Adipocyte-secreted exosomal microRNA-34a inhibits M2 macrophage polarization to promote obesity-induced adipose inflammation
| Autor: | Tianshi Feng, Yong Pan, Ruby L. C. Hoo, Xiaoyan Hui, Aimin Xu, Yu Wang, Karen Siu Ling Lam, Dewei Ye, Cyrus Yuk Cheung Chan |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Panniculitis Kruppel-Like Transcription Factors Adipose tissue Inflammation Intra-Abdominal Fat Exosomes Systemic inflammation Proinflammatory cytokine Kruppel-Like Factor 4 Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Insulin resistance Internal medicine Adipocyte Adipocytes medicine Animals Obesity Mice Knockout business.industry Macrophages General Medicine medicine.disease M2 Macrophage MicroRNAs 030104 developmental biology Endocrinology chemistry MicroRNA 34a 030220 oncology & carcinogenesis medicine.symptom business Research Article |
| Zdroj: | Journal of Clinical Investigation. 129:834-849 |
| ISSN: | 1558-8238 0021-9738 |
| DOI: | 10.1172/jci123069 |
| Popis: | Persistent, unresolved inflammation in adipose tissue is a major contributor to obesity-associated metabolic complications. However, the molecular links between lipid-overloaded adipocytes and inflammatory immune cells in obese adipose tissues remain elusive. Here we identified adipocyte-secreted microRNA-34a (miR-34a) as a key mediator through its paracrine actions on adipose-resident macrophages. The expression of miR-34a in adipose tissues was progressively increased with the development of dietary obesity. Adipose-selective or adipocyte-specific miR-34a-KO mice were resistant to obesity-induced glucose intolerance, insulin resistance, and systemic inflammation, and this was accompanied by a significant shift in polarization of adipose-resident macrophages from proinflammatory M1 to antiinflammatory M2 phenotype. Mechanistically, mature adipocyte-secreted exosomes transported miR-34a into macrophages, thereby suppressing M2 polarization by repressing the expression of Krüppel-like factor 4 (Klf4). The suppressive effects of miR-34a on M2 polarization and its stimulation of inflammatory responses were reversed by ectopic expression of Klf4 in both bone marrow-derived macrophages and adipose depots of obese mice. Furthermore, increased miR-34a expression in visceral fat of overweight/obese subjects correlated negatively with reduced Klf4 expression, but positively with the parameters of insulin resistance and metabolic inflammation. In summary, miR-34a was a key component of adipocyte-secreted exosomal vesicles that transmitted the signal of nutrient overload to the adipose-resident macrophages for exacerbation of obesity-induced systemic inflammation and metabolic dysregulation. |
| Databáze: | OpenAIRE |
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