Abstract 19181: MicroRNA Regulation of Adipose Browning and Glucose Uptake Improves Cardiometabolic Disease

Abstract

The prevalence of obesity is on the rise worldwide. Brown adipose tissue (BAT), a highly vascularized organ, is activated in response to cold temperatures to generate heat and modulate metabolic efficiency. MicroRNAs (miRNAs) are small, noncoding RNAs that are implicated in cardiometabolic disease. However, relevant miRNAs in the endothelium of the microvasculature of BAT, how they crosstalk to the surrounding adipose tissue in cardiometabolic disease is not fully understood. We profiled microRNAs from the endothelial cells (ECs) of brown adipose tissue (BAT) of mice with diet-induced obesity (DIO) using microRNA-Seq and identified microRNA-485-5p ( miR-485 ) as one of the most differentially regulated miRNAs compared to the chow control. MiR-485 expression was rapidly induced in ECs in response to glucose (2.2-fold) and palmitate (1.63-fold). Loss-of-function studies revealed that neutralization of miR-485 increased glucose uptake to 3T3-L1 adipocytes and human adipose organoids co-cultured with conditioned media from ECs deficient in miR-485 ; while also increasing the mRNA and protein expression of brown fat marker, UCP1. Multiplex ELISA analyses of conditioned media from ECs overexpressing miR-485 showed a significant decrease in the release of IL-25 from ECs (22.5%) while the inhibition of miR-485 in ECs increased IL-25 release by 36.3%. Interestingly, IL-25 increased glucose uptake to 3T3-L1 adipocytes. Systemic intravenous delivery of LNA-anti-miR-485 inhibitor increased expression of UCP1 (31.4%) in BAT by confocal immunofluorescence, improved BAT function as measured by multispectral optoacoustic tomography (MSOT), while improving glucose tolerance and insulin resistance by 10.2% and 14.2% respectively. Metabolic profiling revealed increased energy expenditure (25%), decreased respiratory exchange rate (6%), and increased left ventricular ejection fraction (LVEF) (9.5%). The global longitudinal strain was higher by 28% compared to control mice with DIO. Our findings indicate that miR-485 plays a key regulatory role in controlling adipose browning and metabolism in an EC-paracrine mediated crosstalk in DIO, an effect that could be exploited for therapeutic intervention in obesity-induced cardiometabolic disease.