader-Willi Syndrome; Oxytocin; Pandemics; COVID-19; Hyperphagia; Anxiety
PubMed: 36633570
DOI: 10.1210/clinem/dgad015 -
Neuron Jul 2020In this issue of Neuron, Thoeni et al. (2020) demonstrate that both food restriction and a high-fat diet cause an endocannabinoid-dependent inhibition of D1 medium...
In this issue of Neuron, Thoeni et al. (2020) demonstrate that both food restriction and a high-fat diet cause an endocannabinoid-dependent inhibition of D1 medium spiny neuron terminals in the lateral hypothalamus that promotes overeating.
Topics: Humans; Hyperphagia; Hypothalamic Area, Lateral; Neurons; Synapses
PubMed: 32645304
DOI: 10.1016/j.neuron.2020.06.009 -
The Journal of Clinical Endocrinology... Aug 2022Patients with pro-opiomelanocortin (POMC) defects generally present with early-onset obesity, hyperphagia, hypopigmentation and adrenocorticotropin (ACTH) deficiency....
OBJECTIVE
Patients with pro-opiomelanocortin (POMC) defects generally present with early-onset obesity, hyperphagia, hypopigmentation and adrenocorticotropin (ACTH) deficiency. Rodent models suggest that adequate cleavage of ACTH to α-melanocortin-stimulating hormone (α-MSH) and desacetyl-α-melanocortin-stimulating hormone (d-α-MSH) by prohormone convertase 2 at the KKRR region is required for regulating food intake and energy balance.
METHODS
We present 2 sisters with a novel POMC gene variant, leading to an ACTH defect at the prohormone convertase 2 cleavage site, and performed functional studies of this variant.
RESULTS
The patients had obesity, hyperphagia and hypocortisolism, with markerly raised levels of ACTH but unaffected pigmentation. Their ACTH has reduced potency to stimulate the melanocortin (MC) 2 receptor, explaining their hypocortisolism.
CONCLUSION
The hyperphagia and obesity support evidence that adequate cleavage of ACTH to α-MSH and d-α-MSH is also required in humans for feeding control.
Topics: Adrenal Insufficiency; Adrenocorticotropic Hormone; Humans; Hyperphagia; Obesity; Pro-Opiomelanocortin; Proprotein Convertase 2; alpha-MSH
PubMed: 35737586
DOI: 10.1210/clinem/dgac342 -
Epidemiology and Health 2022Hyperphagia is a highly stressful, life-threatening feature of Prader-Willi syndrome (PWS). It is important to assess this complex behavior accurately over time. This...
OBJECTIVES
Hyperphagia is a highly stressful, life-threatening feature of Prader-Willi syndrome (PWS). It is important to assess this complex behavior accurately over time. This study aimed to develop and validate the Pediatric-Youth Hyperphagia Assessment for Prader-Willi syndrome (PYHAP) as a tool targeting children and adolescents.
METHODS
After an extensive literature review and qualitative interviews, the final version of the PYHAP with 14 questions in 3 domains (verbal [5], behavior [4], and social [5]) was developed and tested at Samsung Medical Center in Seoul, Korea from July 2018 to September 2019. Exploratory factor analysis and confirmatory factor analysis (CFA) were performed to confirm construct validity. The correlations between the PYHAP and the Korean Children's Eating Behavior Questionnaire (K-CEBQ) were calculated to evaluate convergent and discriminant validity. Criterion validity and the validity of the response categories were also tested.
RESULTS
Cronbach's alpha coefficient of the PYHAP was 0.91. The fit indices for CFA were good (comparative fit index, 0.87; standardized root mean squared residual, 0.08). The domains of the PYHAP were closely correlated with the relevant domains of the K-CEBQ. The accuracy of the PYHAP score for predicting uncontrolled hyperphagia was good (area under the curve, 0.75; 95% confidence interval, 0.65 to 0.85).
CONCLUSIONS
The PYHAP was confirmed to be a reliable and valid tool to evaluate hyperphagia in children and adolescents with PWS via caregivers' assessments. It is recommended to use the PYHAP to communicate with parents or caregivers about patients' hyperphagia or to monitor and manage extreme behaviors in children with PWS.
Topics: Adolescent; Caregivers; Child; Feeding Behavior; Humans; Hyperphagia; Prader-Willi Syndrome; Surveys and Questionnaires
PubMed: 35038830
DOI: 10.4178/epih.e2022014 -
American Journal of Physiology.... May 2019The main objective of these studies was to characterize metabolic, body composition, and cardiovascular responses to a free-choice high-fat, high-sucrose diet in female...
