Adipocyte-secreted exosomal microRNA-34a inhibits M2 macrophage polarization to promote obesity-induced adipose inflammation

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 mi...

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Veröffentlicht in:The Journal of clinical investigation Jg. 129; H. 2; S. 834 - 849
Hauptverfasser: Pan, Yong, Hui, Xiaoyan, Hoo, Ruby Lai Chong, Ye, Dewei, Chan, Cyrus Yuk Cheung, Feng, Tianshi, Wang, Yu, Lam, Karen Siu Ling, Xu, Aimin
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States American Society for Clinical Investigation 01.02.2019
Schlagworte:
Adipocytes
Adipocytes - metabolism
Adipocytes - pathology
Adipose tissue
Animals
Apoptosis
Biomedical research
Body weight
Bone marrow
Complications and side effects
Cytokines
Diabetes
Ectopic expression
Exosomes
Exosomes - genetics
Exosomes - metabolism
Exosomes - pathology
Fat cells
Gene expression
Genetic aspects
Glucose
Glucose tolerance
Homeostasis
Inflammation
Inflammation - genetics
Inflammation - metabolism
Inflammation - pathology
Insulin
Insulin resistance
Intolerance
Intra-Abdominal Fat - metabolism
Intra-Abdominal Fat - pathology
KLF4 protein
Kruppel-Like Transcription Factors - genetics
Kruppel-Like Transcription Factors - metabolism
Macrophages
Macrophages - metabolism
Macrophages - pathology
Metabolism
Metabolites
Mice
Mice, Knockout
MicroRNA
MicroRNAs
MicroRNAs - genetics
MicroRNAs - metabolism
miRNA
Obesity
Obesity - genetics
Obesity - metabolism
Obesity - pathology
Overweight
Panniculitis - genetics
Panniculitis - metabolism
Panniculitis - pathology
Paracrine signalling
Phenotypes
Polarization
Risk factors
Obesity
Inflammation
Adipose tissue
Macrophages
Metabolism
ISSN:0021-9738, 1558-8238, 1558-8238
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Zusammenfassung: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.
Bibliographie:ObjectType-Article-1
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ISSN:0021-9738
1558-8238
1558-8238
DOI:10.1172/JCI123069