Importance of mitochondrial dynamin-related protein 1 in hypothalamic glucose sensitivity in rats.
Antioxidants & Redox Signaling. 2012-08-01; 17(3): 433-444
DOI: 10.1089/ars.2011.4254
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AIMS: 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.
INNOVATION AND CONCLUSION: 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.