1510-P: Adipocyte MicroRNA-802 Promotes Adipose Tissue Inflammation and Insulin Resistance by Modulating Macrophages in Obesity

Introduction & Objective: Adipose tissue inflammation is now considered to be a key process underlying metabolic diseases in obese individuals. Macrophages accumulate in the adipose tissue and surround the dying or dead adipocytes like corona, which is witnessed to be the contributors to inflammation and obesity-induced insulin resistance. In this study, we aimed to identify key microRNA that regulates inter-cellular communication between lipid-overloaded adipocytes and macrophages, ultimately leading to adipose tissue inflammation and insulin resistance.

Methods: RNA sequencing was performed to analyze the adipocyte tissue of high-fat diet (HFD)-fed mice and those of normal chow-fed mice (NCD). We found progressive increase of microRNA-802 (miR-802) expression in adipose tissue with the development of dietary obesity in obese mice and humans. Then, the mechanism of miR-802 regulating adipose function was investigated by flow cytometric analysis, mouse metabolic studies, magnetic resonance imaging, and animal energy metabolism monitoring system.

Results: Our findings validated miR-802 increasing prior to macrophage accumulation. Adipose tissue-specific knockout of miR-802 lowered macrophage infiltration and ameliorated systemic insulin resistance. Conversely, the specific miR-802 overexpression in adipose tissue aggravated adipose inflammation in mice fed a high-fat diet. Mechanistically, miR-802 activates noncanonical and canonical NF-κB pathways by targeting its negative regulator, TRAF3, which translated into strong recruitment and M1-like polarization of macrophages.

Conclusion: We established that miR-802 expression is an inflammatory signal in adipocytes, and this effect occurs through sensitization of the NF-kB signaling pathway. Collectively, our data raise the possibility that manipulation of miR-802 action axis represents therapeutic potential for adipose inflammation treatment.