Control of energy homeostasis and metabolism is achieved by integrating numerous pathways, and miRNAs are involved in this process by regulating expression of multiple target genes. However, relatively little is known about the posttranscriptional processing of miRNAs and a potential role for the precursors they derive from. Here, we demonstrate that mature miRNA‐22 is more abundant in muscle from male mice relative to females and that this enables sex‐specific regulation of muscular lipid metabolism and body weight by repressing estrogen receptor alpha (ERα) expression. We found that the ERα adjusts its own activity by preventing processing of miR‐22 via direct binding to a conserved ERα‐binding element within the primary miR‐22 precursor. Mutation of the ERα binding site within the pri‐miR‐22 in vivo eliminates sex‐specific differences in miR‐22 expression. We reason that the resulting tissue selective negative feedback regulation is essential to establish sex‐specific differences in muscle metabolism and body weight development.
ERα binds the miRNA‐22 precursor and prevents its processing, while mature miR‐22 represses ERα translation. This feedback loop leads to sex‐specific levels of ERα in muscle with consequences for muscular lipid metabolism and body weight.
ERα directly binds to a specific motif in the primary miR‐22 precursor.
ERα limits the formation of mature miR‐22 in female muscle and allows higher concentration of miR‐22 in male muscle.
Mature miR‐22 represses ERα protein translation in male muscle.
The miR‐22–ERα feedback loop restricts lipid metabolism in male muscle and allows gain of white fat depots in male mice.
- Received November 1, 2016.
- Revision received February 14, 2017.
- Accepted February 16, 2017.
- © 2017 The Authors
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