Type 2 diabetes mellitus(T2DM)and Alzheimer's disease(AD)share several common pathophysiological features.Rare variants of triggering receptor expressed on myeloid cells 2(TREM2)increase the risk of developing AD,suggesting the involvement of TREM2 and innate immunity in AD development.It is still unknown whether TREM2 is related to cognitive impairment in T2DM.Here,we investigated the effects of the hippocampal overexpression of TREM2 on cognitive in long-term high-fat diet(HFD)-fed mice.Male C57BL/6J mice were maintained on HFD for 50 weeks.TREM2 was overexpressed in the hippocampus 36 weeks after HFD feeding using adeno-associated virus vector(AAV)-mediated gene delivery.The results showed that the HFD feeding induced rapid and persistent weight gain,glucose intolerance and significant impairments in learning and memory.Compared with AAV-con,AAV-TREM2 significantly ameliorated cognitive impairment without altering body weight and glucose homeostasis in HFD mice.The overexpression of TREM2 upregulated the synaptic proteins spinophilin,PSD95 and synaptophysin,suggesting the improvement in synaptic transmission.Dendritic complexity and spine density in the CA1 region were rescued after TREM2 overexpression.Furthermore,TREM2 markedly increased the number of iba-1/Arg-1-positive microglia in the hippocampus,suppressed neuroinflammation and microglial activation.In sum,hippocampal TREM2 plays an important role in improving HFD-induced cognitive dysfunction and promoting microglial polarization towards the M2 anti-inflammatory phenotype.Our study also suggests that TREM2 might be a novel target for the intervention of obesity/diabetes-associated cognitive decline.
Traditional thiazolidinediones(TZDs),such as rosiglitazone,are peroxisome proliferator-activated receptor g(PPARg)potent agonists that can be used to treat type 2 diabetes but carry unwanted effects,including increased risk for fracture.The present work aimed to compare the insulin-sensitizing efficacies and bone-loss side effects of CMHX008,a novel TZDs-like PPARg partial agonist,with those of rosiglitazone.A TR-FRET PPARg competitive binding assay was used to compare the binding affinity between CMHX008 and rosiglitazone.Mice were administered vehicle,CMHX008 or rosiglitazone for 16 weeks.Mesenchymal stem cells(MSCs)were used to examine differences in differentiation into osteoblasts after compounds treatment.TR-FRET showed lower affinity to PPARg by CMHX008 compared with rosiglitazone.Mice treated with CMHX008 showed insulin sensitization similar to that of mice treated with rosiglitazone,which was related to the significant inhibition of PPARg Ser273 phosphorylation and improved insulin sensitivity by facilitating the phosphorylation of insulin receptor and Akt in adipose tissues.Micro-CT and histomorphometric analyses demonstrated that the degree of trabecular bone loss after treatment with CMHX008 was weaker than that observed with rosiglitazone,as evidenced by consistent changes in BV/TV,Tb.N,Tb.Th,Tb.Sp,and the mineral apposition rate.MSCs treated with CMHX008 showed higher ALP activity and mRNA levels of bone formation markers than did cells treated with rosiglitazone in the osteoblast differentiation test.Thus,CMHX008 showed insulin-sensitizing effects similar to those of rosiglitazone with a lower risk of bone loss,suggesting that PPARg sparing eliminates the skeletal side effects of TZDs while maintaining their insulin-sensitizing properties.
