Individual characteristics and environmental factors influencing preschoolers' emotional eating.

Emotional eating, which refers to eating in response to emotional states, is prevalent in early childhood. Executive function (EF) and sleep problems are related to preschoolers' self-regulatory abilities during the day and night and have been reported to be associated with their emotional eating. These associations can be stronger in emotionally stressful situations, such as controlling feeding practices. This study explored the role of preschoolers' EF and sleep problems as child characteristics, as well as maternal feeding practices as environmental factors influencing emotional eating during the preschool period. Participants included 363 Korean mothers with preschoolers aged 3- to 5-years old (190 boys, 173 girls). Mothers reported on their own feeding practices, and preschoolers' EF, sleep problems, and emotional eating. Results indicated that preschoolers' EF was negatively associated with emotional over- and undereating, and this association was stronger when mothers applied more pressure to eat. Maternal monitoring had a similar effect, with emotional overeating exerting a greater impact with low levels of maternal monitoring. Finally, maternal pressure to eat moderated the influence of preschoolers' sleep problems on emotional overeating, with higher pressure to eat predicting a stronger relationship between sleep problems and emotional overeating. These findings suggest that maternal feeding practices, which are relatively modifiable, should be considered an important element in intervention programs aimed at preventing emotional eating in preschool children.

Parent's use of coercive control practices with food is associated with poorer emotion regulation and increased emotional overeating in preschoolers.

Emotional overeating is defined as eating in response to emotions. Around the preschool years, there is a shift from emotional undereating to overeating, which suggests environmental influences in the development of overeating. The use of food by parents to control their child's emotions, rather than to teach them appropriate emotion regulation strategies, may impact the child's ability to regulate their own emotions, resulting in emotional overeating. We hypothesized that such coercive control practices with food by parents would be associated with poorer ability of the child to regulate their own emotions, which in turn would lead to increased emotional overeating, but not emotional undereating. Mothers of four- and five-year-olds (N = 221) were recruited through MTurk and Prolific to complete online questionnaires measuring food parenting practices (Comprehensive Feeding Style Questionnaire and Parent Feeding Style Questionnaire), child emotion regulation (Emotion Regulation Checklist), and child emotional eating (Child Eating Behavior Questionnaire). Several mediation models were tested. Parent's use of food to control emotions and behavior was associated with higher levels of emotional overeating, which was mediated by poorer child emotion regulation. However, child emotion regulation did not mediate the association between parent's use of food to control emotions and behavior and the child's emotional undereating. Taken together, these models suggest that parent's use of coercive control with food may lead to child emotional overeating, but not emotional undereating, by teaching children to regulate their emotions through eating rather than more adaptive regulation strategies. Future experimental and longitudinal studies are needed to directly test the nature and direction of these associations and whether coercive control with food teaches children to overeat in response to their emotions in lieu of using appropriate emotion regulation strategies.

The homeodomain transcription factor Six3 regulates hypothalamic Pomc expression and its absence from POMC neurons induces hyperphagia and mild obesity in male mice.

OBJECTIVE: Proopiomelanocortin (POMC) neurons release potent anorexigenic neuropeptides, which suppress food intake and enhance energy expenditure via melanocortin receptors. Although the importance of central melanocortin in physiological regulation is well established, the underlying genetic mechanisms that define the functional identity of melanocortin neurons and maintain hypothalamic Pomc expression remain to be fully determined. In this study, we investigate the functional significance of Six3, a transcriptional regulator notably expressed in embryonic and adult mouse POMC neurons, in the regulation of hypothalamic Pomc expression and downstream physiological consequences. METHODS: We first evaluated the expression of Six3 in the developing and adult hypothalamus by double fluorescence in situ hybridization. Next, we assessed POMC immunoreactivity in mutant mice selectively lacking Six3 from Pomc-expressing neurons and quantified Pomc mRNA levels in a tamoxifen-inducible Six3 knockout mouse model activated at embryonic E9.5 days. We also determined glucose and insulin sensitivity, daily food intake, body composition and body weight in adult male and female mice lacking Six3 specifically from POMC neurons. Lastly, we assessed the physiological consequences of ablating Six3 from POMC neurons in adult mice. RESULTS: Six3 and Pomc were co-expressed in mouse hypothalamic neurons during development and adulthood. Mouse embryos deficient in Six3 showed reduced Pomc expression in the developing hypothalamus. Targeted deletion of Six3 specifically from POMC neurons resulted in decreased hypothalamic Pomc expression, increased daily food intake, enhanced glucose sensitivity and mild obesity in male but not in female mice. Finally, conditional removal of Six3 from POMC neurons in adult mice led to a reduction in hypothalamic POMC immunoreactivity with no significant effects in body weight or food intake. CONCLUSIONS: Altogether, our results demonstrate that Six3 plays an essential role in the early establishment of POMC neuron identity and the maintenance of physiological levels of hypothalamic Pomc expression. In addition, our study demonstrates that the functional significance of Six3 expression in POMC neurons is sexually dimorphic and age-dependent.

