Abstract
Adipose dysfunction with aging increases risk to insulin resistance and other chronic metabolic diseases. We previously showed functional changes in microRNAs involved in pre-adipocyte differentiation with aging resulting in adipose dysfunction. However, the mechanisms leading to this dysfunction in microRNAs in adipose tissue (adipomiRs) during aging are not well understood. We determined the longitudinal changes in expression of adipomiRs and studied their regulatory mechanisms, such as miRNA biogenesis and editing, in an aging rodent model, with Fischer344 × Brown-Norway hybrid rats at ages ranging from 3 to 30 months (male/females, n > 8). Expression of adipomiRs and their edited forms were determined by small-RNA sequencing. RT-qPCR was used to measure the mRNA expression of biogenesis and editing enzymes. Sanger sequencing was used to validate editing with aging. Differential expression of adipomiRs involved in adipocyte differentiation and insulin signaling was altered with aging. Sex- and age-specific changes in edited adipomiRs were observed. An increase in miRNA biogenesis and editing enzymes (ADARs and their splice variants) were observed with increasing age, more so in female than male rats. The adipose dysfunction observed with age is attributed to differences in editing of adipomiRs, suggesting a novel regulatory pathway in aging.
Highlights
Aging is a complex process that involves continuous accumulation of cellular damage
We found sexual dimorphism in the differential expression of miRNAs with age in the visceral adipose tissue
When miRNAs from 3 month old rats were compared to each of the other age groups (6, 15, 25 and 30 months old), several of the differentially expressed miRNAs targeted genes involved in either miRNA biogenesis, adipogenesis or insulin signaling
Summary
Aging is a complex process that involves continuous accumulation of cellular damage. Interventions to prevent these damages will improve aging-related pathologies. Our studies showed that during the differentiation of adipose progenitor cells to mature adipocytes, there was a dysregulation of the key adipogenic miRNAs (miR-143) with aging. RNA editing is one such post-transcriptional RNA regulatory mechanism that cells and tissues use for generating RNA and protein diversity [21,22] This phenomenon occurs through post-transcriptional modification of single nucleotides in the pre-mRNA [23,24]. Our studies showed sex-specific differences in adipomiRs and its editing with aging Exploring these novel mechanisms will help in understanding the complex cellular role of these non-coding RNAs in metabolic tissues and help develop better therapeutics to treat adipose-related pathologies during aging
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