Energetic homeostasis results in the balance between energy intake and expenditure. The hypothalamus plays an important role in the regulation of both energetic metabolism and food intake in sensing hormonal and metabolic signals. For instance, changes in hypothalamic glucose level modulate food intake and insulin secretion. We have previously found that 1) increased hypothalamic glucose level triggers production of mitochondrial reactive oxygen species (mROS) from the electron transport chain; 2) hypothalamic mROS production is involved in glucose homeostasis and food intake control. The molecular mechanisms involved in glucose-induced hypothalamic mROS production are still unknown. Mitochondrial dynamics control mitochondrial morphology through fission or fusion mechanisms. Recent in vitro studies have shown that mitochondrial fission is involved in glucose-induced myoblasts and hepatocytes mROS production. The main hypothesis of my thesis was that mitochondrial dynamics were involved in 1) hypothalamic glucose-induced mROS signaling and 2) hypothalamic glucose sensitivity.We first showed in vivo that increased hypothalamic glucose level in response to an intracarotid glucose injection induces recruitment of the mitochondrial fission protein DRP1 at the mitochondria and triggers mitochondrial fragmentation. The second part of my work was to determine whether mitochondrial fission is involved in hypothalamic glucose sensitivity. Therefore, we inhibited DRP1 expression in the ventromedial hypothalamus (VMH) by siRNA injection. 72h post siDRP1 injection, VMH DRP1 expression was decreased by 80%. At this time, we found that increased hypothalamic glucose level failed to increase hypothalamic mROS production. In addition, intracarotid glucose injection-induced insulin secretion was decreased. Finally, VMH glucose injection-induced food intake inhibition was attenuated in siDRP1 treated animals. In a last set of experiments, we found ex vivo by oxygraphy that hypothalamic mROS production is associated with electron transport chain dysfunction. Altogether, our work shows for the first time that mitochondrial fission is involved in mROS dependent hypothalamic glucose sensitivity. Furthermore, this work demonstrates that mitochondrial fission plays a critical role in the regulation of glucose homeostasis and food intake.
