title: Dipeptidyl peptidase 4 inhibitor improves brain insulin sensitivity, but fails to prevent cognitive impairment in orchiectomy obese rats.
abstract: It is unclear whether the dipeptidyl peptidase 4 (DPP4) inhibitor can counteract brain insulin resistance, brain mitochondrial dysfunction, impairment of hippocampal synaptic plasticity and cognitive decline in testosterone-deprived obese rats. We hypothesized that DPP4 inhibitor vildagliptin improves cognitive function in testosterone-deprived obese rats by restoring brain insulin sensitivity, brain mitochondrial function and hippocampal synaptic plasticity. Thirty male Wistar rats received either a sham-operated (S, n=6) or bilateral orchiectomy (ORX, n=24). ORX rats were divided into two groups and fed with either a normal diet (ND (NDO)) or a high-fat diet (HFO) for 12 weeks. Then, ORX rats in each dietary group were divided into two subgroups (n=6/subgroup) to receive either a vehicle or vildagliptin (3 mg/kg per day, p.o.) for 4 weeks. After treatment, cognitive function, metabolic parameters, brain insulin sensitivity, hippocampal synaptic plasticity and brain mitochondrial function were determined in each rat. We found that HFO rats exhibited peripheral and brain insulin resistance, brain mitochondrial dysfunction, impaired hippocampal synaptic plasticity and cognitive decline. NDO rats did not develop peripheral and brain insulin resistance. However, impaired hippocampal synaptic plasticity and cognitive decline occurred. Vildagliptin significantly improved peripheral insulin sensitivity, restored brain insulin sensitivity and decreased brain mitochondrial reactive oxygen species production in HFO rats. However, vildagliptin did not restore hippocampal synaptic plasticity and cognitive function in both NDO and HFO rats. These findings suggest that vildagliptin could not counteract the impairment of hippocampal synaptic plasticity and cognitive decline in testosterone-deprived subjects, despite its effects on improved peripheral and brain insulin sensitivity as well as brain mitochondrial function.
authors.affiliation: Neurophysiology UnitFaculty of Medicine, Cardiac Electrophysiology Research and Training CenterDepartment of PhysiologyFaculty of MedicineDepartment of Oral Biology and Diagnostic ScienceFaculty of Dentistry, Chiang Mai University, Chiang Mai 50200, Thailand Neurophysiology UnitFaculty of Medicine, Cardiac Electrophysiology Research and Training CenterDepartment of PhysiologyFaculty of MedicineDepartment of Oral Biology and Diagnostic ScienceFaculty of Dentistry, Chiang Mai University, Chiang Mai 50200, Thailand.
authors.forename: Hiranya
authors.initials: H
authors.lastname: Pintana
authors.affiliation: Neurophysiology UnitFaculty of Medicine, Cardiac Electrophysiology Research and Training CenterDepartment of PhysiologyFaculty of MedicineDepartment of Oral Biology and Diagnostic ScienceFaculty of Dentistry, Chiang Mai University, Chiang Mai 50200, Thailand Neurophysiology UnitFaculty of Medicine, Cardiac Electrophysiology Research and Training CenterDepartment of PhysiologyFaculty of MedicineDepartment of Oral Biology and Diagnostic ScienceFaculty of Dentistry, Chiang Mai University, Chiang Mai 50200, Thailand.
authors.forename: Wanpitak
authors.initials: W
authors.lastname: Pongkan
authors.affiliation: Neurophysiology UnitFaculty of Medicine, Cardiac Electrophysiology Research and Training CenterDepartment of PhysiologyFaculty of MedicineDepartment of Oral Biology and Diagnostic ScienceFaculty of Dentistry, Chiang Mai University, Chiang Mai 50200, Thailand Neurophysiology UnitFaculty of Medicine, Cardiac Electrophysiology Research and Training CenterDepartment of PhysiologyFaculty of MedicineDepartment of Oral Biology and Diagnostic ScienceFaculty of Dentistry, Chiang Mai University, Chiang Mai 50200, Thailand.
authors.forename: Wasana
authors.initials: W
authors.lastname: Pratchayasakul
authors.affiliation: Neurophysiology UnitFaculty of Medicine, Cardiac Electrophysiology Research and Training CenterDepartment of PhysiologyFaculty of MedicineDepartment of Oral Biology and Diagnostic ScienceFaculty of Dentistry, Chiang Mai University, Chiang Mai 50200, Thailand Neurophysiology UnitFaculty of Medicine, Cardiac Electrophysiology Research and Training CenterDepartment of PhysiologyFaculty of MedicineDepartment of Oral Biology and Diagnostic ScienceFaculty of Dentistry, Chiang Mai University, Chiang Mai 50200, Thailand.
authors.forename: Nipon
authors.initials: N
authors.lastname: Chattipakorn
authors.affiliation: Neurophysiology UnitFaculty of Medicine, Cardiac Electrophysiology Research and Training CenterDepartment of PhysiologyFaculty of MedicineDepartment of Oral Biology and Diagnostic ScienceFaculty of Dentistry, Chiang Mai University, Chiang Mai 50200, Thailand Neurophysiology UnitFaculty of Medicine, Cardiac Electrophysiology Research and Training CenterDepartment of PhysiologyFaculty of MedicineDepartment of Oral Biology and Diagnostic ScienceFaculty of Dentistry, Chiang Mai University, Chiang Mai 50200, Thailand scchattipakorn@gmail.com siriporn.c@cmu.ac.th.
authors.forename: Siriporn C
authors.initials: SC
authors.lastname: Chattipakorn
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D003071:Cognition / Q000187:drug effects* / Q000502:physiology; D059305:Diet, High-Fat; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D007333:Insulin Resistance; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009473:Neuronal Plasticity / Q000187:drug effects* / Q000502:physiology; D009570:Nitriles / Q000494:pharmacology*; D009765:Obesity / Q000378:metabolism / Q000523:psychology; D009919:Orchiectomy; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D000077597:Vildagliptin
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D009570:Nitriles; D011759:Pyrrolidines; D000077597:Vildagliptin; D000218:Adamantane
keywords: brain mitochondrial function; cognitive function; hippocampal synaptic plasticity; obese-insulin resistance; testosterone deprivation; vildagliptin