Behavioral changes in patients with Prader-Willi syndrome receiving diazoxide choline extended-release tablets compared to the PATH for PWS natural history study.

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 < 0.001) and 52 weeks (LSmean [SE] -9.2 [0.77] vs. -3.4 [0.47], p < 0.001). The comparison between the cohorts remained significant in the worst-case imputation sensitivity analysis. There were also significant improvements in all domains of the PWSP at 26 weeks (all p < 0.001) and 52 weeks (all p ≤ 0.003) for C601/C602 participants compared to the PATH for PWS participants. CONCLUSION: Long-term administration of DCCR to people with PWS resulted in changes in hyperphagia and other behavioral complications of PWS that are distinct from the natural history of the syndrome as exemplified by the cohort from PATH for PWS. The combined effects of administration of DCCR should reduce the burden of the syndrome on the patient, caregivers and their families, and thereby may benefit people with PWS and their families. TRIAL REGISTRATION: Clinical study C601 was originally registered on ClinicalTrials.gov on February 22, 2018 (NCT03440814). Clinical study C602 was originally registered on ClinicalTrials.gov on October 22, 2018 (NCT03714373). PATH for PWS was originally registered on ClinicalTrials.gov on October 24, 2018 (NCT03718416).

From Pleasure to Pathology: Understanding the Neural Basis of Food Addiction in the Context of Obesity.

As rates of severe obesity continue to rise globally, intense efforts are required both from the scientific community, physicians and health policy makers to better understand the mechanisms, prevent and treat obesity in order to stop the upcoming pandemic. Obesity is known to significantly reduce life expectancy and overall quality of life, thus becoming a leading cause of preventable deaths. This article focuses on the relationship between obesity and food addiction, the main neural mechanisms, brain regions, genes, hormones and neurotransmitters involved and on the similarities between food addiction and substance abuse. The definition of obesity is based on the body mass index (BMI). A BMI of 30 or higher is classified as obese. Obesity is not solely a result of overeating, but has multifactorial causes, thus, prevention being extremely difficult. The concept of food addiction implies extreme cravings, lack of self-control, and overeating, especially involving tasty foods. The addiction concept is supported both by clinicalbehavioural research and neurobiological research. These studies demonstrate similarities between binge eating and drug addiction, including cravings, loss of control, excessive intake, tolerance, withdrawal, and distress/dysfunction. Although generally food addiction is thought to be distinct from obesity, most studies identify that a significant percentage of individuals with food addiction are obese. Our aim was to emphasize the need to better understand the neurological basis of obesity and addiction, and its implications for research, treatment, and public health initiatives. Understanding the neural mechanisms underlying food addiction can inform future healthcare policies and interventions aimed at addressing the global obesity epidemic.

Multifactorial influences on successful health outcomes for an adolescent with Prader-Willi syndrome: a qualitative case study.

PURPOSE: Prader-Willi syndrome (PWS) is the most common syndromic cause of childhood obesity. This qualitative case study aimed to identify and describe lifestyle themes of an adolescent with PWS that resulted in maintenance of a healthy body mass index (BMI). CASE DESCRIPTION: The 16-year-old female demonstrated failure to thrive upon birth and underwent 9 months supplemented tube feeding, achieving 50th percentile weight for height. Throughout childhood she received treatment of physical, occupational, and speech therapies, and has maintained a healthy BMI ranging from 25-50th percentile weight for height. METHODS AND RESULTS: Two video interviews were completed separately. Qualitative analysis of the transcribed data identified two overarching themes for maintaining a healthy BMI in this adolescent: 1) adolescent and parent individual characteristics; and 2) family dynamics and lifestyle. Adolescent and parental characteristics included: high level of cognitive function for diagnosis, mild hyperphagia, desire for a regimented schedule, parental type A personalities, intentionality in parental decisions/actions. Family lifestyle characteristics included strong parental involvement and well-defined expectations for their daughter, purposeful integration of physical activity into lifestyle, and presence of a strong family support system. CONCLUSION: The convergence of multiple optimal influences provided an ideal health outcome in the adolescent.

