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).

A protein kinase C α and ß inhibitor blunts hyperphagia to halt renal function decline and reduces adiposity in a rat model of obesity-driven type 2 diabetes.

Type 2 diabetes (T2D) and its complications can have debilitating, sometimes fatal consequences for afflicted individuals. The disease can be difficult to control, and therapeutic strategies to prevent T2D-induced tissue and organ damage are needed. Here we describe the results of administering a potent and selective inhibitor of Protein Kinase C (PKC) family members PKCα and PKCß, Cmpd 1, in the ZSF1 obese rat model of hyperphagia-induced, obesity-driven T2D. Although our initial intent was to evaluate the effect of PKCα/ß inhibition on renal damage in this model setting, Cmpd 1 unexpectedly caused a marked reduction in the hyperphagic response of ZSF1 obese animals. This halted renal function decline but did so indirectly and indistinguishably from a pair feeding comparator group. However, above and beyond this food intake effect, Cmpd 1 lowered overall animal body weights, reduced liver vacuolation, and reduced inguinal adipose tissue (iWAT) mass, inflammation, and adipocyte size. Taken together, Cmpd 1 had strong effects on multiple disease parameters in this obesity-driven rodent model of T2D. Further evaluation for potential translation of PKCα/ß inhibition to T2D and obesity in humans is warranted.

Effectiveness of a transdisciplinary approach on hyperphagia management among patients with Prader Willi syndrome.

BACKGROUND: One of the main characteristics of Prader Willi syndrome (PWS) is hyperphagia and obesity. This study sought to evaluate behaviours related to hyperphagia in individuals with PWS under a non-pharmacological transdisciplinary approach. METHODS: This observational study included PWS patients under a traditional non-pharmacological nutritional approach immersed within a regular transdisciplinary treatment (RTT) and a control group of PWS individuals without RTT. All individuals were evaluated using the Hyperphagia Questionnaire for Clinical Trials (HQ-CT). RESULTS: Forty-three individuals were evaluated. The mean age at baseline (treatment onset) was 18.4±8.3 years in the RTT group and 19.1±6.9 years in the control group (p=0.74). Hyperphagia-related behaviours were significantly lower among those under RTT (RTT 5.7±3.7 vs control 13.1±7.5, p<0.0001). This was also identified within the three categories: arguing or manipulating to obtain food (2.71±2.1 vs 5.41±3.2, p=0.003), sneaking food (1.33±1.5 vs 3.55±3.3, p=0.007), and anger or tantrums related to food (1.67±1.8 vs 4.09±2.7, p=0.001). After a mean treatment duration of 41.0 months, the RTT group had a reduction in body mass index (baseline 38.7±17.1kg/m2 vs follow-up 29.2±9.2kg/m2; p<0.0001). A significant association between RTT duration and BMI reduction (p=0.037) was identified. CONCLUSION: We observed a positive impact on behaviours related to hyperphagia and a BMI reduction in PWS individuals in a context of a non-pharmacological nutritional approach as part of an RTT.

Hyperphagia of female UCP1-deficient mice blunts anti-obesity effects of FGF21.

Increasing energy expenditure through uncoupling protein 1 (UCP1) activity in thermogenic adipose tissue is widely investigated to correct diet-induced obesity (DIO). Paradoxically, UCP1-deficient male mice are resistant to DIO at room temperature. Recently, we uncovered a key role for fibroblast growth factor 21 (FGF21), a promising drug target for treatment of metabolic disease, in this phenomenon. As the metabolic action of FGF21 is so far understudied in females, we aim to investigate potential sexual dimorphisms. Here, we confirm that male UCP1 KO mice display resistance to DIO in mild cold, without significant changes in metabolic parameters. Surprisingly, females gained the same amount of body fat as WT controls. Molecular regulation was similar between UCP1 KO males and females, with an upregulation of serum FGF21, coinciding with beiging of inguinal white adipose tissue and induced lipid metabolism. While energy expenditure did not display significant differences, UCP1 KO females significantly increased their food intake. Altogether, our results indicate that hyperphagia is likely counteracting the beneficial effects of FGF21 in female mice. This underlines the importance of sex-specific studies in (pre)clinical research for personalized drug development.

