Importance of mitochondrial dynamin-related protein 1 in hypothalamic glucose sensitivity in rats.
OBJECTIVE
Hypothalamic mitochondrial reactive oxygen species (mROS)-mediated signaling has been recently shown to be involved in the regulation of energy homeostasis. However, the upstream signals that control this mechanism have not yet been determined. Here, we hypothesize that glucose-induced mitochondrial fission plays a significant role in mROS-dependent hypothalamic glucose sensing.


RESULTS
Glucose-triggered translocation of the fission protein dynamin-related protein 1 (DRP1) to mitochondria was first investigated in vivo in hypothalamus. Thus, we show that intracarotid glucose injection induces the recruitment of DRP1 to VMH mitochondria in vivo. Then, expression was transiently knocked down by intra-ventromedial hypothalamus (VMH) DRP1 siRNA (siDRP1) injection. 72 h post siRNA injection, brain intracarotid glucose induced insulin secretion, and VMH glucose infusion-induced refeeding decrease were measured, as well as mROS production. The SiDRP1 rats decreased mROS and impaired intracarotid glucose injection-induced insulin secretion. In addition, the VMH glucose infusion-induced refeeding decrease was lost in siDRP1 rats. Finally, mitochondrial function was evaluated by oxygen consumption measurements after DRP1 knock down. Although hypothalamic mitochondrial respiration was not modified in the resting state, substrate-driven respiration was impaired in siDRP1 rats and associated with an alteration of the coupling mechanism.


CONCLUSIONS
Collectively, our results suggest that glucose-induced DRP1-dependent mitochondrial fission is an upstream regulator for mROS signaling, and consequently, a key mechanism in hypothalamic glucose sensing. Thus, for the first time, we demonstrate the involvement of DRP1 in physiological regulation of brain glucose-induced insulin secretion and food intake inhibition. Such involvement implies DRP1-dependent mROS production.
Centre des Sciences du Goût et de l'Alimentation (CSGA), Université de Bourgogne, Dijon, France.
Lionel
L
Carneiro
Camille
C
Allard
Christophe
C
Guissard
Xavier
X
Fioramonti
Cécile
C
Tourrel-Cuzin
Danielle
D
Bailbé
Corinne
C
Barreau
Géraldine
G
Offer
Emmanuelle
E
Nédelec
Bénédicte
B
Salin
Michel
M
Rigoulet
Pascale
P
Belenguer
Luc
L
Pénicaud
Corinne
C
Leloup
D000818:Animals; D001069:Appetite Regulation; D001111:Arcuate Nucleus of Hypothalamus / Q000201:enzymology* / Q000378:metabolism / Q000648:ultrastructure; D034281:Dynamins / Q000235:genetics / Q000378:metabolism*; D004736:Energy-Generating Resources; D055785:Gene Knockdown Techniques; D005947:Glucose / Q000378:metabolism* / Q000502:physiology; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000201:enzymology* / Q000378:metabolism / Q000648:ultrastructure; D051336:Mitochondrial Membranes / Q000201:enzymology; D010101:Oxygen Consumption; D021381:Protein Transport; D034622:RNA Interference; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D014697:Ventromedial Hypothalamic Nucleus / Q000201:enzymology* / Q000378:metabolism / Q000648:ultrastructure
D007328:Insulin; D017382:Reactive Oxygen Species; C519851:Dnm1l protein, rat; D034281:Dynamins; D005947:Glucose