Dataset Information

Aerobic Exercise Improves Type 2 Diabetes Mellitus-Related Cognitive Impairment by Inhibiting JAK2/STAT3 and Enhancing AMPK/SIRT1 Pathways in Mice.

ABSTRACT: Type 2 diabetes mellitus (T2DM) is a prevalent risk factor for cognitive impairment. Aerobic exercise can improve T2DM-related cognitive impairment; however, the possible mechanisms remain elusive. Thus, we assessed db/m mice and leptin receptor-deficient (db/db) mice that did or did not perform aerobic exercise (8 m/min, 60 min/day, and 5 days/week for 12 weeks). In this study, cognitive function was significantly impaired in the T2DM mice; aerobic exercise improved cognitive impairment through activating the AMPK/SIRT1 signalling pathway and inhibiting the JAK2/STAT3 signalling pathway in T2DM mice. However, after the application of RO8191 (JAK2 activator) or Compound C (AMPK inhibitor), the positive improvement of the exercise was evidently suppressed. Taken together, our data indicated that long-term aerobic exercise improves type 2 diabetes mellitus-related cognitive impairment by inhibiting JAK2/STAT3 and enhancing AMPK/SIRT1 pathways in mice.

SUBMITTER: Lin L

PROVIDER: S-EPMC9107038 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Aerobic Exercise Improves Type 2 Diabetes Mellitus-Related Cognitive Impairment by Inhibiting JAK2/STAT3 and Enhancing AMPK/SIRT1 Pathways in Mice.

Lin Lili L Wang Yonghua Y Xu Wenli W Huang Chaolu C Hu Jinrong J Chen Xixi X Lv Xinhuang X Qin Yuelin Y Zhao Xiaoyong X Li Haiyan H

Disease markers 20220505

Type 2 diabetes mellitus (T2DM) is a prevalent risk factor for cognitive impairment. Aerobic exercise can improve T2DM-related cognitive impairment; however, the possible mechanisms remain elusive. Thus, we assessed db/m mice and leptin receptor-deficient (db/db) mice that did or did not perform aerobic exercise (8 m/min, 60 min/day, and 5 days/week for 12 weeks). In this study, cognitive function was significantly impaired in the T2DM mice; aerobic exercise improved cognitive impairment through ...[more]

PMID: 35578689

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Project description:ObjectiveTo assess the efficacy of a progressive aerobic exercise training program on cognitive and everyday function among adults with mild subcortical ischemic vascular cognitive impairment (SIVCI).MethodsThis was a proof-of-concept single-blind randomized controlled trial comparing a 6-month, thrice-weekly, progressive aerobic exercise training program (AT) with usual care plus education on cognitive and everyday function with a follow-up assessment 6 months after the formal cessation of aerobic exercise training. Primary outcomes assessed were general cognitive function (Alzheimer's Disease Assessment Scale-Cognitive subscale [ADAS-Cog]), executive functions (Executive Interview [EXIT-25]), and activities of daily living (Alzheimer's Disease Cooperative Study-Activities of Daily Living [ADCS-ADL]).ResultsSeventy adults randomized to aerobic exercise training or usual care were included in intention-to-treat analyses (mean age 74 years, 51% female, n = 35 per group). At the end of the intervention, the aerobic exercise training group had significantly improved ADAS-Cog performance compared with the usual care plus education group (-1.71 point difference, 95% confidence interval [CI] -3.15 to -0.26, p = 0.02); however, this difference was not significant at the 6-month follow-up (-0.63 point difference, 95% CI -2.34 to 1.07, p = 0.46). There were no significant between-group differences at intervention completion and at the 6-month follow-up in EXIT-25 or ADCS-ADL performance. Examination of secondary measures showed between-group differences at intervention completion favoring the AT group in 6-minute walk distance (30.35 meter difference, 95% CI 5.82 to 54.86, p = 0.02) and in diastolic blood pressure (-6.89 mm Hg difference, 95% CI -12.52 to -1.26, p = 0.02).ConclusionsThis study provides preliminary evidence for the efficacy of 6 months of thrice-weekly progressive aerobic training in community-dwelling adults with mild SIVCI, relative to usual care plus education.Clinicaltrialsgov identifierNCT01027858.Classification of evidenceThis study provides Class II evidence that for adults with mild SIVCI, an aerobic exercise program for 6 months results in a small, significant improvement in ADAS-Cog performance.

Project description:BackgroundNonalcoholic steatohepatitis (NASH), a common cause of liver-related morbidity and mortality worldwide, is characterized by inflammation and hepatocellular injury. Our research focuses on lipoprotein-associated phospholipase A2 (Lp-PLA2), an inflammation-related biomarker that has recently garnered interest in the context of NASH due to its potential roles in disease pathogenesis and progression.MethodsWe established a NASH mouse model using a high-fat diet (HFD) and treated it with sh-Lp-PLA2 and/or rapamycin (an mTOR inhibitor). Lp-PLA2 expression in NASH mice was detected by qRT-PCR. Serum levels of liver function parameters and inflammatory cytokines were detected using corresponding assay kits. We examined pathological changes in liver using hematoxylin-eosin, oil red O, and Masson staining, and observed autophagy through transmission electron microscopy. The protein levels of Lp-PLA2, mTOR, light chain 3 (LC3) II/I, phosphorylated Janus kinase 2 (p-JAK2)/JAK2, and phosphorylated signal transducer and activator of transcription 3 (p-STAT3)/STAT3 were determined by western blotting. Kupffer cells extracted from C57BL/6J mice were treated to replicate NASH conditions and treated with sh-Lp-PLA2, rapamycin, and/or a JAK2-inhibitor to further verify the roles and mechanisms of Lp-PLA2 in NASH.ResultsOur data indicate an upregulation of Lp-PLA2 expression in HFD-induced NASH mice. Silencing Lp-PLA2 in NASH mice reduced liver damage and inflammation markers (aspartate aminotransferase (AST), alanine aminotransferase (ALT), total cholesterol (TC), triglycerides (TG), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6)), while increasing IL-10 levels, an anti-inflammatory cytokine. Additionally, Lp-PLA2 silencing decreased lipid and collagen accumulation and promoted autophagy. The beneficial effects of sh-Lp-PLA2 on NASH were enhanced by rapamycin. Furthermore, Lp-PLA2 silencing resulted in the downregulation of the expression of p-JAK2/JAK2 and p-STAT3/STAT3 in NASH mice. Similar results were observed in Kupffer cells treated under NASH conditions; Lp-PLA2 silencing promoted autophagy and repressed inflammation, effects which were potentiated by the addition of rapamycin or a JAK2-inhibitor.ConclusionOur findings suggest that silencing Lp-PLA2 promotes autophagy via deactivating the JAK2/STAT3 signaling pathway, thereby restraining NASH progression. This highlights the potential therapeutic value of targeting Lp-PLA2, adding a new dimension to our understanding of NASH pathogenesis and treatment strategies.

Dataset Information

Aerobic Exercise Improves Type 2 Diabetes Mellitus-Related Cognitive Impairment by Inhibiting JAK2/STAT3 and Enhancing AMPK/SIRT1 Pathways in Mice.

Publications

Aerobic Exercise Improves Type 2 Diabetes Mellitus-Related Cognitive Impairment by Inhibiting JAK2/STAT3 and Enhancing AMPK/SIRT1 Pathways in Mice.

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