Glucose-induced mitochondrial fission through DRP1 is required for redox signaling in hypothalamic glucose sensing mechanism

Archive ouverte

Carneiro, Lionel | Guissard, Christophe | Belenguer, P. | Pénicaud, Luc | Leloup, Corinne

Edité par CCSD -

Communication affichée
Communication affichée. We previously showed that hypothalamic glucose sensing requires a redox signaling in hypothalamic arcuate nucleus, through glucose‐induced mitochondrial H2O2 production (1). ROS implication in nutrient sensing has been confirmed by others studies (2). Recent studies highlight mitochondrial morphology changes under glycemia increase, which depends on mitochondrial dynamics. Changes in mitochondrial dynamics are causative events in mitochondrial reactive oxygen species (mROS) production when glycemia rises. It has been demonstrates that mitochondrial fission blockade decreases mROS production during hyperglycemia in metabolic‐sensitive cells, such as hepatocytes or myoblastes (3). Our objective is to understand whether glucose‐induced mROS production in hypothalamus involves the mitochondrial dynamic balance through the fission mechanism. To that end, fission has been transiently invalidated through siRNA transfection in the arcuate nucleus of living rats. SiRNA were directed against DRP1 (dynamin related protein), a required actor of fission. Control animals received a control siRNA sequence. Both the mitochondrial networks and the expression proteins were validated by Western blotting. Weight gain, feeding, insulinemia and glycemia were measured and functional tests such as feeding behavior (refeeding) or insulin secretion through the hypothalamo‐pancreatic axis tested. Glucose tolerance and insulin sensitivity were checked. siRNA transfection in arcuate nucleus induces near 80% inhibition of the target 72h post‐injection. SiRNA‐DRP1 treated animals present significant increase in food intake, without significant weight gain,. Importantly, hypothalamic glucose sensing induced insulin secretion was dramatically decreased (about 75%) correlated to a 50% decrease of mROS production in the arcuate nucleus. Refeeding test with bilateral arcuate glucose injection strongly abolishes feeding in siRNA‐injected control rats but the satietogenic effect of glucose was impaired in siRNA‐DRP1 injected rats. Finally, siRNA‐DRP1 injected rats showed a higher tolerance to glucose due to increased insulin secretion although insulin sensitivity was decreased, suggesting pancreatic adaptation to hypothalamic control impairment. Altogether, these results demonstrate that mitochondrial morphology through mitochondrial fission is necessary for glucose induced redox signaling in hypothalamus and the consequent adaptative responses.

• Description
• Sujet/Public
• Outil
• Outil d'anticipation
• Mémoire et thèse
• Gestion