The Effect Of Aerobic Exercise On High Fat Diet Induced Benign Prostatic Hyperplasia In Mice By Regulating Androgen And IL-6/JAK1/STAT3 Signaling Pathway

ObjectiveBenign prostatic hyperplasia（BPH）is one of the most common urinary diseases in elderly men.With the aggravation of aging,the prevalence of BPH also increases.The purpose of this study was to investigate the mechanism of androgen and androgen receptor（AR）in the prostate tissue of BPH mice through the androgen/AR signaling pathway.The changes of interleukin-6（IL-6）,Janus kinase 1（JAK1）,signal transducer and activator of transcription 3（STAT3）and related nuclear factor kappa B（NF-κB）in prostate tissue of BPH mice induced by high fat diet were also investigated.Eight weeks treadmill exercise was used to observe the specific mechanism of Androgen/AR/IL-6/STAT3 signaling pathway in the improvement of BPH by aerobic exercise.MethodsForty SPF grade 4-week-old C57BL/6J mice were randomly divided into two groups:Control group（Group C,n=15）and High fat diet group（HFD group,n=25）.After 12weeks of dietary intervention,5 mice in each group were randomly selected,and then the prostate tissue of mice was taken for tissue embedding,sectioning and he staining to observe the changes of prostate gland cavity area in the two groups,so as to judge the successful establishment of BPH mouse model.After 8 weeks of treadmill exercise intervention,mice in group C（n=10）continued to feed normal diet group,HFD group（n=20）continued to feed high-fat diet,and HFD group mice were randomly divided into two groups:Benign prostatic hyperplasia group（H group,n=10）and Exercise group（HE group,n=10）.Mice in group H were fed with high-fat diet,while the mice of group HE were fed with high-fat diet and conducted by treadmill exercise intervention.The exercise intervention of HE group was speed of 14 m/min treadmill exercise lasting for 1 hour（7 p.m.-8 p.m.）.The frequency of exercise was five days a week,lasting for 8 weeks.After exercise intervention,the mice were anesthetized and killed and blood was collected.The prostate tissue was taken to weigh the prostate weight（PW）.The prostate volume（PV）was measured by water substitution method,and the prostate index（PI）was calculated.HE staining was used to observe the pathological changes of prostate and measure the area of gland cavity.ELISA was used to detect serum testosterone（T）,dihydrotestosterone（DHT）,estradiol（E₂）and IL-6,and E₂/T value was calculated.Immunohistochemistry was used to detect AR in prostate tissue.To detect AR in prostate tissue by Western blot.The relative expression levels of AR,IL-6R,JAK1,STAT3,p STAT3 and NF-κB in prostate tissue were detected by Western blot.The experimental results were expressed by mean plus minus standard deviation（m±SD）.During the modeling period,the differences between the two groups were analyzed by independent sample t-test,and the comparison between multiple groups was performed by one-way ANOVA,with P<0.05 as the significant difference.Results1.After 12 weeks of high-fat diet induction,the body weight of HFD group was significantly higher than that of C group（P<0.01）and reached the obesity standard.Compared with the prostatic gland cavity of group C,the area of prostatic gland cavity of group H mice increased,and the results of the two groups were significantly different（P<0.01）;after 8 weeks of aerobic exercise intervention,the area of prostatic gland cavity of group H mice was increased significantly compared with group C（P<0.01）;compared with group H,the area of prostatic gland cavity of group HE mice was recduced significantly（P<0.01）.2.Compared with group C mice with PW（0.08±0.02）g and PV（0.09±0.03）ml,the PW（0.11±0.03）g and PV（0.13±0.04）ml of group H mice were significantly increased（PW:P<0.01,PV:P<0.05）after 8 weeks of aerobic exercise intervention.There was no significant difference in PW（0.09±0.02）g and PV（0.12±0.06）ml between HE group and H group（P>0.05）;there was no significant difference between C group（0.24±0.04）mg/g,H group（0.23±0.07）mg/g and HE group（0.21±0.04）mg/g in PI（P>0.05）.3.After 8 weeks of exercise intervention,compared with the serum T and DHT levels of mice in group C,the serum T and DHT levels of mice in group H were significantly decreased（P<0.05）;there was no significant difference between group HE and group H in serum T and DHT of mice（P>0.05）;among the level of serum E₂ of group C,group H and group HE,there was no significant difference（P>0.05）.Compared with group C,the E₂/T ratio in group H was significantly increased（P<0.01）,and the ratio of E₂/T in group HE was significantly decreased compared with group H（P<0.05）.Compared with group C,the content of serum IL-6 in group H was significantly higher（P<0.01）,and the level of serum IL-6 in group HE was significantly lower than group H（P<0.01）.4.After 8 weeks of aerobic exercise intervention,the average optical density of AR in the prostate of mice in group H decreased significantly when compared with group C（P<0.01）;In group HE,the average optical density of AR in the prostate of mice increased significantly when compared with group H（P<0.01）.5.After 8 weeks of aerobic exercise intervention,compared with group C,the total protein content of AR in prostate tissue in group H mice diminished significantly（P<0.01）;compared with group H,the total protein content of AR in prostate tissue of mice in group HE increased significantly（P<0.05）.6.After 20 weeks of total intervention,compared with group C,the protein contents of IL-6R,JAK1,STAT3,p STAT3 and NF-κB in prostate tissue of mice in group H were significantly magnified（P<0.01）;compared with group H,the protein contents of IL-6R,JAK1,STAT3,p STAT3 and NF-κB in prostate tissue of mice in group he were significantly diminished（P<0.01）.Conclusion1)After 12 weeks of high-fat diet,the area of prostate gland cavity increased and BPH appeared in obese mice.Androgen/AR signaling pathway was significantly inhibited in high-fat diet induced BPH,which might further activate IL-6/STAT3 inflammatory signaling pathway to promote BPH.2)8-week aerobic exercise might reduce the ratio of estrogen to androgen,up regulate the expression of AR protein,inhibit the inflammatory signal pathway of IL-6/STAT3and the proliferation of prostate cells,and then improved the BPH induced by high-fat diet in mice.