Elsevier

Molecular Metabolism

Volume 20, February 2019, Pages 166-177
Molecular Metabolism

Original Article
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

https://doi.org/10.1016/j.molmet.2018.11.007Get rights and content
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Highlights

  • Only three weeks of HFHS diet consumption impairs hypothalamic glucose sensing.

  • HFHS consumption alters central glucose-induced vagal control of insulin secretion.

  • Glucose-induced ROS production and mitochondrial fission are decreased in HFHS rats.

  • Impaired translocation of DRP1in HFHS rats does not involve its phosphorylation.

Abstract

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 animals.

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.

Keywords

Hypothalamus
Glucose sensing
Mitochondria
ROS signaling
Mitochondrial fission
DRP1

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