Prader–Willi syndrome: From genetics to behaviour, with special focus on appetite treatments

Griggs, Joanne L.; Sinnayah, Puspha; Mathai, Michael L.

doi:10.1016/j.neubiorev.2015.10.003

Cited by 45 publications

(45 citation statements)

References 168 publications

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“…Another study showed that oxytocin nasal spray did not induce beneficial effects in individuals with Prader-Willi syndrome (PWS) [34]. This genetic syndrome is characterized by complex physical, behavioral, and intellectual abnormalities, and hyperphagia [35]. If food consumption is left unmanaged, individuals with PWS develop obesity.…”

Section: Discussionmentioning

confidence: 99%

Oxytocin Nasal Spray in the Treatment of Binge Eating Disorder and Obesity: A Pilot, Randomized, Double-Blind Trial

Agabio¹,

Farci²,

Curreli³

et al. 2016

Clin Pharmacol Biopharm

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BackgroundPreclinical studies suggest that the neuropeptide oxytocin reduces food intake and body weight, but only a few clinical studies have investigated the translatability of these findings in humans. The present study investigated the safety and efficacy of oxytocin nasal spray in patients affected by binge eating disorder and obesity. MethodsSeventeen outpatients affected by binge eating disorder and obesity participated in a 8 week double-blind trial and received oxytocin (n=8; 24 IU, four times a day, 20 min before each of three meals and before going to bed) or placebo (n=9) with an energy-restricted diet. Primary outcomes included adverse events and the number of binge eating episodes per week. Secondary measures included body weight, BMI, severity of BED, craving for food, quality of sleep, quality of life, anxiety, and depressive symptoms. ResultsOne patient of oxytocin group discontinued prematurely the trial before the first post-randomization efficacy measure. Among the other 16 participants, 13 (81.2%) completed the trial, and 3 (18.8%) discontinued [3 in the oxytocin group; 0 in the placebo group (p=0.0625, Fisher's exact test)]. No significant difference between groups was found in any outcome evaluated. Patients of the placebo group performed slightly better than patients of the oxytocin group in some secondary outcomes, but these differences were not significant. ConclusionOxytocin nasal spray resulted to be safe, including in women of childbearing age but did not significantly reduce the number of binge eating episodes per week in outpatients affected by binge eating disorder and obesity. These findings are discussed in light of the human oxytocin literature.

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Section: Discussionmentioning

confidence: 99%

Oxytocin Nasal Spray in the Treatment of Binge Eating Disorder and Obesity: A Pilot, Randomized, Double-Blind Trial

Agabio¹,

Farci²,

Curreli³

et al. 2016

Clin Pharmacol Biopharm

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“…We chose a subset of Chow-trained, PF-naive mice (n = 7-9 per Genotype per PO; both sexes) on the Cyfip2 N/N background or untrained, PF-naïve mice on a Cyfip2 J/J background (n= 8-12 per Genotype per PO; both sexes) to examine baseline (PF-naive) gene transcription between Cyfip1 N/versus Cyfip1 N/N mice and PO. We examined Cyfip1, Cyfip2, and Magel2 transcript levels in the hypothalamus, a brain region important for hyperphagia in PWS 40 and for the effects of Magel2 deletion 53,54 on eating behavior and homeostatic function 55 . Haploinsufficiency of MAGEL2 is associated with PWS-like hyperphagia in humans 54,56,57 .…”

Section: Hypothalamus Dissections For Real-time Quantitative Pcr (Qpcr)mentioning

confidence: 99%

“…Additionally, we examined CYFIP1 protein expression in the hypothalamus and nucleus accumbens as a function of both Cyfip1 genotype and PO. Finally, because OC behaviors are associated with BE 37-39 and hyperphagia in PWS 40 , we employed a battery of tests to assess anxiety-like and compulsive-like behaviors and post-BE training behaviors, including compulsive-like eating and concomitant behaviors in the light/dark conflict test 8 in Cyfip1 haploinsufficient mice.…”

Section: Introductionmentioning

confidence: 99%

Cyfip1 haploinsufficiency increases compulsive-like behavior and modulates palatable food intake: Implications for Prader-Willi Syndrome

