Abstract
In response to cold or β3-adrenoreceptor stimulation brown adipose tissue (BAT) promotes non-shivering thermogenesis, leading to energy dissipation. BAT has long been thought to be absent or scarce in adult humans. The recent discovery of thermogenic brite/beige adipocytes has opened the way to development of novel innovative strategies to combat overweight/obesity and associated diseases. Thus it is of great interest to identify regulatory factors that govern the brite adipogenic program. Here, we carried out global microRNA (miRNA) expression profiling on human adipocytes to identify miRNAs that are regulated upon the conversion from white to brite adipocytes. Among the miRNAs that were differentially expressed, we found that Let-7i-5p was down regulated in brite adipocytes. A detailed analysis of the Let-7i-5p levels showed an inverse expression of UCP1 in murine and human brite adipocytes both in vivo and in vitro. Functional studies with Let-7i-5p mimic in human brite adipocytes in vitro revealed a decrease in the expression of UCP1 and in the oxygen consumption rate. Moreover, the Let-7i-5p mimic when injected into murine sub-cutaneous white adipose tissue inhibited partially β3-adrenergic activation of the browning process. These results suggest that the miRNAs Let-7i-5p participates in the recruitment and the function of brite adipocytes.
Highlights
To combat obesity and associated diseases[14]
In the present study we found that Let-7i-5p was negatively associated with uncoupling protein 1 (UCP1) expression in brite compared to white adipocytes in murine and human tissues and cell models
We showed that Let-7i-5p affected brite adipocyte function in vitro through the specific inhibition of UCP1 expression, which impaired the mitochondrial oxygen consumption
Summary
To combat obesity and associated diseases[14]. One therapeutic option is to convert and activate a proportion of white into brite adipocytes, which may lead to normalization of metabolic parameters and to body weight loss. MiRNAs are small (~22 nt long) non-coding RNAs that regulate gene expression post-transcriptionally by binding to the 3′ untranslated region of target mRNAs to adjust protein output either by mRNA destabilization or by translational repression[17,18,19]. Their impact on diseases is acknowledged by their development as drugs and/or drug targets in phase 1 and 2 clinical trials[20]. Our observations showed that Let-7i-5p may play a crucial role in the modulation of brite adipocytes function, and close regulation of its levels might help to shift human adipocytes from an energy storing to an energy dissipating fate
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