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

INTRODUCTION: In 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. METHODS: After 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. CONCLUSIONS: This study identifies a role for the 5-HT2cR in CFE-induced appetite suppression and significant stimulatory feeding disruptions in the snord116del mouse model.

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

Prader-Willi syndrome (PWS) is a neurodevelopmental disorder resulting from a deletion in the expression of the paternally derived alleles in the region of 15q11-q13. PWS has a prevalence rate of 1:10,000-1:30,000 and is characterized by marked endocrine abnormalities including growth hormone deficiency and raised ghrelin levels. The hyperphagic phenotype in PWS is established over a number of phases and is exacerbated by impaired satiety, low energy expenditure and intellectual difficulties including obsessive-compulsive disorder and/or autistic behaviours. Clinical management in PWS typically includes familial/carer restriction and close supervision of food intake. If the supervision of food is left unmanaged, morbid obesity eventuates, central to the risk of cardiorespiratory disorder. None of the current appetite management/intervention strategies for PWS include pharmacological treatment, though recent research shows some promise. We review the established aberrant genetics and the endocrine and neuronal attributes which may determine disturbed regulatory processes in PWS. Focusing on clinical trials for appetite behaviours in PWS, we define the effectiveness of pharmacological treatments with a view to initiating and focusing research towards possible targets for modulating appetite in PWS.

Caralluma Fimbriata Supplementation Improves the Appetite Behavior of Children and Adolescents with Prader-Willi Syndrome.

BACKGROUND: Prader-Willi syndrome (PWS) results from a deletion of the paternal genes in the region of chromosome 15q11-q13. PWS develops hyperphagia, which when left unmanaged, leads to an excessive ingestion of food. To date there is inadequate pharmacological treatment or supplementation for modification of the PWS hyperphagia and/or the associated behaviors. Therefore, the best practice is familial supervision and restriction of diet and environment. AIM: We aimed to determine if the natural supplement of Caralluma fimbriata extract (CFE) could attenuate hyperphagia or the associated appetite behaviors in children and adolescents with PWS over the 4-week pilot trial period. MATERIALS AND METHODS: We conducted a placebo-controlled, double-blind, randomized crossover trial over a 10-week period to investigate the effects of CFE on hunger control, in a cohort of children and adolescents with confirmed PWS (n =15, mean age 9.27 ± 3.16 years, body weight 43.98 ± 23.99 kg). Participants from Australia and New Zealand ingested CFE or a placebo of maltodextrin/cabbage leaf over a 4-week period, with a 2-week washout before the crossover to the other treatment. Weekly comparisons in appetite behavior, severity, and drive were recorded by parents, as scaled time-point measures on a hyperphagia questionnaire validated for PWS. RESULTS: CFE administration was found to induce a significant accumulative easing of hyperphagia (P = 0.05), with decreases evident in one-third of the participants. Furthermore due to CFE supplementation, a significant decrease (P ≤ 0.05) was recorded in the category of behavior and a decrease in hyperphagia (n = 8, P = 0.009) was observed at the highest dose 1,000 mg/day (recommended adult dose). There were no reported adverse effects at any dose. CONCLUSION: We demonstrate that an extract of the Indian cactus succulent Caralluma fimbriata eases hyperphagic appetite behavior within a cohort of children and adolescents (n = 15) with PWS without notable adverse effects. The outcomes of this study will have a potential positive impact on PWS management.