| Background Obesity is a metabolic disease, and its clinical manifestation includes the excessive accumulation of fat within the body and the increase of body weight. With the development of social economy and the change of dietary structure, the proportion of obese and overweight people surged in China and the number of obesity people is almost a quarter of the total population. Obesity is not only referred to overweight but also strongly associated with various diseases, such as diabetes, hypertension, cardiovascular and cerebrovascular diseases, fatty liver disease, hyperlipidemia, and cancer, etc. which severely threatens the people's health. Overweight and obesity has become a serious threat to our people's health and life quality.Cognitive impairment is mainly involved in many psychological disorders. For the obesity patients, the incidence of cognitive impairment is much higher than the normal people, and its underlying mechanisms include hippocampus injury, mitochondrial dysfunction, and insulin resistance. Therefore, to clarify the key mechanism of obesity related cognitive dysfunction and the prevention and control strategy has vital social value and clinical significance. Exercise training is an effective treatment for obesity. It has been suggested that exercise training not only can lose weight, but also can ameliorate cognitive impairment. In recent years, more and more attention has been paid to aerobic interval training(AIT). And AIT has been reportedly to have more advantages than moderate continuous training(MCT). However, whether AIT training can improve the cognitive dysfunction of obese individuals is unclear and so does the potential mechanism of it. SIRT3(Sirtuin3) is a class III histone deacetylase(HDAC). SIRT3 has been demonstrated to play important roles in many physiological and pathophysiological conditions, including metabolism, cell survival, cell death, and aging. In the nervous system, SIRT3 is reported to be neuroprotective. In the nervous system, Neurons is highly dependent on energy supply, so mitochondria SIRT3 dysfunction is bound to affect the normal function of the neuron. Additionally, it has been indicated that aerobic training can up-regulate SIRT3 expression. Therefore, there is reason to speculate that SIRT3 may plays an important role in AIT training to adjust function of hippocampal neurons. To clarify the above assumptions and further perfect the mechanism of obesity related cognitive dysfunction can provide new targets for possible treatment.Aims This study aims to investigate the influence and possible mechanism of aerobic interval training(AIT) on high-fat diet induced obesity(HF) mice hippocampal neuron damage. In the present study, we first established high-fat diet-induced obesity mice. The study aims to investigate the protective effects of AIT on the hippocampus neurons in obesity mice. Then, the study aims to elucidate the role of SIRT3 in the protective effect of AIT using SIRT3 KO mice.Methods Experiment I To confirm the protective effect of AIT on the hippocampus neurons in obesity mice. Forty C57BL/6 mice, aged 2 months, were randomly divided into four groups: control mice with normal diet(Con+STA), AIT mice with normal diet(Con+AIT), high-fat diet(HF+STA), and AIT mice with high-fat diet(HF+AIT). After 12 weeks, the learning and memory ability, the oxidative stress of hippocampus neurons were detected. Experiment II To elucidate the role of SIRT3 in the protective effect of AIT, SIRT3 KO mice were used. Twenty SIRT3 KO C57BL/6 mice, aged 2 months, were randomly divided into two groups: high-fat diet group(HF KO) and high-fat diet + AIT group(HF KO+AIT). After 12 weeks, the oxidative stress and apoptosis of hippocampus neurons were detected.Results Experiment I 1. AIT improved the spatial learning and memory ability of obesity mice. The results of Morris water maze suggested that: the escape latency was significantly increased in the HF group(HF:25.3 s vs Con: 10.5 s, P<0.05, n=4). And the time spent in the platform quadrant was markedly decreased in the HF group(HF:28.1% vs Con:45.8%, P<0.05, n=4).This indicated that high-fat diet significantly decrease the spatial learning and memory ability of obesity mice. However, AIT can improve the spatial learning and memory ability of obesity mice. The escape latency was decreased(HF+AIT:18.2 s vs HF:25.3 s, P<0.05, n=4) and the time spent in the platform quadrant was increased(HF+AIT:38.4% vs HF:28.1%, P<0.05, n=4)in the HF+AIT group. 2. AIT markedly inhibited the MDA and SOD in obesity mice. The level of MDA(Malondialdehyde)and SOD were dramatically increased in the HF group(P<0.05). However, the activity of Mn SOD(HF: 81.7±5.4 vs Con: 124.2±3.8 U/mg prot min-1, P<0.05, n=4) and catalase(HF:40.1±3.2 vs Con: 52.4±2.8 U/mg prot min-1, P<0.05, n=4)in the hippocampus neurons was markedly decreased in the HF group. 3. AIT significantly increased the antioxidative enzyme activity of hippocampus neurons in obesity mice. The expression of SIRT3 in the hippocampus neurons was significantly decreased in the HF group(HF: 0.32±0.04 vs Con: 0.87±0.05 AU, P<0.05, n=4). Compared with the HF group, AIT dramatically increased SIRT3 expression(HF+AIT: 0.64±0.04 vs HF: 0.32±0.04 AU, P<0.05, n=4)and the activity of Mn SOD(HF+AIT: 114.2±4.6 vs HF:81.7±5.4 U/mg prot min-1, P<0.05, n=4)and catalase(HF+AIT: 50.8±2.9 vs HF: 40.1±3.2 U/mg prot min-1, P<0.05, n=4), decreased oxidative stress, and improved learning and memory ability. 4. AIT up-regulated hippocampus neurons SIRT3 expression in obesity mice. SIRT3 is an important upstream regulatory factor of Catalase and Mn SOD. Compared with the Con group, the expression of SIRT3 in hippocampus neurons was significantly decreased in HF group(P<0.05). Nevertheless, AIT sufficiently up-regulate hippocampus neurons SIRT3 expression in HF group(P<0.05). Experiment II 1. AIT regulated the antioxidative enzyme activity of hippocampus neurons in obesity mice via SIRT3. Compared with WT mice, the activity of hippocampus neurons catalase(KO HF: 18.6±6.9 vs HF: 40.1±3.2 U/mg prot min-1, P<0.05, n=4)and Mn SOD(KO HF: 41.5±6.3 vs HF:81.7±5.4 U/mg prot min-1, P<0.05, n=4)was further decreased in SIRT3 KO mice with high-fat diet, oxidative stress was also further deteriorative(ROS KO HF: 143.8±4.2% vs HF: 100±3.2%, P<0.05, n=4). Additionally,AIT failed to improve the antioxidative enzyme activity and oxidative stress in SIRT3 KO mice with high-fat diet(P>0.05),this indicated that SIRT3 is a key signaling mechanism in AIT up-regulating the antioxidative enzyme activity of hippocampus neurons. 2. AIT protected the hippocampus neurons in HF mice via SIRT3. Compared with WT mice, AIT efficiently reduced the apoptosis of hippocampus neurons in HF mice(HF+AIT: 63.5±5.5% vs HF: 100±4.6 %, P<0.05, n=4). However, the apoptosis of hippocampus neurons was markedly increased in SIRT3 KO mice with high-fat diet(KO HF: 124.6±8.2% vs HF: 100±4.6%, P<0.05, n=4). In SIRT3 KO mice, the protective effects of AIT were dramatically abolished(P<0.05).Conclusions AIT can up-regulate SIRT3 expression in the hippocampus neurons, decrease oxidative stress, and attenuate cognitive impairment. SIRT3 may be the key molecule in the neuroprotective effects of AIT against HF-induced hippocampus neuron damage. |
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