PGC-1β, a novel PGC-1 homologue and uses therefor
The invention provides isolated nucleic acid molecules, designated PGC-1β nucleic acid molecules, which encode novel PGC-1 related coactivator molecules. The invention also provides antisense nucleic acid molecules, recombinant expression vectors containing PGC-1β nucleic acid molecules, host cells into which the expression vectors have been introduced, and nonhuman transgenic animals in which a PGC-1β gene has been introduced or disrupted. The invention still further provides isolated PGC-1β proteins, fusion proteins, antigenic peptides and anti-PGC-1β antibodies. Diagnostic and therapeutic methods utilizing compositions of the invention are also provided.
1. A method for identifying a compound capable of treating a metabolic disorder characterized by aberrant PGC-1β nucleic acid expression or PGC-1β polypeptide activity comprising assaying the ability of the compound to modulate PGC-1β nucleic acid expression or PGC-1β polypeptide activity, wherein
a) the PGC-1β nucleic acid is selected from the group consisting of:
i) a nucleic acid molecule comprising a nucleotide sequence which is at least 97% identical the nucleotide sequence of SEQ ID NO:1, 3, 4, or 6, and wherein the nucleic acid molecule encodes a polypeptide with one or more of the following biological activities: interacts with a nuclear receptor, interacts with host cell factor (HCF), interacts with nuclear respiratory factor 1 (NRF1), interacts with a basal transcription factor, modulates the activity of a nuclear receptor and/or NRF1, modulates brown adipose cell determination and/or differentiation, modulates mitochondrial activity and/or biogenesis, or modulates fatty acid β-oxidation; and
ii) a nucleic acid molecule which encodes a polypeptide comprising an amino acid sequence which is at least 97% identical to the amino acid sequence of SEQ ID NO:2 or 5 and wherein the encoded polypeptide maintains one or more of the following biological activities: interacts with a nuclear receptor, interacts with host cell factor (HCF), interacts with nuclear respiratory factor 1 (NRF1), interacts with a basal transcription factor, modulates the activity of a nuclear receptor and/or NRF1, modulates brown adipose cell determination and/or differentiation, modulates mitochondrial activity and/or biogenesis, or modulates fatty acid β-oxidation; and
b) the PGC-1 polypeptide is selected from the group consisting of:
i) a polypeptide which is encoded by a nucleic acid molecule comprising a nucleotide sequence which is at least 97% identical the nucleotide sequence of SEQ ID NO:1, 3, 4, or 6, and wherein the nucleic acid molecule encodes a polypeptide with one or more of the following biological activities: interacts with a nuclear receptor, interacts with host cell factor (HCF), interacts with nuclear respiratory factor 1 (NRF1), interacts with a basal transcription factor, modulates the activity of a nuclear receptor and/or NRF1, modulates brown adipose cell determination and/or differentiation, modulates mitochondrial activity and/or biogenesis, or modulates fatty acid β-oxidation; and
ii) a polypeptide comprising an amino acid sequence which is at least 97% identical to the amino acid sequence of SEQ ID NO:2 or 5 and wherein the encoded polypeptide maintains one or more of the following biological activities: interacts with a nuclear receptor, interacts with host cell factor (HCF), interacts with nuclear respiratory factor 1 (NRF1), interacts with a basal transcription factor, modulates the activity of a nuclear receptor and/or NRF1, modulates brown adipose cell determination and/or differentiation, modulates mitochondrial activity and/or biogenesis, or modulates fatty acid β-oxidation,
thereby identifying a compound capable of treating a metabolic disorder characterized by aberrant PGC-1β nucleic acid expression or PGC-1β polypeptide activity.
2. The method of claim 1 , wherein the metabolic disorder is selected from the group consisting of diabetes, obesity, anorexia, cachexia, and insufficient insulin activity disorders.
3. The method of claim 2 , wherein the metabolic disorder is diabetes.
4. The method of claim 3 , wherein the diabetes is selected from the group consisting of type 1 diabetes, type 2 diabetes, and maturity onset diabetes of the young (MODY).
5. The method of claim 1 or 2 , wherein the PGC-1β nucleic acid is a nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:1, 3, 4, or 6.
6. The method of claim 1 or 2 , wherein the PGC-1β nucleic acid is a nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:1, 3, 4, or 6 and a nucleotide sequence encoding a heterologous polypeptide.
7. The method of claim 1 or 2 , wherein the PGC-1β nucleic acid is a nucleic acid molecule consisting of the nucleotide sequence of SEQ ID NO:1, 3, 4, or 6.
8. The method of claim 1 or 2 , wherein the PGC-1 polypeptide is a polypeptide comprising the amino acid sequence of SEQ ID NO:2 or 5.
9. The method of claim 1 or 2 , wherein the PGC-1 polypeptide is a polypeptide comprising the amino acid sequence of SEQ ID NO:2 or 5 and further comprising a heterologous amino acid sequence.
10. The method of claim 1 or 2 , wherein the PGC-1 polypeptide is a polypeptide consisting of the amino acid sequence of SEQ ID NO:2 or 5.