Abstract
MicroRNAs (miRNAs), a class of small, non-coding RNA molecules, play an important role in the posttranscriptional regulation of gene expression, thereby influencing important cellular functions. In adipocytes, miRNAs show import regulatory features and are described to influence differentiation as well as metabolic, endocrine, and inflammatory functions. We previously identified miR-27a being upregulated under inflammatory conditions in human adipocytes and aimed to elucidate its function in adipocyte biology. Both strands of miR-27a, miR-27a-3p and -5p, were downregulated during the adipogenic differentiation of Simpson–Golabi–Behmel syndrome (SGBS) cells, human multipotent adipose-derived stem cells (hMADS), and human primary adipose-derived stromal cells (hASCs). Using miRNA-mimic transfection, we observed that miR-27a-3p is a crucial regulator of adipogenesis, while miR-27a-5p did not alter the differentiation capacity in SGBS cells. In silico screening predicted lipoprotein lipase (LPL) and peroxisome proliferator activated receptor γ (PPARγ) as potential targets of miR-27a-3p. The downregulation of both genes was verified in vitro, and the interaction of miR-27-3p with target sites in the 3′ UTRs of both genes was confirmed via a miRNA-reporter-gene assay. Here, the knockdown of LPL did not interfere with adipogenic differentiation, while PPARγ knockdown decreased adipogenesis significantly, suggesting that miR-27-3p exerts its inhibitory effect on adipogenesis by repressing PPARγ. Taken together, we identified and validated a crucial role for miR-27a-3p in human adipogenesis played by targeting the essential adipogenic transcription factor PPARγ. Though we confirmed LPL as an additional target of miR-27a-3p, it does not appear to be involved in regulating human adipogenesis. Thereby, our findings call the conclusions drawn from previous studies, which identified LPL as a crucial regulator for murine and human adipogenesis, into question.
Highlights
Obesity is one of the major health problems in the Western world [1]
Key mediators of adipogenesis involve the different transcripts of CAAT/enhancer-binding proteins (C/EBPs) and peroxisome proliferator activated receptor γ (PPARγ), which act in a transcriptional cascade
Prominent examples are miR-103 and miR-107, which were among the first miRNAs described to play important roles in the regulation of insulin sensitivity, and miR-365, which is a key regulator of insulin secretion in pancreatic islets [35,36]. miR-27a was recently discovered as a crucial regulator of insulin sensitivity in skeletal muscle and murine adipocytes and might, thereby, be an important fine tuner of systemic glucose metabolism [37,38]
Summary
Obesity is one of the major health problems in the Western world [1]. The excessive accumulation of adipose tissue leads to a state of chronic, low-grade inflammation and is associated with severe comorbidities such as type 2 diabetes mellitus, hepatic steatosis, cardiovascular disease and an increased risk of cancer [2]. Progenitor cells within the adipose tissue can differentiate into new, mature adipocytes, a mechanism known as hyperplasia [3]. This storage of excess energy in the form of triglycerides in WAT is required to prevent ectopic fat deposition in the liver and muscles, which is associated with insulin resistance and non-alcoholic fatty liver disease [4]. It is of utmost importance to elucidate the processes leading to the formation of new adipocytes from tissue-resident precursor cells Both events, adipogenesis and lipid accumulation, are known to be regulated by distinct signaling pathways. Insulin, mTOR, Notch and Wnt signaling pathways play pivotal roles in adipogenesis [6,7]
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