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 (OxA) and orexin B (OxB) on intestinal glucose transport in the rat.


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 OxB 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) 2R antagonist, indicating involvement of neuronal and endocrine CCK-releasing cells. The OX(1)R antagonist SB334867 had no effect on OxA-induced inhibition, which is likely to occur via a neuronal and/or endocrine OX(2)R. On the other hand, SB334867 induced a significant right shift of the concentration-effect curve for OxB. This OxB-preferring OX(1)R pathway was not sensitive to TTX or to CCKR antagonists, suggesting that OxB may act directly on enterocytic OX(1)R. These distinct effects of OxA and OxB are consistent with the expression of OX(1)R and OX(2)R 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.
Ducroc
Robert
R
Institut National de la Santé et de la Recherche Médicale U773, Centre de Recherche Biomédicale Bichat-Beaujon, 16 rue Henri Huchard, BP16, 75870 Paris cedex 18, France. ducroc@bichat.inserm.fr
Voisin
Thierry
T
El Firar
Aadil
A
Laburthe
Marc
M
D000818:Animals; D005772:Gastrointestinal Transit; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D007031:Hypothalamus / Q000502:physiology; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000187:drug effects / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology*; D007583:Jejunum / Q000187:drug effects / Q000294:innervation / Q000502:physiology; D008297:Male; D009474:Neurons / Q000502:physiology*; D009479:Neuropeptides / Q000235:genetics / Q000502:physiology*; D000068797:Orexins; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013779:Tetrodotoxin / Q000494:pharmacology
D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D000068797:Orexins; D013779:Tetrodotoxin; D012313:RNA; D005947:Glucose