The main objective of these studies was to characterize metabolic, body composition, and cardiovascular responses to a free-choice high-fat, high-sucrose diet in female cycling and pregnant rats. In the nonpregnant state, female Sprague-Dawley rats offered a 3-wk free-choice high-fat, high-sucrose diet had greater energy intake, adiposity, serum leptin, and triglyceride concentrations compared with rats fed with standard chow and developed glucose intolerance. In addition, choice-diet-fed rats had larger cardiac ventricular weights, smaller kidney and pancreas weights, and higher blood pressure than chow-fed rats, but they did not exhibit resistance artery endothelial dysfunction. When the free-choice diet continued throughout pregnancy, rats remained hyperphagic, hyperleptinemic, and obese. Choice pregnant rats exhibited uterine artery endothelial dysfunction and had smaller fetuses compared with chow pregnant rats. Pregnancy normalized mean arterial blood pressure and pancreas weights in choice rats. These studies are the first to provide a comprehensive evaluation of free-choice high-fat, high-sucrose diet on metabolic and cardiovascular functions in female rats, extending the previous studies in males to female cycling and pregnant rodents. Free-choice diet may provide a new model of preconceptual maternal obesity to study the role of increased energy intake, individual food components, and preexisting maternal obesity on maternal and offspring physiological responses during pregnancy and after birth.
Topics: Adiposity; Animal Nutritional Physiological Phenomena; Animals; Behavior, Animal; Biomarkers; Cardiovascular Diseases; Choice Behavior; Diet, High-Fat; Dietary Sucrose; Energy Metabolism; Estrous Cycle; Feeding Behavior; Female; Fetal Growth Retardation; Hemodynamics; Hyperphagia; Maternal Nutritional Physiological Phenomena; Nutritional Status; Obesity; Pregnancy; Rats, Sprague-Dawley; Weight Gain
PubMed: 30758976
DOI: 10.1152/ajpregu.00391.2018 -
Andes Pediatrica : Revista Chilena de... Jun 2021Prader-Willi Syndrome (PWS) is the most common cause of genetic obesity. Hyperphagia and obe sity are the most associated concepts with this condition. However,...
INTRODUCTION
Prader-Willi Syndrome (PWS) is the most common cause of genetic obesity. Hyperphagia and obe sity are the most associated concepts with this condition. However, undernutrition secondary to severe hypotonia and feeding difficulties is the predominant initial feature.
OBJECTIVE
to reprodu ce and communicate the nutritional phases on a series of Chilean cases with PWS.
PATIENTS AND METHOD
Cross-sectional study in which clinical records of PWS individuals under nutritional con trol at the Clínica Santa María in Santiago, Chile between 2017 and 2018 were analyzed. The anthro pometric references of the World Health Organization were used to carry out the nutritional as sessment. The classification into nutritional phases was according to the Miller criteria.
RESULTS
24 patients from infants to adults were included. All children aged under 9 months were in phase I and had malnutrition or were eutrophic; those between 9 and 25 months were classified in phase 2a; pa tients between 2.1 and 4.5 years were distributed between phases 1 and 2 and 66% were eutrophic; those between 4.5 to 8 years, 80% were in phase 2a and 2b and obesity begins to appear, and patients over 8 years of age, 75% were in phase 3 and all are overweight or obese. There was an association bet ween nutritional phase and age but not between it and nutritional status.
CONCLUSIONS
In our series, the nutritional phases described according to age were reproduced according to those internationally described. There was no association between nutritional status and age.
Topics: Adolescent; Adult; Age Factors; Child; Child, Preschool; Cross-Sectional Studies; Disease Progression; Female; Humans; Hyperphagia; Infant; Infant, Newborn; Male; Malnutrition; Pediatric Obesity; Prader-Willi Syndrome; Young Adult
PubMed: 34479241
DOI: 10.32641/andespediatr.v92i3.2400 -
The International Journal of... Sep 2022The dopaminergic partial agonism of the so-called third-generation antipsychotics (TGAs; aripiprazole, brexpiprazole, cariprazine) is hypothesized to cause impulse...
BACKGROUND
The dopaminergic partial agonism of the so-called third-generation antipsychotics (TGAs; aripiprazole, brexpiprazole, cariprazine) is hypothesized to cause impulse control disorders (ICDs). Relevant warnings by the Food and Drug Administration (FDA) were posted on aripiprazole (2016) and brexpiprazole (2018). Our study investigated the FDA Adverse Event Reporting System and the pharmacodynamic CHEMBL database to further characterize TGA-induced ICDs.
METHODS
We downloaded and pre-processed the FDA Adverse Event Reporting System up to December 2020. We adapted Bradford Hill criteria to assess each TGA's -and secondarily other antipsychotics'-causal role in inducing ICDs (pathological gambling, compulsive shopping, hyperphagia, hypersexuality), accounting for literature and disproportionality. ICD clinical features were analyzed, and their pathogenesis was investigated using receptor affinities.