Liraglutide attenuates nicotine self-administration as well as nicotine seeking and hyperphagia during withdrawal in male and female rats.

RATIONALE: Nicotine cessation is associated with increased consumption of highly palatable foods and body weight gain in most smokers. Concerns about body weight gain are a major barrier to maintaining long-term smoking abstinence, and current treatments for nicotine use disorder (NUD) delay, but do not prevent, body weight gain during abstinence. Glucagon-like peptide-1 receptor (GLP-1R) agonists reduce food intake and are FDA-approved for treating obesity. However, the effects of GLP-1R agonist monotherapy on nicotine seeking and withdrawal-induced hyperphagia are unknown. OBJECTIVES: We screened the efficacy of the long-lasting GLP-1R agonist liraglutide to reduce nicotine-mediated behaviors including voluntary nicotine taking, as well as nicotine seeking and hyperphagia during withdrawal. METHODS: Male and female rats self-administered intravenous nicotine (0.03 mg/kg/inf) for ~21 days. Daily liraglutide administration (25 µg/kg, i.p.) started on the last self-administration day and continued throughout the extinction and reinstatement phases of the experiment. Once nicotine taking was extinguished, the reinstatement of nicotine-seeking behavior was assessed after an acute priming injection of nicotine (0.2 mg/kg, s.c.) and re-exposure to conditioned light cues. Using a novel model of nicotine withdrawal-induced hyperphagia, intake of a high fat diet (HFD) was measured during home cage abstinence in male and female rats with a history of nicotine self-administration. RESULTS: Liraglutide attenuated nicotine self-administration and reinstatement in male and female rats. Repeated liraglutide attenuated withdrawal-induced hyperphagia and body weight gain in male and female rats at a dose that was not associated with malaise-like effects. CONCLUSIONS: These findings support further studies investigating the translational potential of GLP-1R agonists to treat NUD.

Intranasal Carbetocin Reduces Hyperphagia, Anxiousness, and Distress in Prader-Willi Syndrome: CARE-PWS Phase 3 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.

Impulse Control Disorders by Dopamine Partial Agonists: A Pharmacovigilance-Pharmacodynamic Assessment Through the FDA Adverse Event Reporting System.

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.

Understanding the Patient Experience of Hunger and Improved Quality of Life with Setmelanotide Treatment in POMC and LEPR Deficiencies.

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.

Very-low-protein diets lead to reduced food intake and weight loss, linked to inhibition of hypothalamic mTOR signaling, in mice.

The protein leverage hypothesis predicts that low dietary protein should increase energy intake and cause adiposity. We designed 10 diets varying from 1% to 20% protein combined with either 60% or 20% fat. Contrasting the expectation, very low protein did not cause increased food intake. Although these mice had activated hunger signaling, they ate less food, resulting in decreased body weight and improved glucose tolerance but not increased frailty, even under 60% fat. Moreover, they did not show hyperphagia when returned to a 20% protein diet, which could be mimicked by treatment with rapamycin. Intracerebroventricular injection of AAV-S6K1 significantly blunted the decrease in both food intake and body weight in mice fed 1% protein, an effect not observed with inhibition of eIF2a, TRPML1, and Fgf21 signaling. Hence, the 1% protein diet induced decreased food intake and body weight via a mechanism partially dependent on hypothalamic mTOR signaling.

The therapeutic potential of GLP-1 analogues for stress-related eating and role of GLP-1 in stress, emotion and mood: a review.

