Methods of treating obesity by inhibiting nicotinamide N-methyl transferase (NNMT)
The present invention, in various embodiments, relates to methods of inhibiting NNMT production or activity in a cell, and methods of treating or preventing obesity or a related metabolic condition in a subject in need thereof, comprising administering a nicotinamide N-methyltransferase (NNMT) antagonist. The invention further provides methods of identifying NNMT antagonists useful for treating obesity and related metabolic disorders.
1. A method of inhibiting the expression or activity of a nicotinamide N-methyltransferase (NNMT) protein in a cell, comprising providing the cell with an effective amount of at least one NNMT antagonist, wherein the NNMT antagonist is a nucleic acid that inhibits production of NNMT protein, one or more activities of an NNMT protein, or a combination thereof, and wherein the cell is an adipocyte or a hepatocyte.
2. The method of claim 1 , wherein the nucleic acid is selected from the group consisting of an antisense oligonucleotide, an siRNA, a microRNA, an aptamer and a ribozyme.
3. The method of claim 2 , wherein the nucleic acid is an antisense oligonucleotide.
4. The method of claim 3 , wherein the antisense oligonucleotide selectively hybridizes to NNMT mRNA.
5. The method of claim 3 , wherein the antisense oligonucleotide comprises RNA.
6. The method of claim 3 , wherein the antisense oligonucleotide comprises DNA.
7. The method of claim 3 , wherein the antisense oligonucleotide includes at least one chemical modification.
8. The method of claim 7 , wherein at least one chemical modification is a phosphorothioate internucleoside linkage, a 2′-O-methoxyethyl sugar modification, a 2′-fluoro sugar modification or a 5-methylcytosine nucleobase.
9. A method of treating or preventing obesity in a subject in need thereof, comprising administering to the subject an effective amount of a nicotinamide N-methyltransferase (NNMT) antagonist, wherein the NNMT antagonist inhibits production of NNMT protein, one or more activities of an NNMT protein, or a combination thereof.
10. The method of claim 9 , wherein the NNMT antagonist is a nucleic acid.
11. The method of claim 10 , wherein the nucleic acid is selected from the group consisting of an antisense oligonucleotide, an siRNA, a microRNA, an aptamer and a ribozyme.
12. The method of claim 11 , wherein the nucleic acid is an antisense oligonucleotide.
13. The method of claim 12 , wherein the antisense oligonucleotide selectively hybridizes to NNMT mRNA.
14. The method of claim 12 , wherein the antisense oligonucleotide comprises RNA.
15. The method of claim 12 , wherein the antisense oligonucleotide comprises DNA.
16. The method of claim 12 , wherein the antisense oligonucleotide includes at least one chemical modification.
17. The method of claim 16 , wherein at least one chemical modification is a phosphorothioate internucleoside linkage, a 2′-O-methoxyethyl sugar modification, a 2′-fluoro sugar modification or a 5-methylcytosine nucleobase.
18. The method of claim 9 , wherein the subject is obese.
19. The method of claim 9 , wherein the subject has a metabolic disorder selected from the group consisting of insulin resistance, type 2 diabetes, hyperglycemia and Metabolic Syndrome, or a combination thereof.
20. A method of treating or preventing a metabolic disorder in a subject in need thereof, comprising administering to the subject an effective amount of a nicotinamide N-methyltransferase (NNMT) antagonist, wherein the NNMT antagonist inhibits production of NNMT protein, one or more activities of an NNMT protein, or a combination thereof.
21. The method of claim 20 , wherein the metabolic disorder is selected from the group consisting of insulin resistance, type 2 diabetes, hyperglycemia and Metabolic Syndrome, or a combination thereof.
22. The method of claim 20 , wherein the NNMT antagonist inhibits production of NNMT protein.
23. The method of claim 20 , wherein the NNMT antagonist inhibits an activity of an NNMT protein.
24. The method of claim 20 , wherein the NNMT antagonist is a nucleic acid.
25. The method of claim 24 , wherein the nucleic acid is selected from the group consisting of an antisense oligonucleotide, an siRNA, a microRNA, an aptamer and a ribozyme.
26. The method of claim 25 , wherein the nucleic acid is an antisense oligonucleotide.
27. The method of claim 26 , wherein the antisense oligonucleotide selectively hybridizes to NNMT mRNA.
28. The method of claim 26 , wherein the antisense oligonucleotide comprises RNA.
29. The method of claim 26 , wherein the antisense oligonucleotide comprises DNA.
30. The method of claim 26 , wherein the antisense oligonucleotide includes at least one chemical modification.
31. The method of claim 30 , wherein at least one chemical modification is a phosphorothioate internucleoside linkage, a 2′-O-methoxyethyl sugar modification, a 2′-fluoro sugar modification or a 5-methylcytosine nucleobase.
32. The method of claim 20 , wherein the subject is obese.
33. The method of claim 20 , wherein the subject has insulin resistance.
34. The method of claim 20 , wherein the subject has type 2 diabetes.