Compositions and methods for manipulation of adipocyte energy consumption regulatory pathway
Provided herein is a pathway for adipocyte energy consumption regulation involving ARID5B, genetic variant rs1421085, IRX3, and IRX5. Compositions and methods for modulating the pathway in vitro and in vivo for anti-cachectic and anti-obesity effects are provided. Methods of identifying subjects at risk of developing a disorder mediated by a dysregulation of the energy consumption pathway are also provided.
1. A method of treating a disorder mediated by a dysregulation of energy consumption in an adipocyte in a patient in need thereof, said method comprising administering an effective amount of one or more agents that modulate one or more of iroquois homeobox protein 3 (IRX3) function, iroquois homeobox protein 5 (IRX5) function, AT-rich interactive domain-containing protein 5B (ARID5B) function, obesity browning enhancer 1 (OBE1) function, or genetic variant rs1421085 function in the adipocyte, wherein the agent is one or more of a genome editing system, a small-interfering ribonucleic acid (siRNA), a microRNA (miRNA), an anti-sense ribonucleic acid (antisense RNA), or an anti-sense deoxyribonucleic acid (antisense DNA).
2. The method of claim 1 , wherein the disorder is obesity, cardiovascular disease, or type 2 diabetes.
3. The method of claim 2 , wherein the one or more agents decrease IRX3 function, decrease IRX5 function, decrease OBE1 function, increase ARID5B function, increase ARID5B binding to genetic variant rs1421085, increase ARID5B binding to OBE1, or any combination thereof.
4. The method of claim 1 , wherein the disorder is cancer or cachexia.
5. The method of claim 4 , wherein the cachexia is cachexia associated with cancer, acquired immune deficiency syndrome (AIDS), multiple sclerosis, tuberculosis, chronic obstructive lung disease, congestive heart failure, familial amyloid polyneuropathy, gadolinium poisoning, mercury poisoning (acrodynia), or hormonal deficiency.
6. The method of claim 4 , wherein the one or more agents increase IRX3 function, increase IRX5 function, increase OBE1 function, decrease ARID5B function, or decrease ARID5B binding to genetic variant rs1421085, decrease ARID5B binding to OBE1, or any combination thereof.
7. The method of claim 1 , wherein the adipocyte is one or more of a stem cell adipocyte precursor, mesenchymal stem cell, a preadipocyte, a mature white adipocyte, a mature beige adipocyte, or a mature brown adipocyte.
8. The method of claim 1 , wherein the one or more agent is one or more of a small-interfering ribonucleic acid (siRNA), a microRNA (miRNA), an anti-sense ribonucleic acid (antisense RNA), or an anti-sense deoxyribonucleic acid (antisense DNA).
9. The method of claim 8 , wherein the agent is an siRNA that targets IRX5.
10. The method of claim 1 , wherein the agent is a genome editing system.
11. The method of claim 1 , wherein the adipocyte is a human adipocyte.
12. The method of claim 1 , wherein the one or more agents modulate one or more genes of IRX3, IRX5, ARID5B, OBE1, or genetic variant rs1421085.
13. The method of claim 1 , wherein the one or more agents modulate one or more regulatory elements of IRX3, IRX5, or ARID5B.
14. The method of claim 1 , wherein the one or more agents modulate one or more gene products of IRX3, IRX5, ARID5B, or OBE1.
15. The method of claim 1 , wherein the genome editing system is a clustered regularly interspaced short palindromic repeat (CRISPR) system.
16. The method of claim 1 , wherein the agent is an siRNA that targets IRX3 or IRX5.
17. The method of claim 16 , wherein the agent is an siRNA that targets IRX3 and wherein the agent comprises one or more sequences selected from the group consisting of SEQ ID NOs: 1-15 and 17-18.
18. The method of claim 8 , wherein the agent is an siRNA that targets IRX3.
19. The method of claim 17 , wherein the agent comprises a mixture of siRNAs comprising one or more sequences selected from SEQ ID NOs: 1-3.