Hyperphagia and hyperleptinemia induced by low-protein, high-carbohydrate diet is reversed at a later stage of development in rats.

This study investigated whether increased food intake after 15 days of low-protein, high-carbohydrate (LPHC) and its normalization in the later period of development change the content of key proteins related to leptin or adiponectin signaling in the hypothalamus. Male rats were divided into five groups: Control groups received a control diet (17% protein, 63% carbohydrate) for 15 (C15) or 45 (C45) days; LPHC groups received an LPHC diet (6% protein, 74% carbohydrate) for 15 (LPHC15) or 45 (LPHC45) days; and Reverse group (R): received LPHC diet for 15 days followed by control diet for another 30 days. The LPHC15 group showed increased adiposity index, leptin level, and adiponectin level, as well as decreased the leptin receptor (ObRb) and pro-opiomelanocortin (POMC) content in the hypothalamus compared with the C15 group. LPHC diet for 45 days or diet reversion (R group) rescued these alterations, except the adiponectin level in LPHC45 rats, which was higher. In summary, LPHC diet reduced hypothalamic leptin action by diminishing ObRb and POMC levels, leading to hyperphagia and adiposity body. Medium-term administration of LPHC diet or reverting to control diet restored the levels of these proteins, thereby improving body lipid mass rearrangement in adulthood.

A case of postoperative cerebellar mutism with hyperphagia in a child following gross total resection of medulloblastoma occupying the cerebellar vermis.

INTRODUCTION: Cerebellar mutism syndrome is a well-known complication following posterior fossa tumor resection. Its incidence is markedly increased among patients with medulloblastoma. Patients typically present with an inability to communicate verbally due to disruption of the dentato-thalamocortical pathway. CASE DESCRIPTION: We present a unique case of cerebellar mutism in a three-year-old girl who underwent gross total resection of medulloblastoma occupying the cerebellar vermis. In addition to mutism, the patient developed hyperphagia. DISCUSSION: This case report aims to contribute to current understanding of the role of cerebello-hypothalamic connections in cerebellar mutism and their clinical significance.

Prader-Willi Syndrome: Possibilities of Weight Gain Prevention and Treatment.

Prader-Willi syndrome (PWS) is a complex genetic disorder which involves the endocrine and neurologic systems, metabolism, and behavior. The aim of this paper is to summarize current knowledge on dietary management and treatment of PWS and, in particular, to prevent excessive weight gain. Growth hormone (GH) therapy is the recommended standard treatment for PWS children, because it improves body composition (by changing the proportion of body fat and lean body mass specifically by increasing muscle mass and energy expenditure), linear growth, and in infants, it promotes psychomotor and IQ development. In early childhood, the predominant symptom is hyperphagia which can lead to early onset, severe obesity with different obesity-related comorbidities. There are several studies on anti-obesity medications (metformin, topiramate, liraglutide, setmelanotide). However, these are still limited, and no widely accepted consensus guideline exists concerning these drugs in children with PWS. Until there is a specific treatment for hyperphagia and weight gain, weight must be controlled with the help of diet and exercise. Below the age of one year, children with PWS have no desire to eat and will often fail to thrive, despite adequate calories. After the age of two years, weight begins to increase without a change in calorie intake. Appetite increases later, gradually, and becomes insatiable. Managing the progression of different nutritional phases (0-4) is really important and can delay the early onset of severe obesity. Multidisciplinary approaches are crucial in the diagnosis and lifelong follow-up, which will determine the quality of life of these patients.

The Orexigenic Force of Olfactory Palatable Food Cues in Rats.