Does Microbiome Matter in Chronic Intestinal Failure Due to Type 1 Short Bowel Syndrome in Adults?

The exact microbiome composition and function of patients with Short Bowel Syndrome (SBS) and Chronic Intestinal Failure (CIF) are still unknown. Patients with type I SBS-CIF (end-jejunostomy/ileostomy) are little represented in available studies. The aim of this study is to evaluate the microbiome characteristics of adult type 1 SBS-CIF patients according to their clinical features. Fecal microbiota was studied by amplicon-based sequencing and volatile organic compounds (VOCs) were assessed by solid-phase microextraction and gas chromatography-mass spectrometry. A total of 44 adult type 1 SBS-CIF patients were enrolled. At the family level, Lactobacillaceae (38% of the relative frequency) and Streptococcaceae (24%) were predominant; at the genus level, Streptococcus (38% of the relative frequency) and Lactobacillus (24%) were the dominant amplicon sequence variants (ASVs). Patients with increased stomal output showed higher ASVs for Lactobacillus (Rho = +0.38; p = 0.010), which was confirmed after adjusting for small bowel length (OR = 1.04; 95% CI 1.01-1.07, p = 0.023). Hyperphagia was associated with higher concentrations of short-chain fatty acid (SCFA) esters, such as butanoic acid ethyl ester (p = 0.005) and hexanoic acid ethyl ester (p = 0.004). Dietary fiber intake was directly correlated with most VOCs. Hyperphagia was associated with dietary fiber, after adjusting for small bowel length (OR = 1.35; 95% CI 1.01-1.81; p = 0.040). In type 1 SBS-CIF patients, a greater frequency of Lactobacilli was associated with increased stomal outputs, while increased fiber intake and concentrations of SCFA esters were associated with hyperphagia. These results might have implications for clinical practice.

Hypothalamic AgRP neurons regulate the hyperphagia of lactation.

OBJECTIVE: The lactational period is associated with profound hyperphagia to accommodate the energy demands of nursing. These changes are important for the long-term metabolic health of the mother and children as altered feeding during lactation increases the risk of mothers and offspring developing metabolic disorders later in life. However, the specific behavioral mechanisms and neural circuitry mediating the hyperphagia of lactation are incompletely understood. METHODS: Here, we utilized home cage feeding devices to characterize the dynamics of feeding behavior in lactating mice. A combination of pharmacological and behavioral assays were utilized to determine how lactation alters meal structure, circadian aspects of feeding, hedonic feeding, and sensitivity to hunger and satiety signals in lactating mice. Finally, we utilized chemogenetic, immunohistochemical, and in vivo imaging approaches to characterize the role of hypothalamic agouti-related peptide (AgRP) neurons in lactational-hyperphagia. RESULTS: The lactational period is associated with increased meal size, altered circadian patterns of feeding, reduced sensitivity to gut-brain satiety signals, and enhanced sensitivity to negative energy balance. Hypothalamic AgRP neurons display increased sensitivity to negative energy balance and altered in vivo activity during the lactational state. Further, using in vivo imaging approaches we demonstrate that AgRP neurons are directly activated by lactation. Chemogenetic inhibition of AgRP neurons acutely reduces feeding in lactating mice, demonstrating an important role for these neurons in lactational-hyperphagia. CONCLUSIONS: Together, these results show that lactation collectively alters multiple components of feeding behavior and position AgRP neurons as an important cellular substrate mediating the hyperphagia of lactation.

Passive overconsumption? Limited evidence of compensation in meal size when consuming foods high in energy density: Two randomised crossover experiments.

