Effect Of Insulin Resistance On Nervous System Diseases

The abnormal nervous system function caused by insulin resistance is closely related to a variety of neurodegenerative diseases and mental disorders.We detected the phenomenon of spontaneous insulin resistance and a series of behavioral defects,including cognition,anxiety and depression and autism,by detecting serum insulin levels in normally reared mice.In the first part,we describe the changes in transcription levels and chromatin openness in spontaneously insulin-resistant mice.Most of the altered genes are metabolically related.By using metabolic cages and glucose metabolomics,the mice showed a state of high metabolism and high consumption with significant abnormalities in glycolysis and pentose phosphate pathways.Our previous work found that in the insulin resistance model,the level of HK2 protein in neurons was significantly reduced,and HK2 was the rate-limiting enzyme of glycolysis,which was consistent with the results of our mouse model,suggesting that HK2 was involved in the occurrence and development of insulin resistance.Next,we constructed a mouse model with specific knockdown of HK2 in the excitatory neurotransmitter,which showed significant mood disorders.However,why insulin resistance occurs under physiological conditions and how HK2 participates in the occurrence and development of insulin resistance need to be further studied.Our previous study found that insulin resistance induces neuronal aging,and inhibition of HK2 kinase activity in neurons also leads to neuronal aging,with increased expression of p16 and p21.In the second part,we describe the roles of p16 and p21 in neurons.Firstly,p16 and p21 viruses were infected in the hippocampus of adult mice at different times,and it was found that they could not induce neuronal senescence,but led to neuronal death.We then injected p16 and p21 viruses into the lateral ventricles of P0 mice and found that the increase of p16 and p21 proteins did not induce neuronal senescence or apoptosis.At the time point before neuron death,we found autophagy by electron microscopy,and p16 and p21 may induce neuron death by increasing the occurrence of autophagy.So how p16 and p21 cause autophagy remains to be further studied.Mitochondria are an important suborganelle of metabolism,and We found significant metabolic abnormalities in insulin-resistant mice.In the third part,the loss of mitochondrial related protein CEND1 leads to cognitive changes and anxiety.In AD model,we found that CEND1 protein deletion causes learning and cognitive deficits and anxiety and other mental disorders in mice.Overexpression of CEND1 by virus injection in AD mice can help alleviate cognitive deficits caused by CEND1 deficiency,and overexpression in cells can increase ATP production.In addition,we confirmed through IP that CEND1 can interact with mitochondrial division protein Drp1 to affect mitochondrial function,thus affecting the occurrence of cognitive disorders and anxiety disorders.However,it remains to be further studied how CEND1 can affect mitochondrial function when there are only three mitochondrial localization signal peptides.In conclusion,insulin resistance plays a role in anxiety,depression,cognitive deficits and neuronal aging.