RESULTS
A total of 2708 reports of TGA-related ICDs were found, primarily recording aripiprazole (2545 reports, 94%) among the drugs, and gambling (2018 reports, 75%) among the events. Bradford-Hill criteria displayed evidence for a causal role of each TGA consistent across subpopulations and when correcting for biases. Significant disproportionalities also emerged for lurasidone with compulsive shopping, hyperphagia, and hypersexuality, and olanzapine and ziprasidone with hyperphagia. Time to onset varied between days and years, and positive dechallenge was observed in 20% of cases. Frequently, co-reported events were economic (50%), obsessive-compulsive (44%), and emotional conditions (34%). 5-Hydroxytryptamine receptor type 1a agonism emerged as an additional plausible pathogenetic mechanism.
CONCLUSIONS
We detected an association between TGAs and ICDs and identified a new signal for lurasidone. ICD characteristics are behavior specific and may heavily impact on life. The role of 5-Hydroxytryptamine receptor type 1a agonism should be further explored.
Topics: Antipsychotic Agents; Aripiprazole; Disruptive, Impulse Control, and Conduct Disorders; Dopamine; Dopamine Agonists; Humans; Hyperphagia; Lurasidone Hydrochloride; Olanzapine; Pharmacovigilance; Quinolones; Receptors, Serotonin; Thiophenes; United States; United States Food and Drug Administration
PubMed: 35639870
DOI: 10.1093/ijnp/pyac031 -
Biochimica Et Biophysica Acta.... Oct 2017The burden of disability, premature death, escalating health care costs and lost economic productivity due to obesity and its associated complications including... (Review)
Review
The burden of disability, premature death, escalating health care costs and lost economic productivity due to obesity and its associated complications including hypertension, stroke, cardiovascular disease and type 2 diabetes is staggering [1,2]. A better understanding of metabolic homeostatic pathways will provide us with insights into the biological mechanisms of obesity and how to fundamentally address this epidemic [3-6]. In mammals, energy balance is maintained via a homeostatic system involving both peripheral and central melanocortin systems; changes in body weight reflect an unbalance of the energetic state [7-9]. Although the primary cause of obesity is unknown, there is significant effort to understand the role of the central melanocortin pathway in the brain as it has been shown that deficiency of proopiomelanocortin (POMC) [10,11] and melanocortin 4 receptors (MC4R) [12-15] in both rodents and humans results in severe hyperphagia and obesity [16-23]. In this review, we will summarize how the central melanocortin pathway helps regulate body mass and adiposity within a 'healthy' range through the 'nutrient sensing' network [24-28]. This article is part of a Special Issue entitled: Melanocortin Receptors - edited by Ya-Xiong Tao.
Topics: Animals; Energy Metabolism; Humans; Hyperphagia; Melanocortins; Mutation; Neurons; Obesity; Pro-Opiomelanocortin; Receptor, Melanocortin, Type 4; Signal Transduction
PubMed: 28499988
DOI: 10.1016/j.bbadis.2017.05.007 -
Journal of Neuroendocrinology Jul 2021Prader-Willi Syndrome (PWS) is a rare and incurable congenital neurodevelopmental disorder, resulting from the absence of expression of a group of genes on the... (Review)
Review
Prader-Willi Syndrome (PWS) is a rare and incurable congenital neurodevelopmental disorder, resulting from the absence of expression of a group of genes on the paternally acquired chromosome 15q11-q13. Phenotypical characteristics of PWS include infantile hypotonia, short stature, incomplete pubertal development, hyperphagia and morbid obesity. Hypothalamic dysfunction in controlling body weight and food intake is a hallmark of PWS. Neuroimaging studies have demonstrated that PWS subjects have abnormal neurocircuitry engaged in the hedonic and physiological control of feeding behavior. This is translated into diminished production of hypothalamic effector peptides which are responsible for the coordination of energy homeostasis and satiety. So far, studies with animal models for PWS and with human post-mortem hypothalamic specimens demonstrated changes particularly in the infundibular and the paraventricular nuclei of the hypothalamus, both in orexigenic and anorexigenic neural populations. Moreover, many PWS patients have a severe endocrine dysfunction, e.g. central hypogonadism and/or growth hormone deficiency, which may contribute to the development of increased fat mass, especially if left untreated. Additionally, the role of non-neuronal cells, such as astrocytes and microglia in the hypothalamic dysregulation in PWS is yet to be determined. Notably, microglial activation is persistently present in non-genetic obesity. To what extent microglia, and other glial cells, are affected in PWS is poorly understood. The elucidation of the hypothalamic dysfunction in PWS could prove to be a key feature of rational therapeutic management in this syndrome. This review aims to examine the evidence for hypothalamic dysfunction, both at the neuropeptidergic and circuitry levels, and its correlation with the pathophysiology of PWS.
Topics: Animals; Humans; Hyperphagia; Hypogonadism; Hypothalamic Hormones; Hypothalamus; Nerve Net; Neuropeptides; Obesity; Prader-Willi Syndrome
PubMed: 34156126
DOI: 10.1111/jne.12994