Research has drawn contradictory conclusions as to whether humans adjust meal size based on meal energy density (ED) or exhibit 'passive overconsumption'. Recent observational research has suggested that meal EDs greater than 1.7-2 kcal/g are compensated for through consumption of smaller meal sizes. We tested the relationship between ED and meal size by examining energy intake of meals at three levels of ED: low (∼1.0 kcal/g), medium (1.7-2.0 kcal/g) and high (>3.0 kcal/g). Two randomised, crossover experiments were conducted with adult participants. In experiment 1 (n = 34, 62% female, mean age 37.4 years), participants were served a lunch including a familiar low, medium or high ED dessert to eat ad libitum. In experiment 2 (n = 32, 66% female, mean age 36.4 years), participants were served a lunch meal manipulated to be low, medium or high ED to eat ad libitum. For experiment 2, later energy intake (post-meal energy intake) was also measured. In experiment 1, participants consumed a similar amount of energy from the low vs. medium ED food. The high ED food was associated with an increased intake of approximately 240 kcals compared to medium (p < 0.001, Cohen's d = 2.31) and low (p < 0.001, Cohen's d = 4.42) ED foods. In experiment 2, there were no significant differences in meal size (grams) between ED meals, resulting in a largely linear relationship between meal ED and energy intake across the three ED conditions ('passive overconsumption'). There were no differences in later energy intake between ED conditions. Contrary to recent suggestions, foods higher in ED were not associated with adjustments to meal size and were associated with increased energy intake across two experiments. Reformulation of foods high in ED may be an effective population level approach to reducing energy intake and obesity. Clinical trial registry number: NCT05744050; https://clinicaltrials.gov/ct2/show/NCT05744050.

Evidence of a self-serving bias in people's attributions for their food intake.

People often fail to acknowledge external influences on their food intake, but there might be some circumstances in which people are willing to report that those external factors influenced their behavior. This study examined whether participants who believed that they had overeaten would indicate that the portion size they were served influenced their food intake. Participants (119 women) ate a pasta lunch at two separate sessions, one week apart. At the second session, participants were randomly assigned to receive either a regular portion of pasta (the same portion as the first session) or a large portion of pasta (a portion that was twice the size), and to receive false feedback about their food intake indicating that they had either eaten about the same as or substantially more than they had at the previous session. Participants were then asked to indicate the extent to which the amount of food served influenced how much they ate at that second session. Compared to participants who were informed that they had eaten the same amount across the two sessions, those who were informed that they ate more at the second session reported a stronger influence of the amount of food served if they also received a large portion of pasta, but not if they received a regular portion of pasta. These findings suggest that the willingness to implicate external influences (e.g., portion size) on one's food intake may be driven by a self-serving bias, providing an "excuse" for overeating. However, the external cue must be salient enough to be a plausible explanation for one's behavior.

Detraining after short-term exercise induces hyperphagia and obesity with fatty liver and brown adipose tissue whitening in young male OLETF rats.

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

GABAergic disinhibition from the BNST to PNOCARC neurons promotes HFD-induced hyperphagia.

Activation of prepronociceptin (PNOC)-expressing neurons in the arcuate nucleus (ARC) promotes high-fat-diet (HFD)-induced hyperphagia. In turn, PNOCARC neurons can inhibit the anorexic response of proopiomelanocortin (POMC) neurons. Here, we validate the necessity of PNOCARC activity for HFD-induced inhibition of POMC neurons in mice and find that PNOCARC-neuron-dependent inhibition of POMC neurons is mediated by gamma-aminobutyric acid (GABA) release. When monitoring individual PNOCARC neuron activity via Ca2+ imaging, we find a subpopulation of PNOCARC neurons that is inhibited upon gastrointestinal calorie sensing and disinhibited upon HFD feeding. Combining retrograde rabies tracing and circuit mapping, we find that PNOC neurons from the bed nucleus of the stria terminalis (PNOCBNST) provide inhibitory input to PNOCARC neurons, and this inhibitory input is blunted upon HFD feeding. This work sheds light on how an increase in caloric content of the diet can rewire a neuronal circuit, paving the way to overconsumption and obesity development.

Time-dependent changes in feeding behavior and energy balance associated with weight gain in mice fed obesogenic diets.

