Effects of aerobic exercise on hypothalamic autophagy and leptin resis-tance in obese mice
10.3969/j.issn.1000-4718.2025.08.001
- VernacularTitle:有氧运动对肥胖小鼠下丘脑细胞自噬和瘦素抵抗的影响及其机制
- Author:
Guangming ZHU
1
;
Ziyi YANG
;
Xinzhuang WANG
;
Yan LIU
;
Chunlu FANG
;
Liangming LI
;
Shujing LIU
Author Information
1. 广州体育学院,广东 广州 510500;广州华南商贸职业学院,广东 广州 510550
- Publication Type:Journal Article
- Keywords:
aerobic exercise;
hypothalamus;
autophagy;
leptin resistance;
irisin
- From:
Chinese Journal of Pathophysiology
2025;41(8):1457-1466
- CountryChina
- Language:Chinese
-
Abstract:
AIM:This study aims to investigate the effects of aerobic exercise on hypothalamic autophagy and central leptin resistance in obese mice,and to explore the potential mechanisms.METHODS:Forty male C57BL/6J mice,aged 7 to 8 weeks,were randomly assigned to 5 groups:normal control(CON)group,high-fat diet(HFD)group,HFD+exercise(HFD+Exe)group,HFD+phosphate-buffered saline(PBS)group,and HFD+rilmenidine(autophagy ago-nist)group,with 8 mice in each group.Additionally,twelve fibronectin type Ⅲ domain-containing protein 5(Fndc5)gene(encoding irisin precursor protein)knockout(Fndc5 KO)mice were randomly allocated to Fndc5 KO+HFD group and Fndc5 KO+HFD+Exe group,with 6 mice in each group.All mice were fed for 28 weeks.The mice in CON group re-ceived a normal diet,while those in the remaining groups were provided with an HFD.The mice in HFD+Exe and Fndc5 KO+HFD+Exe groups engaged in aerobic treadmill exercise while continuing an HFD from weeks 17 to 28.The mice in HFD+PBS group received intraperitoneal injections of PBS as a control,while those in HFD+rilmenidine group received in-traperitoneal injections of rilmenidine(10 mg?kg-1?d-1),4 times a week over a total duration of 12 weeks(weeks 17 to 28).Following the intervention,serum metabolite levels,as well as concentrations of leptin and irisin,were quantified by ELISA.Morphological alterations in the liver and white adipose tissues were evaluated through oil red O staining and he-matoxylin-eosin(HE)staining.Western blot was utilized to assess the hypothalamic protein levels of autophagy markers,autophagy-related protein 7(ATG7),beclin-1,microtubule-associated protein 1 light chain 3(LC3)and p62,and leptin resistance markers,suppressor of cytokine signaling 3(SOCS3)and protein tyrosine phosphatase 1B(PTP1B).RE-SULTS:Observations of mouse phenotypes indicated that HFD feeding significantly increased body weight,blood lipid content and serum leptin level(P<0.05).The results of HE and oil red O staining demonstrated that HFD feeding marked-ly promoted lipid accumulation in the liver and caused ballooning of white adipocytes.Western blot analyses revealed that HFD feeding significantly down-regulated the protein levels of ATG7,beclin-1 and LC3-Ⅱ/LC3-I,but up-regulated the pro-tein level of p62(P<0.05),thus reducing cellular autophagy capacity.Furthermore,HFD feeding elevated the protein levels of leptin resistance markers SOCS3 and PTP1B(P<0.05).Aerobic exercise and autophagy agonist were found to partially reverse these changes,enhancing cellular autophagy capacity and alleviating leptin resistance.However,these effects were diminished after knockout of Fndc5 gene,further substantiating the role of irisin in exercise-mediated en-hancement of cellular autophagy and attenuation of leptin resistance.CONCLUSION:Aerobic exercise alleviates hypo-thalamic autophagy defect and central leptin resistance in obese mice,which may be associated with exercise-induced irisin.
