miRNA modulators of thermogenesis
Provided are novel methods and compositions for the modulation of thermogenesis. Such methods are particularly advantageous in that they allow for the reduction of body fat in a subject without the subject having to adjust their caloric intake through dieting, modify their physical activity or undergo bariatric surgery. Accordingly, the methods of the invention are particularly useful for treating or preventing obesity. Also provided are methods of screening for novel agents that modulate the activity of thermogenic regulators.
1. A method for modulating thermogenesis in a subject, the method comprising administering to the subject an effective amount of an antagomir of miR-22-3p, wherein the antagomir is from 7 to 18 nucleotides in length.
2. The method of claim 1 , wherein the antagomir is from 8 to 14 nucleotides in length.
3. The method of claim 2 , wherein the antagomir is 8 nucleotides in length.
4. The method of claim 1 , wherein the antagomir binds to the seed sequence of miR-22 3p.
5. The method of claim 1 , wherein the antagomir comprises one or more modified nucleotides.
6. The method of claim 5 , wherein the one or more modified nucleotides comprise one or more locked nucleic acids, backbone modifications, or 5-methylcytosines.
7. The method of claim 5 , wherein the one or more modified nucleotides comprise a modification at the 2′ position of the sugar.
8. The method of claim 7 , wherein the modification at the 2′ position of the sugar comprises a 2′-O-methyl, 2′-fluoro, or 2′-O-(2-methoxyethyl) modification.
9. The method of claim 6 , wherein the backbone modification comprises a phosphorothioate or peptide nucleic acid modification.
10. The method of claim 1 , wherein the antagomir is comprised in a liposome or nanoparticle.
11. The method of claim 1 , wherein the antagomir is linked to a targeting moiety that specifically binds to CD36/Fatty Acid Transporter (FAT)/SR-B2.
12. The method of claim 1 , wherein the antagomir is linked to a targeting moiety that delivers the antagomir to adipose tissue.
13. The method of claim 12 , wherein the targeting moiety comprises an antibody.
14. The method of claim 1 , wherein the antagomir modulates the activity or expression of UCP1 or UCP2.
15. The method of claim 1 , wherein the subject has a genetic or epigenetic predisposition to obesity.
16. The method of claim 15 , wherein the subject has type 2 diabetes mellitus.
17. The method of claim 16 , wherein the type 2 diabetes mellitus is early onset type 2 diabetes mellitus.