Role of Cholecystokinin in Anorexia Induction Following Oral Exposure to the 8-Ketotrichothecenes Deoxynivalenol, 15-Acetyldeoxynivalenol, 3-Acetyldeoxynivalenol, Fusarenon X, and Nivalenol

Abstract

Cereal grain contamination by trichothecene mycotoxins is known to negatively impact human and animal health with adverse effects on food intake and growth being of particular concern. The head blight fungus Fusarium graminearum elaborates five closely related 8-ketotrichothecene congeners: (1) deoxynivalenol (DON), (2) 3-acetyldeoxynivalenol (3-ADON), (3) 15-acetyldeoxynivalenol (15-ADON), (4) fusarenon X (FX), and (5) nivalenol (NIV). While anorexia induction in mice exposed intraperitoneally to DON has been linked to plasma elevation of the satiety hormones cholecystokinin (CCK) and peptide YY₃₋₃₆ (PYY₃₋₃₆), the effects of oral gavage of DON or of other 8-keotrichothecenes on release of these gut peptides have not been established. The purpose of this study was to (1) compare the anorectic responses to the aforementioned 8-ketotrichothecenes following oral gavage at a common dose (2.5 mg/kg bw) and (2) relate these effects to changes plasma CCK and PYY₃₋₃₆ concentrations. Elevation of plasma CCK markedly corresponded to anorexia induction by DON and all other 8-ketotrichothecenes tested. Furthermore, the CCK1 receptor antagonist SR 27897 and the CCK2 receptor antagonist L-365,260 dose-dependently attenuated both CCK- and DON-induced anorexia, which was consistent with this gut satiety hormone being an important mediator of 8-ketotrichothecene-induced food refusal. In contrast to CCK, PYY₃₋₃₆ was moderately elevated by oral gavage with DON and NIV but not by 3-ADON, 15-ADON, or FX. Taken together, the results suggest that CCK plays a major role in anorexia induction following oral exposure to 8-ketotrichothecenes, whereas PYY₃₋₃₆ might play a lesser, congener-dependent role in this response.

Role of tumor necrosis factor-α and interleukin-1β in anorexia induction following oral exposure to the trichothecene deoxynivalenol (vomitoxin) in the mouse

“…This anorectic response was transient with food consumption recovering to control levels within 6 hr. Recently, we have observed the concomitant induction of anorexia and satiety hormones cholecystokinin (CCK) and peptide YY (PYY) following oral administration of DON using this mouse model, suggesting that these two hormones may involve in DON-induced anorexia (Wu et al, 2014a). In support of this viewpoint, anorexia induction by DON was attenuated using CCK or PYY receptor inhibitors, respectively Wu et al, 2014a).…”

“…Third, DON may evoke secretion of satiety hormones or neurotransmitters that regulate food intake. CCK, PYY and 5-Hydroxytryptamine (5-HT) have been implicated in anorexia induction by DON (Prelusky et al, 1997;Flannery et al, 2012;Wu et al, 2014a).…”

“…For cytokine-induced anorexia, mice were IP injected with 100 µL 0.1 mg/kg TNF-α or 0.002 mg/kg IL-1β with a sterile 27 G, 0.5'' needle, respectively. The doses were chosen based on previous data (Flannery et al, 2011;Wu et al, 2014a) and preliminary experiments. Following treatment, mice were then immediately provided two preweighed food pellets (≈7 g) and food intake measured at 1 hr, 2 hr, 3 hr, 6 hr, and 16 hr after DON and cytokines exposure.…”

“…Anorexia induced by DON is of particular concern from the perspective of human and animal health (Forsell et al, 1986;Iverson et al, 1995;JECFA, 2011). However, the mechanistic basis for this adverse effect remains not fully understood but likely results from upregulation of proinflammatory cytokines and neuroendocrine hormones that influence food intake and appetite (Amuzie et al, 2009;Flannery et al, 2011;Girardet et al, 2011a;Wu et al, 2014a).…”

Novel Mechanism of Fatty Acid Sensing in Enteroendocrine Cells: Specific Structures in Oxo‐Fatty Acids Produced by Gut Bacteria Are Responsible for CCK Secretion in STC‐1 Cells via GPR40

“…We expected that the fatty acids would exert an inhibitory effect on gastric emptying in vivo, as delaying gastric emptying is a distinct physiological function of several gut hormones including CCK . Although the effect was relatively smaller than that of 2t,4t‐dacadienal at the same weight dose (25 mg kg −1 ), the oral administration of 13‐oxo‐9c,15c‐18:2 decreased the gastric emptying rate as evaluated by two independent methods, while 10‐oxo‐11t‐18:1 did not (Figure A,B).…”