Environmental cues recalling palatable foods motivate eating beyond metabolic need, yet the timing of this response and whether it can develop towards a less palatable but readily available food remain elusive. Increasing evidence indicates that external stimuli in the olfactory modality communicate with the major hub in the feeding neurocircuitry, namely the hypothalamic arcuate nucleus (Arc), but the neural substrates involved have been only partially uncovered. By means of a home-cage hidden palatable food paradigm, aiming to mimic ubiquitous exposure to olfactory food cues in Western societies, we investigated whether the latter could drive the overeating of plain chow in non-food-deprived male rats and explored the neural mechanisms involved, including the possible engagement of the orexigenic ghrelin system. The olfactory detection of a familiar, palatable food impacted upon meal patterns, by increasing meal frequency, to cause the persistent overconsumption of chow. In line with the orexigenic response observed, sensing the palatable food in the environment stimulated food-seeking and risk-taking behavior, which are intrinsic components of food acquisition, and caused active ghrelin release. Our results suggest that olfactory food cues recruited intermingled populations of cells embedded within the feeding circuitry within the Arc, including, notably, those containing the ghrelin receptor. These data demonstrate the leverage of ubiquitous food cues, not only for palatable food searching, but also to powerfully drive food consumption in ways that resonate with heightened hunger, for which the orexigenic ghrelin system is implicated.

Nutritional phases of Prader-Willi syndrome. / Fases nutricionales en Síndrome de Prader-Willi.

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.

Perceived Stress and Increased Food Consumption during the 'Third Wave' of the COVID-19 Pandemic in Spain.

The COVID-19 pandemic has impacted the mental health of people worldwide. An increase in perceived stress can lead to unhealthy behaviors such as increased food consumption. The aim of this study was to find the level of perceived stress and its relationship with increased food consumption during the "third wave" of the COVID-19 pandemic in Spain. This was a cross-sectional study that employed anonline self-reported frequency of consumption questionnaire and the Perceived Stress Scale-10. A total of 637 subjects participated and 83.6% of respondents had moderate or high stress-more prevalent in the female and young respondents. Moreover, 36.1% of respondents reported that they had increased the frequency of consumption of some foods, mainly nuts, snacks, and jellybeans, along with coffee, tea, cocoa, and soft drinks. Eating between meals was more pronounced in those with high stress (65.1%) than in those with moderate stress (40.4%) and low stress (20.2%). Furthermore, the respondents with high stress reported greater weight gain. Thus, the results show that the level of perceived stress during the 'third wave' of this pandemic increased food consumption.

Excessive eating and weight gain:A rare post-acute COVID-19 syndrome.

The coronavirus disease - 2019 (COVID-19) is a multisystem illness associated with several metabolic derangements. Studies report that post-acute COVID-19 syndromes (PACs) continue to evolve, however, polyphagia is not uncommon. Herein, we report a rare occurrence of polyphagia in a patient following acute COVID-19 illness. A-41-year-old Ugandan female with a negative past medical history presented with complains of excessive appetite, eating large amounts of food, inability to feel satisfied, failure to control desire to eat, and weight gain 6 months following recovery from a mild episode of acute COVID-19 pneumonia. Her body mass index rose to 30 Kg/m2 from 22 Kg/m2 prior to suffering from COVID-19. There was no history of polyuria, polydipsia, pruritus, or prior eating disorder or related history. Investigation found that brain computed tomography scan was normal, fasting blood sugar to be 5.6 mmol/L (normal range, 3.9-7.0 mmol/L), adrenocorticotropin hormone level to be 8.763 pg/mL (normal range, 6-40 pg/mL), erythrocyte sedimentation rate to be 12 mm/hour (0-30 mm/hour), but there was an elevation in glycosylated hemoglobin level (HbA1c, 7.7%). She was commenced on psychotherapy and behavioral changes with good outcomes. Polyphagia may be one of the rare PACs, requiring further research.

Hypothalamic neuropeptides and neurocircuitries in Prader Willi syndrome.

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.

Loss of CREB Coactivator CRTC1 in SF1 Cells Leads to Hyperphagia and Obesity by High-fat Diet But Not Normal Chow Diet.

