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Delayed Exercise Training Improves Obesity-Induced Chronic Kidney Disease by Activating AMPK Pathway in High-Fat Diet-Fed Mice.

ABSTRACT: Exercise training is now recognized as an interesting therapeutic strategy in managing obesity and its related disorders. However, there is still a lack of knowledge about its impact on obesity-induced chronic kidney disease (CKD). Here, we investigated the effects of a delayed protocol of endurance exercise training (EET) as well as the underlying mechanism in obese mice presenting CKD. Mice fed a high-fat diet (HFD) or a low-fat diet (LFD) for 12 weeks were subsequently submitted to an 8-weeks EET protocol. Delayed treatment with EET in obese mice prevented body weight gain associated with a reduced calorie intake. EET intervention counteracted obesity-related disorders including glucose intolerance, insulin resistance, dyslipidaemia and hepatic steatosis. Moreover, our data demonstrated for the first time the beneficial effects of EET on obesity-induced CKD as evidenced by an improvement of obesity-related glomerulopathy, tubulo-interstitial fibrosis, inflammation and oxidative stress. EET also prevented renal lipid depositions in the proximal tubule. These results were associated with an improvement of the AMPK pathway by EET in renal tissue. AMPK-mediated phosphorylation of ACC and ULK-1 were particularly enhanced leading to increased fatty acid oxidation and autophagy improvement with EET in obese mice.

SUBMITTER: Juszczak F

PROVIDER: S-EPMC7795787 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Delayed Exercise Training Improves Obesity-Induced Chronic Kidney Disease by Activating AMPK Pathway in High-Fat Diet-Fed Mice.

Juszczak Florian F Vlassembrouck Maud M Botton Olivia O Zwakhals Thomas T Decarnoncle Morgane M Tassin Alexandra A Caron Nathalie N Declèves Anne-Emilie AE

International journal of molecular sciences 20201231 1

Exercise training is now recognized as an interesting therapeutic strategy in managing obesity and its related disorders. However, there is still a lack of knowledge about its impact on obesity-induced chronic kidney disease (CKD). Here, we investigated the effects of a delayed protocol of endurance exercise training (EET) as well as the underlying mechanism in obese mice presenting CKD. Mice fed a high-fat diet (HFD) or a low-fat diet (LFD) for 12 weeks were subsequently submitted to an 8-weeks ...[more]

PMID: 33396267

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Project description:Background: Metabolic syndrome is characterized by central obesity, hyperglycemia and hyperlipidemia. Insulin resistance is the leading risk factor for metabolic syndrome. Kun-Dan decoction (KD), a traditional Chinese medicine, has been applied to treat patients with metabolic syndrome for over ten years. It is increasingly recognized that autophagy deficiency is the key cause of metabolic syndrome. Therefore, we aimed to explore whether KD can activate autophagy to improve metabolic syndrome. Methods: Network pharmacology was used to explore the underlying mechanism of KD in the treatment of metabolic syndrome. The high-fat diet-fed rats and oleic acid-induced LO2 cells were employed in our study. Oral glucose tolerance test and insulin tolerance test, obesity and histological examination, serum cholesterol, triglyceride, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), homeostasis model assessment of insulin resistance (HOMA-IR) and insulin sensitivity in high-fat diet-fed rats were analyzed. Furthermore, the protein expressions of adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK), phospho-AMPK, mammalian target of rapamycin (mTOR), phospho-mTOR, p62, autophagy related protein (Atg) 5, Atg7, Atg12, Atg13, Atg16L1 and microtubule-associated protein 1A/1B-light chain 3 (LC3)-Ⅱ/Ⅰ were examined in rats and LO2 cells. Moreover, autophagy activator rapamycin and inhibitor 3-methyladenine, and small interfering RNA against Atg7 were utilized to verify the role of autophagy in the treatment of metabolic syndrome by KD in oleic acid-induced LO2 cells. Results: Results from network pharmacology indicated that targeted insulin resistance might be the critical mechanism of KD in the treatment of metabolic syndrome. We found that KD significantly suppressed obesity, serum cholesterol, triglyceride and LDL-C levels and increased serum HDL-C level in high-fat diet-fed rats. Furthermore, KD enhanced insulin sensitivity and attenuated HOMA-IR in high-fat diet-fed rats. Western blot showed that KD could enhance autophagy to increase the insulin sensitivity of high-fat diet-fed rats and oleic acid-induced LO2 cells. Furthermore, 3-methyladenine and small interfering RNA against Atg7 could reverse the protective effect of KD on LO2 cells. However, rapamycin could cooperate with KD to enhance autophagic activation to increase insulin sensitivity in LO2 cells. Conclusion: The induction of autophagy may be the major mechanism for KD to improve insulin resistance and metabolic syndrome.

Project description:Key pointsObesity results in perilymphatic inflammation and lymphatic dysfunction. Lymphatic dysfunction in obesity is characterized by decreased lymphatic vessel density, decreased collecting lymphatic vessel pumping frequency, decreased lymphatic trafficking of immune cells, increased lymphatic vessel leakiness and changes in the gene expression patterns of lymphatic endothelial cells. Aerobic exercise, independent of weight loss, decreases perilymphatic inflammatory cell accumulation, improves lymphatic function and reverses pathological changes in gene expression in lymphatic endothelial cells.AbstractAlthough previous studies have shown that obesity markedly decreases lymphatic function, the cellular mechanisms that regulate this response remain unknown. In addition, it is unclear whether the pathological effects of obesity on the lymphatic system are reversible with behavioural modifications. The purpose of this study, therefore, was to analyse lymphatic vascular changes in obese mice and to determine whether these pathological effects are reversible with aerobic exercise. We randomized obese mice to either aerobic exercise (treadmill running for 30 min per day, 5 days a week, for 6 weeks) or a sedentary group that was not exercised and analysed lymphatic function using a variety of outcomes. We found that sedentary obese mice had markedly decreased collecting lymphatic vessel pumping capacity, decreased lymphatic vessel density, decreased lymphatic migration of immune cells, increased lymphatic vessel leakiness and decreased expression of lymphatic specific markers compared with lean mice (all P < 0.01). Aerobic exercise did not cause weight loss but markedly improved lymphatic function compared with sedentary obese mice. Exercise had a significant anti-inflammatory effect, resulting in decreased perilymphatic accumulation of inflammatory cells and inducible nitric oxide synthase expression. In addition, exercise normalized isolated lymphatic endothelial cell gene expression of lymphatic specific genes, including VEGFR-3 and Prox1. Taken together, our findings suggest that obesity impairs lymphatic function via multiple mechanisms and that these pathological changes can be reversed, in part, with aerobic exercise, independent of weight loss. In addition, our study shows that obesity-induced lymphatic endothelial cell gene expression changes are reversible with behavioural modifications.

Dataset Information

Delayed Exercise Training Improves Obesity-Induced Chronic Kidney Disease by Activating AMPK Pathway in High-Fat Diet-Fed Mice.

Publications

Delayed Exercise Training Improves Obesity-Induced Chronic Kidney Disease by Activating AMPK Pathway in High-Fat Diet-Fed Mice.

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