Nat Comm . . . Xu Yong's team reveals the secrets of sugar-sensitive neuronal perception to regulate blood sugar.

Diabetic patients receiving intensive insulin therapy often suffer from severe hypoglycemia and life-threatening problems.there are many glucose sensing neurons in the brain. They can rapidly and violently change their own discharge activities when the extracellular glucose concentration fluctuates, and restore the blood glucose homeostasis by regulating the feeding behavior of animals and the levels of several peripheral hormones (such as insulin, glucagon, corticosterone, etc.).although glucose sensitive neurons in the brain are considered to be an important part of maintaining blood glucose balance, the mechanism of how these glucose sensitive neurons sense changes in extracellular glucose concentration and how to regulate blood glucose is not clear.on May 1, Professor Xu Yong of Baylor Medical College published a research paper in nature Communications: estrogen receptor - α - expressing nerves in the ventrolateral VMH regular glucose balance.they successfully located the neurons that sense blood glucose and analyzed the mechanism of blood glucose control.there are a large number of Er α expressing neurons (ER α vlvmh neurons) in the ventral subarea of the ventral hypothalamic nucleus (vlvmh).Xu Yong's team first used fluorescent labeled transgenic mice (ER α - ZsGreen) to record 576 Er α vlvmh neurons from 65 mice with patch clamp recording. The results were surprised to find that every Er α vlvmh neuron recorded was a glucose sensitive neuron. Br / > the neurons activated by high glucose, called VMH α, are inhibited by high glucose (vmer α).Xu Yong's team then found that gi-er α vlvmh neurons overexpressed a chloride channel, anoctamin 4 (ano4), while ge-er α vlvmh neurons highly expressed ABCC8, an important subunit of ATP dependent potassium channel (KATP).Xu Yong's team continued to use pharmacology and CRISPR gene editing methods to prove that gi-er α vlvmh neurons were activated by opening ano4 channel while ge-er α vlvmh neurons were inhibited by opening KATP channel when extracellular glucose concentration decreased.at the same time, Xu Yong's team used anterograde and retrograde tracking techniques, combined with optogenetics, patch clamp and optical fiber recording methods, found that among the numerous projection brain regions of Er α vlvmh neurons, two brain regions were very special.one of them is the medial posterior subregion (mparh) of the arcuate nucleus (ARH); most of the ER α vlvmh neurons projecting to mparh are gi glucose inhibitory neurons.that is to say, when hypoglycemia occurs, the circuit from Er α vlvmh neurons to mparh is activated.then Xu Yong's team used photogenetics to activate this circuit in mice with normal blood glucose, and found that blood glucose levels increased significantly.another special projection area is the dorsal raphe nucleus (DRN) of the midbrain; most Er α vlvmh neurons projecting to DRN are Ge glucose excited neurons.that is to say, when hypoglycemia occurs, the circuit from Er α vlvmh neurons to DRN is inhibited.when this circuit was suppressed by photogenetics in mice with normal blood glucose, blood glucose levels were also significantly increased.in this study, Xu Yong's team found a group of very sensitive glucose inhibitory and glucose excited neurons in the hypothalamus, and revealed the different ionic mechanisms of these glucose inhibited and glucose excited neurons to sense the changes of extracellular glucose concentration.it is important that these glucose sensitive neurons can help maintain blood glucose homeostasis through different downstream circuits, regardless of whether these glucose sensitive neurons are glucose inhibited or glucose excited.the research results promote the understanding of the mechanism of blood glucose homeostasis regulation, provide a new theoretical basis for the pathophysiology of diabetes and other diseases, and provide a new target for the prevention and treatment of such diseases.it's interesting why such a group of glucose sensitive neurons happen to be labeled with estrogen receptors? Can estrogen or estrogen receptor signaling regulate their glucose sensitivity? What's more, do these Er α vlvmh neurons regulate blood glucose differently between male and female? These problems need to be further explored.original link: plate maker: Qi sauce