OBJECTIVE: Obesity is characterized by dysregulated homeostatic mechanisms resulting in positive energy balance; however, when this dysregulation occurs is unknown. We assessed the time course of alterations to behaviors promoting weight gain in male and female mice switched to an obesogenic high-fat diet (HFD). METHODS: Male and female C57BL/6J mice were housed in metabolic chambers and were switched from chow to a 60% or 45% HFD for 4 and 3 weeks, respectively. Food intake, meal patterns, energy expenditure (EE), and body weight were continuously measured. A separate cohort of male mice was switched from chow to a 60% HFD and was given access to locked or unlocked running wheels. RESULTS: Switching mice to obesogenic diets promotes transient bouts of hyperphagia during the first 2 weeks followed by persistent caloric hyperphagia. EE increases but not sufficiently enough to offset increased caloric intake, resulting in a sustained net positive energy balance. Hyperphagia is associated with consumption of calorically larger meals (impaired satiation) more frequently (impaired satiety), particularly during the light cycle. Running wheel exercise delays weight gain in male mice fed a 60% HFD by enhancing satiation and increasing EE. However, exercise effects on satiation are no longer apparent after 2 weeks, coinciding with weight gain. CONCLUSIONS: Exposure to obesogenic diets engages homeostatic regulatory mechanisms for ~2 weeks that ultimately fail, and consequent weight gain is characterized by impaired satiation and satiety. Insights into the etiology of obesity can be obtained by investigating changes to satiation and satiety mechanisms during the initial ~2 weeks of HFD exposure.

Short-Term Postnatal Overfeeding Induces Long-Lasting Cardiometabolic Syndrome in Mature and Old Mice Associated with Increased Sensitivity to Myocardial Infarction.

SCOPE: Perinatal nutritional disturbances may "program" an increased cardio-metabolic risk in adulthood; however, few experimental studies have explored their effects on mature and/or old animal. This study aims to investigate the influence of postnatal overfeeding (PNOF) on cardiac function, sensitivity to ischemia-reperfusion (I-R) injury in vivo, glucose metabolism, and metabolic profile of pericardial adipose tissue (PAT) in young (4 months), adult (6 months), old (12 months), and very old (18 months) male mice. METHODS AND RESULTS: Two days after birth, PNOF is induced by adjusting the litter size of C57BL/6 male mice to three pups/mother, while the normally fed (NF) control group is normalized to nine pups/mother. After weaning, all mice have free access to standard diet. Glucose/insulin tests and in vivo myocardial I-R injury are conducted on mice aged from 2 to 12 months, while echocardiography is performed at all ages up to 18 months. PNOF mice exhibit an early and persistent 10-20% increase in body weight and a 10% decrease in left ventricular ejection fraction throughout their lifespan. In PNOF mice aged 4, 6, and 12 months, glucose intolerance and insulin resistance are observed, as well as a 27-34% increase in infarct size. This is accompanied by a higher PAT mass with increased inflammatory status. CONCLUSION: Short-term PNOF results in nutritional programming, inducing long-lasting alterations in glucose metabolism and cardiac vulnerability in male mice, lasting up to 12 months.

Psychogenic Hyperphagia: Excessive Eating as Stereotypy in a Patient with Catatonia.

Catatonia is a complex syndrome with unique cognitive, psychomotor, and mood features. Mannerisms and stereotypies are catatonic signs that have been extensively observed and described in the literature, mostly in the context of movements or motor acts. Stereotypies are commonly described as repetitive psychomotor or verbal acts with the abnormality not inherent in the act but in its frequency. Mannerisms, like stereotypies, are repetitive psychomotor or verbal acts, but they are fundamentally odd in nature. Recently, several reports have described these phenomena in the context of complex behaviors, such as eating and drinking. Identification and appreciation of personal and cultural norms, in addition to a careful analysis of behavioral processes and actions, are important tools for clinicians to identify these potentially elusive and often missed patterns of behavior in patients with catatonia. We present the case of a 30-year-old male with a psychiatric history of treatment-resistant, recurrent major depressive disorder with psychotic features who presented to the inpatient psychiatric unit with signs of catatonia, including repeated, purposeless eating. The patient's chart was reviewed, and a literature review was conducted using PubMed with the keywords catatonia, stereotypies, mannerisms, and hyperphagia. The patient, who was diagnosed with catatonia and expressed hyperphagia as a stereotypy, responded to lorazepam. This case shows that hyperphagia may present as a stereotypy in patients with catatonia.

Interaction between the gut microbiota and colonic enteroendocrine cells regulates host metabolism.

