Detection of extracellular glucose by GLUT2 contributes to hypothalamic control of food intake.
The sugar transporter GLUT2, present in several tissues of the gut-brain axis, has been reported to be involved in the control of food intake. GLUT2 is a sugar transporter sustaining energy production in the cell, but it can also function as a receptor for extracellular glucose. A glucose-signaling pathway is indeed triggered, independently of glucose metabolism, through its large cytoplasmic loop domain. However, the contribution of the receptor function over the transporter function of GLUT2 in the control of food intake remains to be determined. Thus, we generated transgenic mice that express a GLUT2-loop domain, blocking the detection of glucose but leaving GLUT2-dependent glucose transport unaffected. Inhibiting GLUT2-mediated glucose detection augmented daily food intake by a mechanism that increased the meal size but not the number of meals. Peripheral hormones (ghrelin, insulin, leptin) were unaffected, leading to a focus on central aspects of feeding behavior. We found defects in c-Fos activation by glucose in the arcuate nucleus and changes in the amounts of TRH and orexin neuropeptide mRNA, which are relevant to poorly controlled meal size. Our data provide evidence that glucose detection by GLUT2 contributes to the control of food intake by the hypothalamus. The sugar transporter receptor, i.e., "transceptor" GLUT2, may constitute a drug target to treat eating disorders and associated metabolic diseases, particularly by modulating its receptor function without affecting vital sugar provision by its transporter function.
Stolarczyk
Emilie
E
Unité Mixte de Recherche (UMR) S872, Centre de Recherche des Cordeliers, 15 rue de l'Ecole de médecine, Paris, F-75006 France.
Guissard
Christophe
C
Michau
Aurélien
A
Even
Patrick C
PC
Grosfeld
Alexandra
A
Serradas
Patricia
P
Lorsignol
Anne
A
Pénicaud
Luc
L
Brot-Laroche
Edith
E
Leturque
Armelle
A
Le Gall
Maude
M
D000704:Analysis of Variance; D000818:Animals; D001692:Biological Transport / Q000502:physiology; D001835:Body Weight / Q000502:physiology; D002452:Cell Count; D004435:Eating / Q000502:physiology*; D004734:Energy Metabolism; D005247:Feeding Behavior / Q000502:physiology; D054439:Ghrelin / Q000097:blood; D005947:Glucose / Q000378:metabolism*; D051273:Glucose Transporter Type 2 / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology; D007031:Hypothalamus / Q000378:metabolism*; D007150:Immunohistochemistry; D007328:Insulin / Q000097:blood; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D020738:Leptin / Q000097:blood; D051379:Mice; D008822:Mice, Transgenic; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism; D000068797:Orexins; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D018709:Statistics, Nonparametric; D013973:Thyrotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism
D054439:Ghrelin; D051273:Glucose Transporter Type 2; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D020738:Leptin; D009479:Neuropeptides; D000068797:Orexins; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D013973:Thyrotropin-Releasing Hormone; D005947:Glucose