Cyclic adenosine monophosphate responsive element-binding protein-1-regulated transcription coactivator-1 (CRTC1) is a cytoplasmic coactivator that translocates to the nucleus in response to cyclic adenosine monophosphate. Whole-body knockdown of Crtc1 causes obesity, resulting in increased food intake and reduced energy expenditure. CRTC1 is highly expressed in the brain; therefore, it might play an important role in energy metabolism via the neuronal pathway. However, the precise mechanism by which CRTC1 regulates energy metabolism remains unknown. Here, we showed that mice lacking CRTC1, specifically in steroidogenic factor-1 expressing cells (SF1 cells), were sensitive to high-fat diet (HFD)-induced obesity, exhibiting hyperphagia and increased body weight gain. The loss of CRTC1 in SF1 cells impaired glucose metabolism. Unlike whole-body CRTC1 knockout mice, SF1 cell-specific CRTC1 deletion did not affect body weight gain or food intake in normal chow feeding. Thus, CRTC1 in SF1 cells is required for normal appetite regulation in HFD-fed mice. CRTC1 is primarily expressed in the brain. Within the hypothalamus, which plays an important role for appetite regulation, SF1 cells are only found in ventromedial hypothalamus. RNA sequencing analysis of microdissected ventromedial hypothalamus samples revealed that the loss of CRTC1 significantly changed the expression levels of certain genes. Our results revealed the important protective role of CRTC1 in SF1 cells against dietary metabolic imbalance.

COVID-19 Stress and Food Intake: Protective and Risk Factors for Stress-Related Palatable Food Intake in U.S. Adults.

(1) Background: The coronavirus (COVID-19) pandemic has caused disruptions to what people eat, but the pandemic's impact on diet varies between individuals. The goal of our study was to test whether pandemic-related stress was associated with food intake, and whether relationships between stress and intake were modified by appetitive and cognitive traits. (2) Methods: We cross-sectionally surveyed 428 adults to examine current intake frequency of various food types (sweets/desserts, savory snacks, fast food, fruits, and vegetables), changes to food intake during the pandemic, emotional overeating (EOE), cognitive flexibility (CF), and COVID-19-related stress. Models tested associations of stress, EOE, and CF with food intake frequency and changes to intake. (3) Results: Models demonstrated that the positive relationship between stress and intake of sweets/desserts was stronger with higher EOE, while the positive relationship between stress and intake of chips/savory snacks was weaker with higher CF. Higher EOE was associated with greater risk of increased intake of palatable foods. (4) Conclusions: Findings suggest that emotional overeating may escalate stress-associated intake of high-sugar foods, and cognitive flexibility may attenuate stress-associated intake of high-fat foods. Differences in appetitive and cognitive traits may explain changes to and variability in food intake during COVID-19, and efforts to decrease emotional overeating and encourage cognitive flexibility could help lessen the effect of COVID-19-related stress on energy dense food intake.

Maternal obesity interrupts the coordination of the unfolded protein response and heat shock response in the postnatal developing hypothalamus of male offspring in mice.

Maternal obesity malprograms offspring obesity and associated metabolic disorder. As a common phenomenon in obesity, endoplasmic reticulum (ER) stress also presents early prior to the development. Here, we investigate metabolic effect of early activated hypothalamic ER stress in offspring exposed to maternal obesogenic environment and the underlying mechanism in ICR mice model. We found higher body weight, hyperphagia and defective hypothalamic feeding-circuit in the offspring born to obese dams, with hypothalamic ER stress, and even more comprehensive cell proteotoxic stress were induced during the early postnatal period. However, neonatal inhibition of hypothalamic ER stress worsened the metabolic end. We believe that the uncoordinated interaction between the unfolded protein response and the heat shock response, regulated by heat shock protein 70, might be responsible for the malformed hypothalamic feeding circuit of the offspring exposure to maternal obesogenic conditions and were linked with deleterious metabolism in adulthood, especially when exposure to high-energy conditions.

Gut Hormones in Health and Obesity: The Upcoming Role of Short Chain Fatty Acids.

