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

• Published in: The Journal of clinical investigation Vol. 129; no. 2; pp. 834 - 849
• Main Authors: 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
• Language: English
• Published: United States American Society for Clinical Investigation 01.02.2019
• Subjects: 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
• DOI: 10.1172/JCI123069

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.