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

Abstract

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.

Single-Case Study of Appetite Control in Prader-Willi Syndrome, Over 12-Years by the Indian Extract Caralluma fimbriata

“…This receptor is involved in anorexigenic signalling within hypothalamic appetite pathways of the central nervous system (CNS). Previously we reported that an extract of Caralluma fimbriata (CFE) used as the intervention in this case study was involved in enhancing 5-HT2c receptor activity in a PWS animal model [18]. This activity conforms to a model of increased satiety.…”

A Review of Prader–Willi Syndrome

“…Caralluma is a wild shrub used in Indian folk medicine as an appetite suppressant. In PWS animal models, it has shown to enhance 5-HT2c receptor activity, the same receptor to which hyperphagia-associated SNORD116 and SNORD115 deletions are thought to interfere with in the hypothalamus [83]. A case report [84] of Caralluma therapy over 12 years in a 14-year-old female PWS patient was notable for a dramatic reduction in hyperphagia that permitted her to safely have freedom around food, which reverted to baseline upon the cessation of therapy.…”

Preclinical Testing in Translational Animal Models of Prader-Willi Syndrome: Overview and Gap Analysis

“…twice daily, 24 μg/kg, 17 daysofood intaken = 7–9, M6–12 months 113 Abnormal response to the anorexic effect of GHS-R inhibitors and exenatide in male Snord116 deletion mouse model for PWSSnord116 tm1.1Uta GHSR agonist HM01s.c. daily, 30 μg/g, 14 dayspbody weight, length, mortalityn = 9–17, M and F1–14 days 114 Ghrelin receptor agonist rescues excess neonatal mortality in a Prader-Willi syndrome mouse modelSnord116 tm1.1Uta Carraluma fimbriata extractorally in gel, 33 or 100 mg/kg/day, 10 weeksqfood intake after stimulationn = 6, M and F4–15 weeks 165 Caralluma fimbriata extract activity involves the 5-HT2c receptor in PWS Snord116 deletion mouse modelSnord116 tm1.1Uta thermoneutral (30°C)16 weeksrbody weight, body comp, length, BMD, energy intaken = 9–14, Mfrom 4 to 20 weeks 106 Ambient temperature modulates the effects of the PWS candidate gene Snord116 on energy homeostasisSnrpn tm2Cbr (PWS-ICdel)thermoneutral (30°C)9 weekssfood intake, fat mass, weight gainn = 5–6, M and F6–15 months 118 Paradoxical leanness in the imprinting-center deletion mouse model for PWSSnrpn tm2Cbr (PWS-ICdel)WAY-161503s.c. single injection, 3 mg/kg or 10 mg/kgtpostfast refeedingn = 12–14, M and Fadult 122 Increased alternate splicing of Htr2c in a mouse model for Prader-Willi syndrome leads disruption of 5HT2C receptor mediated appetiteDel(7Ube3a-Snrpn)1AlbUNC0642i.p.…”