Mitochondrial Dynamin-Related Protein 1 (DRP1) translocation in response to cerebral glucose is impaired in a rat model of early alteration in hypothalamic glucose sensing.
Molecular Metabolism. 2019-02-01; 20: 166-177
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OBJECTIVE: Hypothalamic glucose sensing (HGS) initiates insulin secretion (IS)
via a vagal control, participating in energy homeostasis. This requires
mitochondrial reactive oxygen species (mROS) signaling, dependent on
mitochondrial fission, as shown by invalidation of the hypothalamic DRP1 protein.
Here, our objectives were to determine whether a model with a HGS defect induced
by a short, high fat-high sucrose (HFHS) diet in rats affected the fission
machinery and mROS signaling within the mediobasal hypothalamus (MBH).
METHODS: Rats fed a HFHS diet for 3 weeks were compared with animals fed a normal
chow. Both in vitro (calcium imaging) and in vivo (vagal nerve activity
recordings) experiments to measure the electrical activity of isolated MBH
gluco-sensitive neurons in response to increased glucose level were performed. In
parallel, insulin secretion to a direct glucose stimulus in isolated islets vs.
insulin secretion resulting from brain glucose stimulation was evaluated.
Intra-carotid glucose load-induced hypothalamic DRP1 translocation to
mitochondria and mROS (H2O2) production were assessed in both groups. Finally,
compound C was intracerebroventricularly injected to block the proposed
AMPK-inhibited DRP1 translocation in the MBH to reverse the phenotype of HFHS fed
RESULTS: Rats fed a HFHS diet displayed a decreased HGS-induced IS. Responses of
MBH neurons to glucose exhibited an alteration of their electrical activity,
whereas glucose-induced insulin secretion in isolated islets was not affected.
These MBH defects correlated with a decreased ROS signaling and glucose-induced
translocation of the fission protein DRP1, as the vagal activity was altered.
AMPK-induced inhibition of DRP1 translocation increased in this model, but its
reversal through the injection of the compound C, an AMPK inhibitor, failed to
restore HGS-induced IS.
CONCLUSIONS: A hypothalamic alteration of DRP1-induced fission and mROS signaling
in response to glucose was observed in HGS-induced IS of rats exposed to a 3 week
HFHS diet. Early hypothalamic modifications of the neuronal activity could
participate in a primary defect of the control of IS and ultimately, the
development of diabetes.
Copyright © 2018 The Authors. Published by Elsevier GmbH.. All rights reserved.