Stress and low mood are powerful triggers for compulsive overeating, a maladaptive form of eating leading to negative physical and mental health consequences. Stress-vulnerable individuals, such as people with obesity, are particularly prone to overconsumption of high energy foods and may use it as a coping mechanism for general life stressors. Recent advances in the treatment of obesity and related co-morbidities have focused on the therapeutic potential of anorexigenic gut hormones, such as glucagon-like peptide 1 (GLP-1), which acts both peripherally and centrally to reduce energy intake. Besides its appetite suppressing effect, GLP-1 acts on areas of the brain involved in stress response and emotion regulation. However, the role of GLP-1 in emotion and stress regulation, and whether it is a viable treatment for stress-induced compulsive overeating, has yet to be established. A thorough review of the pre-clinical literature measuring markers of stress, anxiety and mood after GLP-1 exposure points to potential divergent effects based on temporality. Specifically, acute GLP-1 injection consistently stimulates the physiological stress response in rodents whereas long-term exposure indicates anxiolytic and anti-depressive benefits. However, the limited clinical evidence is not as clear cut. While prolonged GLP-1 analogue treatment in people with type 2 diabetes improved measures of mood and general psychological wellbeing, the mechanisms underlying this may be confounded by associated weight loss and improved blood glucose control. There is a paucity of longitudinal clinical literature on mechanistic pathways by which stress influences eating behavior and how centrally-acting gut hormones such as GLP-1, can modify these. (250).

Oxytocin in young children with Prader-Willi syndrome: Results of a randomized, double-blind, placebo-controlled, crossover trial investigating 3 months of oxytocin.

CONTEXT: Prader-Willi syndrome (PWS) is characterized by hypothalamic dysfunction, hyperphagia and a typical behavioural phenotype, with characteristics of autism spectrum disorder (ASD) like stubbornness, temper tantrums and compulsivity. It has been suggested that the oxytocin system in patients with PWS is dysfunctional. In ASD, intranasal oxytocin treatment has favourable effects on behaviour. OBJECTIVE: To evaluate the effects of 3 months of twice daily intranasal oxytocin (dose range 16-40 IU/day), compared to placebo, on behaviour and hyperphagia in children with PWS. DESIGN: Randomized, double-blind, placebo-controlled, crossover study in the Dutch PWS Reference Center. PATIENTS: Twenty-six children with PWS aged 3-11 years. MAIN OUTCOME MEASURES: (Change in) behaviour and hyperphagia measured by Oxytocin Questionnaire and Dykens hyperphagia questionnaire. RESULTS: In the total group, no significant effects of oxytocin on social behaviour or hyperphagia were found. However, in boys, the Oxytocin Questionnaire scores improved significantly during oxytocin treatment, compared to a deterioration during placebo (4.5 (-0.8 to 15.3) vs. -4.0 (-11.3 to 0.8), P = .025). The Dykens hyperphagia questionnaire scores remained similar during oxytocin treatment, while there was a deterioration during placebo (0.0 (-0.8 to 4.3) vs. -3.5 (-6.0 to 0.0), P = .046). Patients with a deletion had significant improvements in both questionnaire scores during oxytocin treatment, but deteriorations during placebo. Oxytocin treatment was well tolerated, and there were no serious adverse events. CONCLUSIONS: Intranasal oxytocin treatment has positive effects on social and eating behaviour in 3-11 years aged boys with PWS and in children with a deletion without safety concerns. Intranasal oxytocin in children with PWS might be considered, but individual effects should be carefully evaluated and treatment discontinued if no effects are found.

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.

Metabolomic profiles associated with a mouse model of antipsychotic-induced food intake and weight gain.