Nutrient handling is an essential function of the gastrointestinal tract. Hormonal responses of small intestinal enteroendocrine cells (EECs) have been extensively studied but much less is known about the role of colonic EECs in metabolic regulation. To address this core question, we investigated a mouse model deficient in colonic EECs. Here we show that colonic EEC deficiency leads to hyperphagia and obesity. Furthermore, colonic EEC deficiency results in altered microbiota composition and metabolism, which we found through antibiotic treatment, germ-free rederivation and transfer to germ-free recipients, to be both necessary and sufficient for the development of obesity. Moreover, studying stool and blood metabolomes, we show that differential glutamate production by intestinal microbiota corresponds to increased appetite and that colonic glutamate administration can directly increase food intake. These observations shed light on an unanticipated host-microbiota axis in the colon, part of a larger gut-brain axis, that regulates host metabolism and body weight.

GHSR in a Subset of GABA Neurons Controls Food Deprivation-Induced Hyperphagia in Male Mice.

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

Long-term changes in eating-related problems and quality of life in children with overweight and obesity attending a 10-week lifestyle camp.

BACKGROUND: Eating-related problems (e.g., binge eating (BE)) and impaired quality of life (QoL) is more prevalent in children with overweight and obesity. This study aimed to investigate changes in self-reported overeating (OE), BE, and QoL in children with overweight or obesity attending multicomponent 10-week lifestyle camps with a 52-weeks follow-up. Additionally, the study sought to investigate whether self-reported OE/BE before camp was associated with changes in QoL. METHODS: Children aged 7 to 14-years could attend camp if they had overweight/obesity, were lonely, unhappy, or had social or family-related problems. In this study only children with overweight and obesity were included (n:185). OE, BE, and QoL were measured using self-reported questionnaires. RESULTS: In total, 38 % of the children reported regular BE at baseline. Regular OE, occasional BE, and occasional OE was reported by 14 %, 13 %, and 11 %, respectively, while 24 % reported no eating-related problems. The relative risk of experiencing eating-related problems decreased at 10-weeks compared to baseline. Additionally, the probability of regular OE (RR 0.12 (95 % CI 0.04;0.38) (X2 = 8.44, p = 0.004)) and regular BE (RR 0.01 (95 % CI 0.00;0.11) (X2 = 9.91, p = 0.002)) remained lower at 52-weeks relative to baseline. All QoL dimensions improved after camp, and the presence of self-reported OE and regular BE at baseline was significantly associated with lower QoL at baseline, 10 and 52-weeks. CONCLUSION: Children self-reporting OE and BE may be a particular vulnerable group that needs more support from camp staff and healthcare professionals to improve QoL. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov with ID: NCT04522921.

Therapeutic Strategies Against Metabolic Imbalance in a Male Mouse Model With 5-HT2CR Loss-of-Function.

The serotonin 2C receptor (5-HT2CR)-melanocortin pathway plays well-established roles in the regulation of feeding behavior and body weight homeostasis. Dysfunctions in this system, such as loss-of-function mutations in the Htr2c gene, can lead to hyperphagia and obesity. In this study, we aimed to investigate the potential therapeutic strategies for ameliorating hyperphagia, hyperglycemia, and obesity associated with a loss-of-function mutation in the Htr2c gene (Htr2cF327L/Y). We demonstrated that reexpressing functional 5-HT2CR solely in hypothalamic pro-opiomelanocortin (POMC) neurons is sufficient to reduce food intake and body weight in Htr2cF327L/Y mice subjected to a high-fat diet (HFD). In addition, 5-HT2CR expression restores the responsiveness of POMC neurons to lorcaserin, a selective agonist for 5-HT2CR. Similarly, administration of melanotan II, an agonist of the melanocortin receptor 4 (MC4R), effectively suppresses feeding and weight gain in Htr2cF327L/Y mice. Strikingly, promoting wheel-running activity in Htr2cF327L/Y mice results in a decrease in HFD consumption and improved glucose homeostasis. Together, our findings underscore the crucial role of the melanocortin system in alleviating hyperphagia and obesity related to dysfunctions of the 5-HT2CR, and further suggest that MC4R agonists and lifestyle interventions might hold promise in counteracting hyperphagia, hyperglycemia, and obesity in individuals carrying rare variants of the Htr2c gene.

Conditioned overconsumption is dependent on reinforcer type in lean, but not obese, mice.

