Compositions and methods for brown fat induction and activity using FNDC5
The invention provides compositions and methods for brown fat induction and activity through modulation of Fndc5 activity and/or expression. Also provided are methods for preventing or treating metabolic disorders in a subject through modulation of Fndc5 activity and/or expression. Further provided are methods for identifying compounds that are capable of modulating Fndc5 activity and/or expression.
1. An isolated polypeptide consisting of the amino acid sequence of residues 30-140 of SEQ ID NO:2, and further comprising a heterologous polypeptide.
2. The isolated polypeptide of claim 1 , wherein said isolated polypeptide is glycosylated or pegylated.
3. The isolated polypeptide of claim 1 , wherein said isolated polypeptide is secreted by a mammalian cell.
4. The isolated polypeptide of claim 1 , wherein said isolated polypeptide has the ability to promote one or more of biological activities selected from the group consisting of:
(a) expression of a marker selected from the group consisting of: cidea, adiponectin, adipsin, otopetrin, type II deiodinase, cig30, ppar gamma 2, pgc1α, ucp1, elovl3, cAMP, Prdm16, cytochrome C, cox4i1, coxIII, cox5b, cox7a1, cox8b, glut4, atpase b2, cox II, atp5o, ndufb5, ap2, ndufs1, GRP109A, acylCoA-thioesterase 4, EARA1, claudin1, PEPCK, fgf21, acylCoA-thioesterase 3, and dio2;
(b) thermogenesis in adipose cells;
(c) differentiation of adipose cells;
(d) insulin sensitivity of adipose cells;
(e) basal respiration or uncoupled respiration;
(f) hepatosteatosis reduction;
(g) appetite reduction;
(h) insulin secretion of pancreatic beta cells;
(i) cardiac function reduction;
(j) cardiac hypertrophy; and
(k) muscle hypoplasia reduction.
5. The isolated polypeptide of claim 1 , wherein said isolated polypeptide has the ability to promote the expression of fgf21 or ucp1.
6. The isolated polypeptide of claim 1 , wherein said isolated polypeptide has the ability to promote the expression of fgf21 and ucp1.
7. The isolated polypeptide of claim 1 , wherein said isolated polypeptide has the ability to induce brown fat differentiation.
8. A pharmaceutical composition comprising the isolated polypeptide of claim 1 and a pharmaceutically acceptable excipient, diluent, or carrier.
9. The pharmaceutical composition of claim 8 , wherein the isolated polypeptide has the ability to modulate a metabolic response in a subject.
10. The pharmaceutical composition of claim 9 , wherein the subject has at least one metabolic disorder selected from the group consisting of: obesity, insulin resistance, hyperinsulinemia, hypoinsulinemia, type II diabetes, hypertension, hyperhepatosteatosis, hyperuricemia, fatty liver, non-alcoholic fatty liver disease, polycystic ovarian syndrome, acanthosis nigricans, hyperphagia, endocrine abnormalities, triglyceride storage disease, Bardet-Biedl syndrome, Lawrence-Moon syndrome, Prader-Labhart-Willi syndrome, muscle hypoplasia, neurodegenerative diseases, and Alzheimer's disease.
11. An isolated polypeptide consisting of the amino acid sequence of residues 30-140 of SEQ ID NO:2, and further comprising a heterologous polypeptide, wherein said heterologous polypeptide comprises an Fc domain.
12. The isolated polypeptide of claim 11 , wherein said isolated polypeptide is glycosylated or pegylated.
13. The isolated polypeptide of claim 11 , wherein said isolated polypeptide is secreted by a mammalian cell.
14. The isolated polypeptide of claim 11 , wherein said isolated polypeptide has the ability to promote one or more of biological activities selected from the group consisting of:
(a) expression of a marker selected from the group consisting of: cidea, adiponectin, adipsin, otopetrin, type II deiodinase, cig30, ppar gamma 2, pgc1α, ucp1, elovl3, cAMP, Prdm16, cytochrome C, cox4i1, coxIII, cox5b, cox7a1, cox8b, glut4, atpase b2, cox II, atp5o, ndufb5, ap2, ndufs1, GRP109A, acylCoA-thioesterase 4, EARA1, claudin1, PEPCK, fgf21, acylCoA-thioesterase 3, and dio2;
(b) thermogenesis in adipose cells;
(c) differentiation of adipose cells;
(d) insulin sensitivity of adipose cells;
(e) basal respiration or uncoupled respiration;
(f) hepatosteatosis reduction;
(g) appetite reduction;
(h) insulin secretion of pancreatic beta cells;
(i) cardiac function reduction;
(j) cardiac hypertrophy; and
(k) muscle hypoplasia reduction.
15. The isolated polypeptide of claim 11 , wherein said isolated polypeptide has the ability to promote the expression of fgf21 or ucp1.
16. The isolated polypeptide of claim 11 , wherein said isolated polypeptide has the ability to promote the expression of fgf21 and ucp1.
17. The isolated polypeptide of claim 11 , wherein said isolated polypeptide has the ability to induce brown fat differentiation.
18. A pharmaceutical composition comprising the isolated polypeptide of claim 11 and a pharmaceutically acceptable excipient, diluent, or carrier.
19. The pharmaceutical composition of claim 18 , wherein the isolated polypeptide has the ability to modulate a metabolic response in a subject.
20. The pharmaceutical composition of claim 19 , wherein the subject has at least one metabolic disorder selected from the group consisting of: obesity, insulin resistance, hyperinsulinemia, hypoinsulinemia, type II diabetes, hypertension, hyperhepatosteatosis, hyperuricemia, fatty liver, non-alcoholic fatty liver disease, polycystic ovarian syndrome, acanthosis nigricans, hyperphagia, endocrine abnormalities, triglyceride storage disease, Bardet-Biedl syndrome, Lawrence-Moon syndrome, Prader-Labhart-Willi syndrome, muscle hypoplasia, neurodegenerative diseases, and Alzheimer's disease.