Antipsychotic drugs (AP) are used to treat a multitude of psychiatric conditions including schizophrenia and bipolar disorder. However, APs also have metabolic side effects including increased food intake and body weight, but the underlying mechanisms remain unknown. We previously reported that minocycline (MINO) co-treatment abrogates olanzapine (OLZ)-induced hyperphagia and weight gain in mice. Using this model, we investigated the changes in the pharmacometabolome in the plasma and hypothalamus associated with OLZ-induced hyperphagia and weight gain. Female C57BL/6 mice were divided into groups and fed either i) control, CON (45% fat diet) ii) CON + MINO, iii) OLZ (45% fat diet with OLZ), iv) OLZ + MINO. We identified one hypothalamic metabolite indoxylsulfuric acid and 389 plasma metabolites (including 19 known metabolites) that were specifically associated with AP-induced hyperphagia and weight gain in mice. We found that plasma citrulline, tricosenoic acid, docosadienoic acid and palmitoleic acid were increased while serine, asparagine and arachidonic acid and its derivatives were decreased in response to OLZ. These changes were specifically blocked by co-treatment with MINO. These pharmacometabolomic profiles associated with AP-induced hyperphagia and weight gain provide candidate biomarkers and mechanistic insights related to the metabolic side effects of these widely used drugs.

A Role for GLP-1 in Treating Hyperphagia and Obesity.

Obesity is a chronic recurring disease whose prevalence has almost tripled over the past 40 years. In individuals with obesity, there is significant increased risk of morbidity and mortality, along with decreased quality of life. Increased obesity prevalence results, at least partly, from the increased global food supply that provides ubiquitous access to tasty, energy-dense foods. These hedonic foods and the nonfood cues that through association become reward predictive cues activate brain appetitive control circuits that drive hyperphagia and weight gain by enhancing food-seeking, motivation, and reward. Behavioral therapy (diet and lifestyle modifications) is the recommended initial treatment for obesity, yet it often fails to achieve meaningful weight loss. Furthermore, those who lose weight regain it over time through biological regulation. The need to effectively treat the pathophysiology of obesity thus centers on biologically based approaches such as bariatric surgery and more recently developed drug therapies. This review highlights neurobiological aspects relevant to obesity causation and treatment by emphasizing the common aspects of the feeding-inhibitory effects of multiple signals. We focus on glucagon like peptide-1 receptor (GLP-1R) signaling as a promising obesity treatment target by discussing the activation of intestinal- and brain-derived GLP-1 and GLP-1R expressing central nervous system circuits resulting from normal eating, bariatric surgery, and GLP-1R agonist drug therapy. Given the increased availability of energy-dense foods and frequent encounters with cues that drive hyperphagia, this review also describes how bariatric surgery and GLP-1R agonist therapies influence food reward and the motivational drive to overeat.

The Potential Role of Activating the ATP-Sensitive Potassium Channel in the Treatment of Hyperphagic Obesity.

To evaluate the potential role of ATP-sensitive potassium (KATP) channel activation in the treatment of hyperphagic obesity, a PubMed search was conducted focused on the expression of genes encoding the KATP channel, the response to activating the KATP channel in tissues regulating appetite and the establishment and maintenance of obesity, the evaluation of KATP activators in obese hyperphagic animal models, and clinical studies on syndromic obesity. KATP channel activation is mechanistically involved in the regulation of appetite in the arcuate nucleus; the regulation of hyperinsulinemia, glycemic control, appetite and satiety in the dorsal motor nucleus of vagus; insulin secretion by ß-cells; and the synthesis and ß-oxidation of fatty acids in adipocytes. KATP channel activators have been evaluated in hyperphagic obese animal models and were shown to reduce hyperphagia, induce fat loss and weight loss in older animals, reduce the accumulation of excess body fat in growing animals, reduce circulating and hepatic lipids, and improve glycemic control. Recent experience with a KATP channel activator in Prader-Willi syndrome is consistent with the therapeutic responses observed in animal models. KATP channel activation, given the breadth of impact and animal model and clinical results, is a viable target in hyperphagic obesity.

Anagliptin suppresses diet-induced obesity through enhancing leptin sensitivity and ameliorating hyperphagia in high-fat high-sucrose diet fed mice.

