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.
Highlights
In Prader–Willi syndrome (PWS), nonprotein coding small nucleolar RNAs are involved in the paternally deleted region of chromosome 15q11.2‐ q13, which is believed to cause the hyperphagic phenotype of PWS
The Snord116del strains food intake were indicative of signaling disruptions with significant inhibition of food intake in response to 2‐deoxyglu‐ cose (2DG), SAL—SNO100CFE 1.27 ± 0.27 g in comparison with 2DG—SNO100CFE 0.78 ± 0.37 g (p = 0.002); SAL—SNO33CFE 1.47 ± 0.23 g; 2DG—SNO33CFE 0.98 ± 0.29 g (p =
The results of the experiments investigating CFE determined an involvement of serotonin via the 5‐HT2cR in the inhibitory ef‐ fect of CFE on food appetite
Summary
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. It is proposed that CFE’s mechanism of action involves the pregnane glycosides, both as an antihyperglycemic (Priya, Rajaram, & Sureshkumar, 2014) and as an antinociceptive (Rajendran et al, 2014) and that the various steroidal glycosides increase stimula‐ tion of the anorexigenic melanocortin pathway (Komarnytsky et al, 2013). These specific hypothalamic appetite pathways are believed to be disturbed due to genetic modifications, one in‐ volved in modifying the genetic translation of the 5‐HT2c receptor
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