We are currently facing an obesity pandemic, with worldwide obesity rates having tripled since 1975. Obesity is one of the main risk factors for the development of non-communicable diseases, which are now the leading cause of death worldwide. This calls for urgent action towards understanding the underlying mechanisms behind the development of obesity as well as developing more effective treatments and interventions. Appetite is carefully regulated in humans via the interaction between the central nervous system and peripheral hormones. This involves a delicate balance in external stimuli, circulating satiating and appetite stimulating hormones, and correct functioning of neuronal signals. Any changes in this equilibrium can lead to an imbalance in energy intake versus expenditure, which often leads to overeating, and potentially weight gain resulting in overweight or obesity. Several lines of research have shown imbalances in gut hormones are found in those who are overweight or obese, which may be contributing to their condition. Therefore, this review examines the evidence for targeting gut hormones in the treatment of obesity by discussing how their dysregulation influences food intake, the potential possibility of altering the circulating levels of these hormones for treating obesity, as well as the role of short chain fatty acids and protein as novel treatments.

Obesity, eating behavior and physical activity during COVID-19 lockdown: A study of UK adults.

Eating, physical activity and other weight-related lifestyle behaviors may have been impacted by the COVID-19 crisis and people with obesity may be disproportionately affected. We examined weight-related behaviors and weight management barriers among UK adults during the COVID-19 social lockdown. During April-May of the 2020 COVID-19 social lockdown, UK adults (N = 2002) completed an online survey including measures relating to physical activity, diet quality, overeating and how mental/physical health had been affected by lockdown. Participants also reported on perceived changes in weight-related behaviors and whether they had experienced barriers to weight management, compared to before the lockdown. A large number of participants reported negative changes in eating and physical activity behavior (e.g. 56% reported snacking more frequently) and experiencing barriers to weight management (e.g. problems with motivation and control around food) compared to before lockdown. These trends were particularly pronounced among participants with higher BMI. During lockdown, higher BMI was associated with lower levels of physical activity and diet quality, and a greater reported frequency of overeating. Reporting a decline in mental health because of the COVID-19 crisis was not associated with higher BMI, but was predictive of greater overeating and lower physical activity in lockdown. The COVID-19 crisis may have had a disproportionately large and negative influence on weight-related behaviors among adults with higher BMI.

A case of isolated hypothalamitis with a literature review and a comparison with autoimmune hypophysitis.

Idiopathic hypothalamitis is a rare condition that can cause anterior pituitary dysfunction and central diabetes insipidus (CDI), occasionally accompanied by a disturbance of autonomic regulation known as hypothalamic syndrome. This condition has been described as a subtype of autoimmune (lymphocytic) hypophysitis; however, some cases of isolated hypothalamic involvement with no inflammatory lesions in either the pituitary gland or infundibulum have been reported. The detailed epidemiology and pathophysiology of isolated hypothalamitis have not been clarified. We herein report a case of a solitary hypothalamic lesion in a young woman who showed spontaneous development of CDI and panhypopituitarism accompanied by hyperphagia. The hypothalamic lesion increased from 11 × 7 to 17 × 7 mm over 16 months based on the sagittal slices of magnetic resonance imaging examinations. The negative results for anti-pituitary antibodies and anti-Rabphilin-3A antibodies suggested that upward extension of lymphocytic adenohypophysitis or infundibulo-neurohypophysitis was unlikely. Infectious disease, granulomatosis, Langerhans cell histiocytosis, vasculitis, and systemic neoplastic diseases were excluded by the findings of a laboratory investigation, cerebrospinal fluid examination, and imaging studies. To make a definitive diagnosis, we performed a ventriculoscopic biopsy of the hypothalamic lesion. Histology revealed an infiltration of nonspecific lymphoplasmacytes with no evidence of neoplasm, which was consistent with a diagnosis of idiopathic hypothalamitis. Subsequently, the patient was treated with methylprednisolone pulse therapy followed by oral prednisolone. The hypothalamic lesion improved and remained undetectable after withdrawal of the prednisolone, suggesting that the glucocorticoid treatment was effective for isolated hypothalamitis while the patient remains dependent on the replacement of multiple hormones.

Intranasal oxytocin versus placebo for hyperphagia and repetitive behaviors in children with Prader-Willi Syndrome: A randomized controlled pilot trial.

