MicroRNA-10a-5p regulates macrophage polarization and promotes therapeutic adipose tissue remodeling

Yoon Keun Cho, Yeonho Son, Sang-Nam Kim, Hyun-Doo Song, Minsu Kim, Ji-Hyun Park, Young-Suk Jung, Sang-Yeop Ahn, Abhirup Saha, James G. Granneman, Yun-Hee Lee

Adipose tissue macrophages (ATMs) are a major immune cell type in adipose tissue that are thought to play important roles in adipose tissue remodeling. Presently, little is known about the mechanisms that regulate different macrophage phenotypes – proinflammatory or anti-inflammatory – in this context. Cho, Son, Kim, et al. found that generation of miRNAs in macrophages is necessary for the antiinflammatory polarization of macrophages. They identified miR-10a-5p as a key miRNA that facilitates antiinflammatory polarization of macrophages.

Objective: This study investigated the role of microRNAs generated from adipose tissue macrophages (ATMs) during adipose tissue remodeling induced by pharmacological and nutritional stimuli.

Methods: Macrophage-specific Dicer knockout (KO) mice were used to determine the roles of microRNA generated in macrophages in adipose tissue remodeling induced by the β3-adrenergic receptor agonist CL316,243 (CL). RNA-seq was performed to characterize microRNA and mRNA expression profiles in isolated macrophages and PDGFRα+ adipocyte stem cells (ASCs). The role of miR-10a-5p was further investigated in cell culture, and in adipose tissue remodeling induced by CL treatment and high fat feeding.

Results: Macrophage-specific deletion of Dicer elevated pro-inflammatory gene expression and prevented CL-induced de novo beige adipogenesis in gonadal white adipose tissue (gWAT). Co-culture of ASCs with ATMs of wild type mice promoted brown adipocyte gene expression upon differentiation, but co-culture with ATMs of Dicer KO mice did not. Bioinformatic analysis of RNA expression profiles identified miR-10a-5p as a potential regulator of inflammation and differentiation in ATMs and ASCs, respectively. CL treatment increased levels of miR-10a-5p in ATMs and ASCs in gWAT. Interestingly, CL treatment elevated levels of pre-mir-10a in ATMs but not in ASCs, suggesting possible transfer from ATMs to ASCs. Elevating miR-10a-5p levels inhibited proinflammatory gene expression in cultured RAW 264.7 macrophages and promoted the differentiation of C3H10T1/2 cells into brown adipocytes. Furthermore, treatment with a miR-10a-5p mimic in vivo rescued CL-induced beige adipogenesis in Dicer KO mice. High fat feeding reduced miR-10a-5p levels in ATMs of gWAT, and treatment of mice with a miR-10a-5p mimic suppressed pro-inflammatory responses, promoted the appearance of new white adipocytes in gWAT, and improved systemic glucose tolerance.

Conclusions: These results demonstrate an important role of macrophage-generated microRNAs in adipogenic niches and identify miR-10a-5p as a key regulator that reduces adipose tissue inflammation and promotes therapeutic adipogenesis.