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 (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-22in vivoeliminates 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.
Department of Cardiac Development and Remodelling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
Judith
J
Schweisgut
Department of Cardiac Development and Remodelling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
Christian
C
Schutt
Department of Cardiac Development and Remodelling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
Stas
S
Wüst
MRI Service Group, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
Astrid
A
Wietelmann
Vesalius Research Center (VRC), VIB-KULeuven, Campus Gasthuisberg, Leuven, Belgium.
Bart
B
Ghesquière
Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, Leuven, Belgium.|Department of Oncology, Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, University of Leuven, Leuven, Belgium.
Peter
0000-0001-7961-1821
P
Carmeliet
Department of Anesthesiology, Intensive-Care Medicine and Pain Therapy, University Hospital Frankfurt, Frankfurt, Germany.
Stefan
S
Dröse
Receptor Biology Group, Reproductive and Developmental Biology Laboratory, Research Triangle Park, NC, USA.
Kenneth S
KS
Korach
Department of Cardiac Development and Remodelling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany thomas.braun@mpi-bn.mpg.de thomas.boettger@mpi-bn.mpg.de.
Thomas
T
Braun
Department of Cardiac Development and Remodelling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany thomas.braun@mpi-bn.mpg.de thomas.boettger@mpi-bn.mpg.de.
Thomas
0000-0003-4280-8449
T
Boettger
D000818:Animals; D047628:Estrogen Receptor alpha / Q000096:biosynthesis*; D005786:Gene Expression Regulation; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D009132:Muscles / Q000378:metabolism*; D012737:Sex Factors
D047628:Estrogen Receptor alpha; D035683:MicroRNAs; C574876:Mirn22 microRNA, mouse
ERα; miRNA processing; miR‐22; muscle lipid metabolism; sexual dimorphism