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.
Hiranya Pintana, Wanpitak Pongkan, Wasana Pratchayasakul, Nipon Chattipakorn and Siriporn C Chattipakorn
Apiwan Arinno, Nattayaporn Apaijai, Puntarik Kaewtep, Wasana Pratchayasakul, Thidarat Jaiwongkam, Sasiwan Kerdphoo, Siriporn Chattipakorn and Nipon Chattipakorn
Although a physiological dose of testosterone replacement therapy (p-TRT) has been shown to improve left ventricular (LV) function, some studies reported that it increased the risk of myocardial infarction in testosterone-deprived men. We previously reported that vildagliptin might be used as an alternative to the p-TRT. In this study, we hypothesized that a combined low-dose TRT with vildagliptin exerts greater efficacy than single regimen in improving cardiometabolic function in obese-insulin resistant rats with testosterone deprivation. Male rats were fed on a normal diet or high-fat diet for 12 weeks. Then, they were divided into 2 subgroups; sham operation and orchiectomy (NDO, HFO) and fed their diets for another 12 weeks. At week 25, orchiectomized rats were subdivided into 4 groups, vehicle, p-TRT, vildagliptin, and combined drugs. At week 29, cardiometabolic and biochemical parameters were determined. HFO rats had obese-insulin resistance with a worse LV dysfunction, compared with sham. Vildagliptin and combined drugs effectively reduced insulin resistance. All treatments reduced blood pressure, cardiac autonomic imbalance, LV dysfunction, mitochondrial dysfunction, apoptosis, and increased mitochondrial fusion in NDO and HFO rats. However, p-TRT and combined drugs, but not vildagliptin, reduced mitochondrial fission in NDO and HFO rats. We concluded that combined low-dose TRT with vildagliptin mitigated LV function at a similar level to the p-TRT alone and vildagliptin via improving mitochondrial fusion, reducing mitochondrial dysfunction and apoptosis in testosterone-deprived rats. Our findings suggest that low-dose TRT combined with vildagliptin may be an alternative for p-TRT in conditions of obese-insulin resistance with testosterone deprivation.