Sex‐specific, reciprocal regulation of ERα and miR‐22 controls muscle lipid metabolism in male mice

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 (ER alpha) expression. We found that the ER alpha adjusts its own activity by preventing processing of miR-22 via direct binding to a conserved ER alpha-binding element within the primary miR-22 precursor. Mutation of the ER alpha 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.