Effects Of Aerobic Exercise On Autophagy And Leptin Resistance In Hypothalamus Cells Of Obese Mice And The Related Mechanisms

Objective:The incidence of obesity and related metabolic diseases is rising rapidly around the world.Leptin resistance is an important pathological mechanism of the occurrence and development of obesity,which may be related to the weakening of autophagy.The improvement of leptin resistance is beneficial to improve the energy balance and reduce obesity.Autophagy plays an important role in energy metabolism.Obese bodies are often characterized by defective cell autophagy,and exercise can promote autophagy,which may be related to the stimulation of Iris secreted by skeletal muscle by exercise.Aerobic exercise can improve leptin resistance and enhance autophagy,but it is not clear whether it can promote autophagy of hypothalamic neurons and have an effect on leptin resistance.The purpose of this study is to explore the effects of aerobic exercise on hypothalamic autophagy and leptin resistance and the related mechanism of Irisin,so as to provide theoretical basis for exercise prevention and treatment of obesity and related metabolic diseases.Methods:50 wild-type C57BL/6J male mice were randomly divided into low fat diet group(n=10)and high fat diet group(n=40)after adaptive feeding for 1 week.The high-fat diet group reached the obesity model standard after 16 weeks of high fat diet.After successful modeling,all wild type mice were divided into low-fat diet group(LFD),high-fat diet group(HFD),high-fat exercise group(HE),high-fat injection phosphate buffer saline group(HFD+PBS)and high-fat injection autophagy agonist group(HFD+rilmenidine),8 mice in each group.12 FNDC5 knockout male mice were divided into high-fat knockout group(FNDC5-KO+HFD)and high-fat exercise knockout group(FNDC5KO+HE).All the mice were fed for 28 weeks.Except for the LFD group,the other groups were given high-fat diet.From the 17 th week to the 28 th week,the mice in HE group and FNDC5-KO+HE group were fed with high-fat diet and aerobic treadmill exercise intervention.HFD+PBS group received intraperitoneal injection of phosphate buffer as control,while HFD+rilmenidine group received intraperitoneal injection of rilmenidine autophagy agonist(10mg/kg/day)4 times a week for 12 weeks(week 17 to week 28).The contents of TG,TC,HDL-C,LDL-C,leptin and Irisin in serum were measured,and the pathological changes of liver were observed by oil red O staining and H&E staining.The expression of hypothalamic autophagy related proteins ATG7,beclin1,LC3II/I,p62 and leptin signal proteins SOCS3 and PTP1 B were detected by Western Blot.Results:⒈ Aerobic exercise could improve the autophagy deficiency and leptin resistance in hypothalamus of obese mice induced by high fat diet.Compared with LFD group,the expression levels of autophagy related proteins ATG7,beclin1,LC3II/I and p62 increased significantly in HFD group,and the expression levels of leptin signaling proteins SOCS3 and PTP1 B increased,indicating that obesity can lead to the decrease of hypothalamic autophagy activity and leptin sensitivity.Compared with HFD group,the expression of autophagy-related proteins ATG7,beclin1 and LC3II/I was significantly up-regulated and p62 was down-regulated in HE group,while the expression of leptin signal proteins SOCS3 and PTP1 B was significantly down-regulated in HE group.⒉ The increase of autophagy ability of hypothalamic cells in obese mice was helpful to improve central leptin resistance.Compared with HFD+PBS group,the expression levels of ATG7,beclin1,LC3II/I and p62 in hypothalamus of HFD+rilmenidine group were up-regulated and p62 down-regulated,and the expression levels of leptin signal proteins SOCS3 and PTP1 B were significantly down-regulated.This suggests that the improvement of hypothalamic leptin resistance in obese mice is related to the increase of autophagy activity.⒊ After FNDC5 gene knockout,the effect of exercise on autophagy and leptin resistance of hypothalamic cells disappeared.Compared with FNDC5-KO+HFD group,there was no significant difference in autophagy-related proteins ATG7,beclin1,LC3II/I,p62,leptin signal proteins SOCS3 and PTP1 B between FNDC5-KO+HE group and FNDC5-KO+HE group.Conclusions:⒈Aerobic exercise can improve hypothalamic autophagy deficiency and central leptin resistance in obese mice.⒉ The increase of hypothalamic autophagy activity in obese mice is helpful to improve leptin resistance.⒊ Aerobic exercise may improve hypothalamic autophagy deficiency and leptin resistance in obese mice through Irisin.