Babbs

Ruan

Kelliher

et al. 2018

Preprint

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Binge eating (BE) is a heritable trait associated with eating disorders and involves consumption of a large quantity of food in a short time. We identified cytoplasmic FMRP-interacting protein 2 (Cyfip2) as a major genetic factor underlying BE and concomitant compulsive-like behaviors in mice. CYFIP2 is a gene homolog of CYFIP1 -one of four paternally deleted genes in patients with the more severe Type I Prader-Willi Syndrome (PWS). PWS is a neurodevelopmental genetic disorder where 70% of cases involve paternal deletion of 15q11-q13. PWS is defined phenotypically by the emergence of hyperphagia and obesity during childhood as well as cognitive deficits and obsessive-compulsive behaviors. We tested the hypothesis that Cyfip1 haploinsufficiency would enhance premorbid compulsive-like behavior and palatable food (PF) consumption in a parent-of-origin-selective manner.Additionally, because our initial studies involved mice on a C57BL/6N background that possess the BEassociated missense mutation in Cyfip2, we tested mice on a mixed background where mice were homozygous for the C57BL/6J (B6J) allele at the Cyfip2 locus. Cyfip1 haploinsufficiency increased compulsive-like behavior on both backgrounds and PF consumption was greater with paternal inheritance. Gene expression in the hypothalamus revealed a paternal effect of Cyfip1 deletion on transcription of Cyfip1 but not Cyfip2 or Magel2. To summarize, the selective increased compulsive-like behavior and PF consumption in paternally deleted Cyfip1 +/-mice could translate to enhancing hyperphagia in a subset of individuals with neurodevelopmental disorders involving reduced expression or haploinsufficiency of CYFIP1, including PWS but also Fragile X Syndrome and 15q11.2 Microdeletion Syndrome.

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“…We hypothesized that CFE steroidal glycosides were involved in appetite suppression by enhancing 5‐HT2c receptor signaling (Canton et al, ; Doe et al, ; Falaleeva et al, ; Schellekens et al, ). Though typically 5‐HT or serotonin may be increased through pharmaceutical treatment, that is, selective serotonin reuptake inhibition (SSRI) (Griggs, Sinnayah, et al, ; Selikowitz, Sunman, & Wright, ); treatments of this nature require active 5‐HT receptors to release second messenger activity within the appetite pathways of the central nervous system (CNS). The literature describes 5‐HT2cR's anorexigenic receptor activity predominantly within the arcuate nucleus (ARC) of the hypothalamus (Reynolds, Hill, & Kirk, ).…”

Section: Introductionmentioning

confidence: 99%

Caralluma fimbriata extract activity involves the 5‐HT2c receptor in PWS Snord116 deletion mouse model

2018

Self Cite

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IntroductionIn Prader–Willi syndrome (PWS), nonprotein coding small nucleolar (sno) RNAs are involved in the paternally deleted region of chromosome 15q11.2‐q13, which is believed to cause the hyperphagic phenotype of PWS. Central to this is SnoRNA116. The supplement Caralluma fimbriata extract (CFE) has been shown to decrease appetite behavior in some individuals with PWS. We therefore investigated the mechanism underpinning the effect of CFE on food intake in the Snord116del mouse. Experiments utilized appetite stimulants which included a 5‐hydroxytryptamine (5‐HT) 2c receptor antagonist (SB242084), as the 5‐HT2cR is implicated in central signaling of satiety.MethodsAfter 9‐week chronic CFE treatment (33 mg or 100 mg kg−1 day−1) or placebo, the 14‐week‐old Snord116del (SNO) and wild‐type mice (n = 72) were rotated through intraperitoneal injections of (a) isotonic saline; (b) 400 mg/kg of 2‐deoxyglucose (2DG) (glucose deprivation); (c) 100 mglkg beta‐mercaptoacetate (MA), fatty acid signaling; and (d) SB242084 (a selective 5HT2cR antagonist), with 5 days between reagents. Assessments of food intake were from baseline to 4 hr, followed by immunohistochemistry of neural activity utilizing c‐Fos, neuropeptide Y, and alpha‐melanocyte‐stimulating hormone within hypothalamic appetite pathways.Results Caralluma fimbriata extract administration decreased food intake more strongly in the SNO100CFE group with significantly stimulated food intake demonstrated during coadministration with SB242084. Though stimulatory deprivation was expected to stimulate food intake, 2DG and MA resulted in lower intake in the snord116del mice compared to the WT animals (p = <0.001). Immunohistochemical mapping of hypothalamic neural activity was consistent with the behavioral studies.ConclusionsThis study identifies a role for the 5‐HT2cR in CFE‐induced appetite suppression and significant stimulatory feeding disruptions in the snord116del mouse model.

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Prader–Willi syndrome: From genetics to behaviour, with special focus on appetite treatments

Cited by 45 publications

References 168 publications

Oxytocin Nasal Spray in the Treatment of Binge Eating Disorder and Obesity: A Pilot, Randomized, Double-Blind Trial

Oxytocin Nasal Spray in the Treatment of Binge Eating Disorder and Obesity: A Pilot, Randomized, Double-Blind Trial

Cyfip1 haploinsufficiency increases compulsive-like behavior and modulates palatable food intake: Implications for Prader-Willi Syndrome

Caralluma fimbriata extract activity involves the 5‐HT2c receptor in PWS Snord116 deletion mouse model

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