Obesity is a major risk factors for type 2 diabetes, and weight loss is beneficial to diabetic patients who are obese or overweight. Dipeptidyl peptidase-4 (DPP-4) inhibitors are anti-diabetic drugs. Although it has been known that the effect of most of the DPP-4 inhibitors on body weight is neutral, several studies suggested that some DPP-4 inhibitors suppressed body weight. Nonetheless, the mechanisms underlying DPP-4 inhibitor-induced weight loss are not fully understood. In this study, the mice fed high-fat high sucrose diet (HFHSD) containing a DPP4 inhibitor, anagliptin, showed reduced food intake and body weight compared to the mice fed non-treated HFHSD, but oxygen consumption and respiratory exchange ratio (RER) were not altered. Sequential administration of leptin suppressed food intake and body weight more apparently in anagliptin treated HFHSD fed mice than non-treated HFHSD fed mice. Oxygen consumption and RER were comparable between anagliptin treated and non-treated mice after leptin administration. The number of phospho STAT3 expressed cells in the arcuate nucleus after leptin administration was increased in anagliptin treated mice compared to non-treated mice. These data suggested that anagliptin ameliorated leptin resistance induced by HFHSD and thereby decreased food intake and body weight. These effects of anagliptin could be beneficial to the treatment of obese diabetic patients.

Prader Willi syndrome: endocrine updates and new medical therapies.

PURPOSE OF REVIEW: Prader Willi syndrome is characterized not only by hyperphagia frequently resulting in obesity, but also by endocrine dysfunction across a variety of axes. This article reviews the most recent literature regarding possible causes of hyperphagia and the nature of endocrinopathies seen in Prader Willi syndrome, as well as current research into possible therapies. RECENT FINDINGS: Investigation into neurologic, metabolic and hormonal drivers of hyperphagia and obesity has revealed new insights and clarified underlying pathophysiology. Additional studies continue to elucidate the hormonal deficiencies seen in the syndrome, allowing for improvements in clinical care. SUMMARY: The underlying causes of the hyperphagia and progressive obesity frequently seen in Prader Willi Syndrome are largely unknown and likely multifactorial. Understanding the hormonal and metabolic drivers at work in PWS, as well as the nature of other hormonal dysfunction seen in the syndrome is necessary to guide current management and future research directions.

Effect of topiramate on eating behaviours in Prader-Willi syndrome: TOPRADER double-blind randomised placebo-controlled study.

Prader-Willi Syndrome (PWS) is a rare genetic syndrome leading to severe behavioural disorders and mild cognitive impairment. The objective of this double-blind randomised placebo-controlled trial was to study the efficacy and tolerance of topiramate on behavioural disorders in patients with PWS. Participants (aged 12-45 years) had genetically confirmed PWS and severe irritability/impulsivity, eating disorders and/or obesity, and skin picking. Thirty-two participants received a placebo (PBO), and 30 participants received topiramate (TOP) (50-200 mg/day) for 8 weeks. The primary outcome was the rate of responders using the Clinical Global Impression-Improvement (CGI-I) scale. The secondary outcome measures included the Aberrant Behaviour Checklist, the Dykens Hyperphagia Questionnaire (DHK), the Self-Injurious Behaviour Scale (SIBS) and the body mass index (BMI). We found no significant difference in the primary outcome (the CGI-I): 9 (30%) patients were very much or much improved in the TOP group compared to 7 (22.6%) patients in the PBO group. However, the DHK behaviour and severity scores improved significantly more over time in patients treated with topiramate versus those receiving a placebo, with a significant dose-effect relationship. DHK scores were also significantly associated with genetic subtypes and hospitalisation status. The effects of topiramate on eating behaviours remained significant after adjusting for genetic subtype and hospitalisation. Topiramate had therefore a significant effect on eating disorders, with a dose-effect relationship. Given the burden of eating disorders in PWS, we believe that topiramate may become the first psychotropic option within the global care of obesity in individuals with PWS.