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 which:
comprises amino acid residues 30-140 of SEQ ID NO:2, wherein said polypeptides does not include an Fndc5 signal peptide and amino acid residues 141-209 of SEQ ID NO: 2 or fragments thereof.
2. The isolated polypeptide of claim 1 , which comprises amino acid residues 29-140 of SEQ ID NO:2.
3. The isolated polypeptide of claim 1 , having a molecular weight of about 20 kilodaltons.
4. The isolated polypeptide of claim 3 , wherein the molecular weight is as determined by gel electrophoresis under deglycosylated, reduced, and denatured conditions.
5. The isolated polypeptide of claim 1 , wherein the polypeptide has the ability to promote one or more 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, pgc 1 o, ucp1, elovl3, cAMP, Prdm16, cytochrome C, cox4i1, coxIII, cox5b, cox7a1, cox8b, glut4, atpase b2, cox II, atpSo, ndufb5, ap2, ndufs1, GRPI09A, acylCoA-thioesterase 4, EARA1, claudin1, PEPCK, fgf21, acylCoA-thioesterase 3, and dio′Z;
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;
10 i) cardiac function reduction;
j) cardiac hypertrophy; and
k) muscle hypoplasia reduction.
6. The isolated polypeptide of claim 1 , wherein said polypeptide has the ability to promote the expression of fgf21.
7. The isolated polypeptide of claim 1 , wherein said polypeptide has the ability to promote the expression of ucp1.
8. The isolated polypeptide of claim 1 , wherein said polypeptide has the ability to promote the expression of fgf21 and ucp1.
9. The isolated polypeptide of claim 1 , wherein the polypeptide has the ability to induce brown fat differentiation.
10. The isolated polypeptide of claim 1 , wherein the polypeptide is less than 195 amino acids in length.
11. The isolated polypeptide of claim 1 , wherein the polypeptide is between 110 and 125 amino acids in length.
12. The isolated polypeptide of claim 1 , wherein the polypeptide is more than 110 amino acids in length and less than 135 amino acids in length.
13. The isolated polypeptide of claim 1 , wherein at least one amino acid residue is glycosylated.
14. The isolated polypeptide of claim 1 , wherein at least one amino acid residue is pegylated.
15. The isolated polypeptide of claim 1 , wherein the polypeptide is secreted by a mammalian cell.
16. The isolated polypeptide of claim 1 , further comprising a heterologous polypeptide.
17. The isolated polypeptide of claim 16 , wherein the heterologous polypeptide comprises a dimerization or oligomerization domain.
18. The isolated polypeptide of claim 16 , wherein the heterologous polypeptide is an agent that promotes plasma solubility.
19. The isolated polypeptide of claim 16 , wherein the heterologous polypeptide comprises an Fc domain.
20. The isolated polypeptide of claim 1 , wherein the polypeptide is at least 75% pure.