OBJECTIVE: The effects of intranasal oxytocin and placebo on hyperphagia and repetitive behaviors were compared in children and adolescents with Prader Willi Syndrome (PWS). METHODS: Children and adolescents with PWS were enrolled in an 8-week double-blind placebo-controlled intranasal oxytocin randomized trial. Twenty-three (23) subjects were assigned to oxytocin (N = 11) or placebo (N = 12). Hyperphagia was measured with the Hyperphagia Questionnaire (HQ), and repetitive behavior was measured with Repetitive Behavior Scale- Revised (RBS-R). RESULTS: There were modest significant treatment by-time interactions indicating reduction in hyperphagia and repetitive behaviors across time for placebo but no reduction for oxytocin. Total HQ score showed a greater average reduction of 1.81 points/week for the placebo group vs. oxytocin, with maximum reduction at week 4. There were also greater reductions on HQ-Drive and HQ-Behavior subscales on placebo vs. oxytocin. RBS-R subscales followed similar patterns to the HQ, with a significantly greater reduction in sameness subscale behaviors (average 0.825 points/week) in the placebo group compared to the oxytocin group. Oxytocin was well tolerated, and the only adverse event that was both more common and possibly related to oxytocin vs. placebo was nocturia (n = 1 vs 0). CONCLUSION: Placebo was associated with modest improvement in hyperphagia and repetitive behaviors in childhood PWS whereas intranasal oxytocin was not associated with improvement in these domains. More work is needed to understand the meaning and mechanism of these findings on hyperphagia and repetitive behaviors in PWS.

Mid-gestation low-dose LPS administration results in female-specific excessive weight gain upon a western style diet in mouse offspring.

Gestational complications, including preeclampsia and gestational diabetes, have long-term adverse consequences for offspring's metabolic and cardiovascular health. A low-grade systemic inflammatory response is likely mediating this. Here, we examine the consequences of LPS-induced gestational inflammation on offspring's health in adulthood. LPS was administered to pregnant C57Bl/6J mice on gestational day 10.5. Maternal plasma metabolomics showed oxidative stress, remaining for at least 5 days after LPS administration, likely mediating the consequences for the offspring. From weaning on, all offspring was fed a control diet; from 12 to 24 weeks of age, half of the offspring received a western-style diet (WSD). The combination of LPS-exposure and WSD resulted in hyperphagia and increased body weight and body fat mass in the female offspring. This was accompanied by changes in glucose tolerance, leptin and insulin levels and gene expression in liver and adipose tissue. In the hypothalamus, expression of genes involved in food intake regulation was slightly changed. We speculate that altered food intake behaviour is a result of dysregulation of hypothalamic signalling. Our results add to understanding of how maternal inflammation can mediate long-term health consequences for the offspring. This is relevant to many gestational complications with a pro-inflammatory reaction in place.

Maternal High Fat Diet Programs Male Mice Offspring Hyperphagia and Obesity: Mechanism of Increased Appetite Neurons via Altered Neurogenic Factors and Nutrient Sensor AMPK.

Maternal high-fat (HF) is associated with offspring hyperphagia and obesity. We hypothesized that maternal HF alters fetal neuroprogenitor cell (NPC) and hypothalamic arcuate nucleus (ARC) development with preferential differentiation of neurons towards orexigenic (NPY/AgRP) versus anorexigenic (POMC) neurons, leading to offspring hyperphagia and obesity. Furthermore, these changes may involve hypothalamic bHLH neuroregulatory factors (Hes1, Mash1, Ngn3) and energy sensor AMPK. Female mice were fed either a control or a high fat (HF) diet prior to mating, and during pregnancy and lactation. HF male newborns were heavier at birth and exhibited decreased protein expression of hypothalamic bHLH factors, pAMPK/AMPK and POMC with increased AgRP. As adults, these changes persisted though with increased ARC pAMPK/AMPK. Importantly, the total NPY neurons were increased, which was consistent with the increased food intake and adult fat mass. Further, NPCs from HF newborn hypothalamic tissue showed similar changes with preferential NPC neuronal differentiation towards NPY. Lastly, the role of AMPK was further confirmed with in vitro treatment of Control NPCs with pharmacologic AMPK modulators. Thus, the altered ARC development of HF offspring results in excess appetite and reduced satiety leading to obesity. The underlying mechanism may involve AMPK/bHLH pathways.