Associative learning can drive many different types of behaviors, including food consumption. Previous studies have shown that cues paired with food delivery while mice are hungry will lead to increased consumption in the presence of those cues at later times. We previously showed that overconsumption can be driven in male mice by contextual cues, using chow pellets. Here we extended our findings by examining other parameters that may influence the outcome of context-conditioned overconsumption training. We found that the task worked equally well in males and females, and that palatable substances such as high-fat diet and Ensure chocolate milkshake supported learning and induced overconsumption. Surprisingly, mice did not overconsume when sucrose was used as the reinforcer during training, suggesting that nutritional content is a critical factor. Interestingly, we also observed that diet-induced obese mice did not learn the task. Overall, we find that context-conditioned overconsumption can be studied in lean male and female mice, and with multiple reinforcer types.

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).

Examining parents' experiences and challenges of feeding preschool children with avid eating behaviour.

Avid eating behaviours, including greater responsiveness to food cues and emotional over-eating, have been linked to child overweight and obesity. Parental feeding practices are modifiable components of a child's food environment and may be key levers for behaviour change in tailored interventions to support parents of children with avid eating behaviour. However, there is a lack of research examining parents' experiences in this context. This study aimed to explore parents' experiences of feeding children with avid eating behaviour and to understand any challenges experienced in this context. Semi-structured interviews with parents (N = 15) of a preschool child (3-5 years) identified as having an avid eating behaviour profile explored how children's avid eating manifests, the parental feeding practices used to manage avid eating, and the perceived effectiveness of these strategies. Data were analysed using reflexive thematic analysis. Four core themes were generated. Theme one, 'Have they got worms? Children's insatiable hunger', captures parents' interpretation of the complex ways in which avid eating behaviour manifests. Theme two, 'Parenthood as a duty', illustrates how parents' perceived responsibilities shape their feeding practices. Theme three, 'Lifelong habits', captures parents' use of responsive feeding practices to support children's healthy relationship with food. Theme four, 'Picking battles', captures the structure- and coercive-based feeding strategies commonly used to manage children's avid eating. This novel study provides an in-depth understanding of the complex ways that children's avid eating behaviour manifests, and the strategic and creative parental feeding practices used to manage these behaviours. Such findings are valuable for informing the development of future support resources for parents/caregivers to help their children with avid eating behaviours to develop a healthy relationship with food.

Mesenchymal-specific Alms1 knockout in mice recapitulates metabolic features of Alström syndrome.

OBJECTIVE: Alström Syndrome (AS), caused by biallelic ALMS1 mutations, includes obesity with disproportionately severe insulin resistant diabetes, dyslipidemia, and fatty liver. Prior studies suggest that hyperphagia is accounted for by loss of ALMS1 function in hypothalamic neurones, whereas disproportionate metabolic complications may be due to impaired adipose tissue expandability. We tested this by comparing the metabolic effects of global and mesenchymal stem cell (MSC)-specific Alms1 knockout. METHODS: Global Alms1 knockout (KO) mice were generated by crossing floxed Alms1 and CAG-Cre mice. A Pdgfrα-Cre driver was used to abrogate Alms1 function selectively in MSCs and their descendants, including preadipocytes. We combined metabolic phenotyping of global and Pdgfrα+ Alms1-KO mice on a 45% fat diet with measurements of body composition and food intake, and histological analysis of metabolic tissues. RESULTS: Assessed on 45% fat diet to promote adipose expansion, global Alms1 KO caused hyperphagia, obesity, insulin resistance, dyslipidaemia, and fatty liver. Pdgfrα-cre driven KO of Alms1 (MSC KO) recapitulated insulin resistance, fatty liver, and dyslipidaemia in both sexes. Other phenotypes were sexually dimorphic: increased fat mass was only present in female Alms1 MSC KO mice. Hyperphagia was not evident in male Alms1 MSC KO mice, but was found in MSC KO females, despite no neuronal Pdgfrα expression. CONCLUSIONS: Mesenchymal deletion of Alms1 recapitulates metabolic features of AS, including fatty liver. This confirms a key role for Alms1 in the adipose lineage, where its loss is sufficient to cause systemic metabolic effects and damage to remote organs. Hyperphagia in females may depend on Alms1 deficiency in oligodendrocyte precursor cells rather than neurones. AS should be regarded as a forme fruste of lipodystrophy.