Although long non-coding RNAs (lncRNAs) are non-protein-coding transcripts by definition, recent studies have shown that a number of putative small open reading frames within lncRNAs are translated. The biological significance of these hidden polypeptides is still unclear, although studies have demonstrated functional significance for some polypeptides.

Recently, our lab discovered a novel micropeptide ORF60 encoded by a lncRNA. The micropeptide is conserved across species. Topology prediction indicates that the micropeptide is likely transmembrane. RNA transcript expression is nearly ubiquitous across tissues. In mice, ORF60 expression was found to be increased in the setting of high fat diet (HFD). Using CRISPR/Cas9 technology we developed ORF60 KO mice. In both mice feeding on normal chow diet and HFD, we observed impaired glucose tolerance in KO mice compared to wild type mice. ORF60 KO mice also demonstrated impaired response to insulin compared to WT mice on insulin tolerance testing (ITT), suggesting insulin resistance. Mouse tissue harvested under the condition of insulin infusion demonstrated insulin signaling attenuation in white adipose tissue (WAT) and brown adipose tissue (BAT). We are currently dissecting the molecular mechanism underlying ORF60’s influence on insulin signaling pathways.

In summary, our results demonstrate that the conserved micropeptide ORF60 regulates insulin sensitivity in WAT and BAT in mice. Micropeptides involved in diabetes may serve as novel drug targets.


N. Gupta: None. Y. Shi: None. P. Li: None. H. Cao: None.

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