Objective To investigate the neural basis of glucagon-like peptide-1(GLP-1)in regulating glucose homeostasis and elucidate the molecular mechanisms.Methods Male Glp1r-IRES-Cre,Glp1r-KO,and wild-type mice were used in this study.Fiber photometry was employed to record Ca2+signals of neurons in ventromedial hypothalamus(VMH)and patch-clamp was used to analyze electrophysiological properties of GLP-1 receptor-positive(GLP-1RVMH)neurons.Viral stereotaxic injections,chemogenetics,plasma hormone assays,and routine glucose metabolism assessments were combined to determine the regulatory role of GLP-1RVMH neurons in glucose homeostasis.Tissue and cell mitochondrial respiratory function assays,transmission electron microscopy,and conventional molecular biology methods were used to explore the mechanism by which GLP-1R agonists regulate glucose homeostasis.Results When the glucose concentration decreased from 5.0 mmol/L to 0.5 mmol/L,the action potential frequency of GLP-1RVMH neuron decreased significantly[(4.51±0.80)Hz vs.(1.43±0.51)Hz,P<0.01].Activation of GLP-1RVMH neuron significantly enhanced insulin secretion[(7.60±0.56)μU/mL vs.(11.34±0.93)μU/mL,P<0.01],while inhibition of these neuronal activities impaired the hypoglycemic efficiency of GLP-1 agonists[(32.03%±0.91%)vs.(25.77%±1.09%),P<0.001)].Mechanistically,GLP-1 regulated glucose homeostasis through Drp1 phosphorylation-mediated mitochondrial fission and improved mitochondrial energy metabolism.Conclusion GLP-1RVMH neurons are a class of glucose-excited neurons,and which activated directly promotes secretion of insulin.The hypoglycemic effect of GLP-1R agonists depend on the neuronal activity of GLP-1RVMH.

Objective To investigate the neural basis of glucagon-like peptide-1(GLP-1)in regulating glucose homeostasis and elucidate the molecular mechanisms.Methods Male Glp1r-IRES-Cre,Glp1r-KO,and wild-type mice were used in this study.Fiber photometry was employed to record Ca2+signals of neurons in ventromedial hypothalamus(VMH)and patch-clamp was used to analyze electrophysiological properties of GLP-1 receptor-positive(GLP-1RVMH)neurons.Viral stereotaxic injections,chemogenetics,plasma hormone assays,and routine glucose metabolism assessments were combined to determine the regulatory role of GLP-1RVMH neurons in glucose homeostasis.Tissue and cell mitochondrial respiratory function assays,transmission electron microscopy,and conventional molecular biology methods were used to explore the mechanism by which GLP-1R agonists regulate glucose homeostasis.Results When the glucose concentration decreased from 5.0 mmol/L to 0.5 mmol/L,the action potential frequency of GLP-1RVMH neuron decreased significantly[(4.51±0.80)Hz vs.(1.43±0.51)Hz,P<0.01].Activation of GLP-1RVMH neuron significantly enhanced insulin secretion[(7.60±0.56)μU/mL vs.(11.34±0.93)μU/mL,P<0.01],while inhibition of these neuronal activities impaired the hypoglycemic efficiency of GLP-1 agonists[(32.03%±0.91%)vs.(25.77%±1.09%),P<0.001)].Mechanistically,GLP-1 regulated glucose homeostasis through Drp1 phosphorylation-mediated mitochondrial fission and improved mitochondrial energy metabolism.Conclusion GLP-1RVMH neurons are a class of glucose-excited neurons,and which activated directly promotes secretion of insulin.The hypoglycemic effect of GLP-1R agonists depend on the neuronal activity of GLP-1RVMH.