Development of obesity and diabetes is the consequence of impaired glucose homeostasis regulation. The hypothalamic area of the brain and more precisely the arcuate nucleus (ARC) plays a critical role in this regulation. The ARC detects changes in blood glucose level and triggers appropriate physiological responses. For instance, increased brain glucose level increases insulin secretion and decreases food intake. Different populations of glucose sensitive neurons have been characterize in the ARC. Glucose excited (GE) neurons increase their electrical activity when extracellular glucose level rises from 2.5 to 5 mM, 2.5 mM being the physiological basal brain glucose level. By analogy, high-glucose excited (HGE) neurons increase their activity as glucose levels rises above 5 mM. Despite being studied by many groups, the molecular mechanisms and physiological roles of GE and HGE neurons are not fully understood.
Preliminary work suggests that ARC mitochondrial reactive oxygen species (mROS) production is involved in glucose homeostasis. We showed that inhibition of ARC mROS production impairs increased brain glucose level-induced insulin secretion and food intake inhibition. We hypothesize that mROS production is involved in GE and/or HGE neurons glucose sensitivity. Four specific aims will test our hypothesis. Specific Aim 1 will determine whether ARC GE and/or HGE neurons produce mROS in response to increased glucose level and. Specific Aim 2 and 3 will determine whether whether mROS are involved in ARC GE and HGE neurons glucose sensitivity. Finally, Specific Aim 4 will determine whether ARC HGE neurons are involved in glucose homeostasis.
This project is highly original and innovative in regards of the hypothesis proposed and technical strategies used. Understanding molecular mechanisms and physiological roles of ARC GE and HGE neurons will significantly improve the knowledge in glucose homeostasis against development of diabetes and obesity.