Mitochondrial reactive oxygen species are required for hypothalamic glucose sensing.
The physiological signaling mechanisms that link glucose sensing to the electrical activity in metabolism-regulating hypothalamus are still controversial. Although ATP production was considered the main metabolic signal, recent studies show that the glucose-stimulated signaling in neurons is not totally dependent on this production. Here, we examined whether mitochondrial reactive oxygen species (mROS), which are physiologically generated depending on glucose metabolism, may act as physiological sensors to monitor the glucose-sensing response. Transient increase from 5 to 20 mmol/l glucose stimulates reactive oxygen species (ROS) generation on hypothalamic slices ex vivo, which is reversed by adding antioxidants, suggesting that hypothalamic cells generate ROS to rapidly increase glucose level. Furthermore, in vivo, data demonstrate that both the glucose-induced increased neuronal activity in arcuate nucleus and the subsequent nervous-mediated insulin release might be mimicked by the mitochondrial complex blockers antimycin and rotenone, which generate mROS. Adding antioxidants such as trolox and catalase or the uncoupler carbonyl cyanide m-chlorophenylhydrazone in order to lower mROS during glucose stimulation completely reverses both parameters. In conclusion, the results presented here clearly show that the brain glucose-sensing mechanism involved mROS signaling. We propose that this mROS production plays a key role in brain metabolic signaling.
Leloup
Corinne
C
UMR 5018-CNRS UPS, Institut L. Bugnard, IFR31, BP 84432, 31 432 Toulouse cedex 4, France. coleloup@toulouse.inserm.fr
Magnan
Christophe
C
Benani
Alexandre
A
Bonnet
Emilie
E
Alquier
Thierry
T
Offer
Géraldine
G
Carriere
Audrey
A
Périquet
Alain
A
Fernandez
Yvette
Y
Ktorza
Alain
A
Casteilla
Louis
L
Pénicaud
Luc
L
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology; D005182:Flavin-Adenine Dinucleotide / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D007031:Hypothalamus / Q000502:physiology*; D007700:Kinetics; D008297:Male; D008928:Mitochondria / Q000378:metabolism*; D009243:NAD / Q000378:metabolism; D009474:Neurons / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012402:Rotenone / Q000494:pharmacology
D000975:Antioxidants; D017382:Reactive Oxygen Species; D012402:Rotenone; D009243:NAD; D005182:Flavin-Adenine Dinucleotide; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D005947:Glucose