Orexins control intestinal glucose transport by distinct neuronal, endocrine, and direct epithelial pathways

OBJECTIVE-Orexins are neuropeptides involved in energy homeostasis. We investigated the effect of orexin A (OX-A) and orexin B (OxB) on intestinal glucose transport in the rat. RESEARCH DESIGN AND METHODS AND RESULTS-Injection of orexins led to a decrease in the blood glucose level in oral glucose tolerance tests (OGTTs). Effects of orexins on glucose entry were analyzed in Ussing chambers using the Na+-dependent increase in short-circuit current (Isc) to quantify jejunal glucose transport. The rapid and marked increase in Isc induced by luminal glucose was inhibited by 10 nmol/l OxA or OxB (53 and 59%, respectively). Response curves to OxA and OxI3 were not significantly different with half-maximal inhibitory concentrations at 0.9 and 0.4 nmol/l, respectively. On the one hand, OxA-induced inhibition of Isc was reduced by the neuronal blocker tetrodotoxin (TTX) and by a cholecystokinin (CCK) 21R antagonist, indicating involvement of neuronal and endocrine CCK-releasing cells. The OX1R antagonist SB334867 had no effect on OxA-induced inhibition, which is likely to occur via a neuronal and/or endocrine OX2R. On the other hand, SB334867 induced a significant right shift of the concentration-effect curve for OxB. This OxB-preferring OX1R pathway was not sensitive to TTX or to CCKR antagonists, suggesting that OxB may act directly on enterocytic OX1R. These distinct effects of OxA and OxB are consistent with the expression of OX1R and OX2R mRNA in the epithelial and nonepithelial tissues, respectively CONCLUSIONS-Our data delineate a new function for orexins as inhibitors of intestinal glucose absorption and provide a new basis for orexin-induced short-term control of energy homeostasis.