Alternative titles; symbols
HGNC Approved Gene Symbol: PPARGC1B
Cytogenetic location: 5q32 Genomic coordinates (GRCh38) : 5:149,730,310-149,857,959 (from NCBI)
By searching genomic databases with sequence of mouse Pcg1 (PPARGC1A; 604517) as query, Lin et al. (2002) identified a homologous mouse gene, termed Ppargc1b. Ppargc1b encodes a predicted 1,014-amino acid protein, and human and mouse PPARGC1B share 70% amino acid sequence identity. Ppargc1b contains 3 N-terminal LXXLL motifs, 2 glutamic/aspartic acid-rich acidic domains, a binding site for host cell factor (HCF1; 300019), and a C-terminal RNA recognition motif. Northern blot analysis showed abundant expression of 9- and 5-kb mouse Ppargc1b transcripts in brown adipose tissue and heart, and moderate expression in skeletal muscle, liver, and white adipose tissue.
Kressler et al. (2002) used RT-PCR to amplify full-length human PPARGC1B, which they referred to as PERC (PGC1-related estrogen receptor coactivator), from HeLa cells. PPARGC1B encodes a 1,023-amino acid protein with the same structural features as Ppargc1b, reported by Lin et al. (2002), and a shorter isoform lacking 39 amino acids (residues 156-194). Immunofluorescence analysis showed that PPARGC1B localizes to the nucleus. RT-PCR analysis of mouse Ppargc1b showed abundant expression of the long isoform in heart and skeletal muscle, intermediate levels in brain, kidney, liver, and adrenal gland, and low levels in ovary, intestine, and white adipose tissue.
Lin et al. (2002) showed that murine Ppargc1b shows no change of expression in brown adipose cells in response to cold exposure, and that Ppargc1b and Pgc1 have inverse expression levels during brown fat cell differentiation. However, Ppargc1b expression is increased in liver during fasting, similar to Pgc1. Immunoprecipitation and reporter construct activation showed that Ppargc1b interacts with and enhances the activity of hepatic nuclear factor-4 (600281), peroxisome proliferator-activated receptor-alpha (170998), and glucocorticoid receptor (138040). Immunoprecipitation showed HCF1 binds to Ppargc1b and can increase Ppargc1b transcriptional activity. Ppargc1b is also a potent regulator of the transcriptional activity of NRF1 (600879), a central transcription factor in the control of mitochondrial biogenesis.
By transfection of COS-7 cells followed by reporter construct activation, Kressler et al. (2002) showed that PPARGC1B coactivates estrogen receptor-alpha (ESR1; 133430). Yeast 2-hybrid analysis showed ligand-dependent binding of the 2 LXXLL motifs of PPARGC1B to the ligand-binding domain of ESR1. The PPARGC1B LXXLL motifs and the ESR1 ligand-binding domain are necessary for ESR1 coactivation. An N-terminal transcriptional activation domain in PPARGC1B is also necessary for ESR1 coactivation. PPARGC1B differed from PPARGC1A in its enhancement of ESR1 activation in various promoter constructs, and PPARGC1B enhanced ESR1-mediated response to the partial agonist tamoxifen while PPARGC1A repressed it.
Using cotransfection assays in mammalian cells, Hentschke et al. (2002) showed that mouse Ppargc1b coactivates estrogen-related receptor-gamma (ESRRG; 602969). GST pull-down assays showed that Ppargc1b binds ESRRG in vitro.
Kamei et al. (2003) showed that PGC1B functioned as a ligand for orphan estrogen receptor-related receptors (ERRs) in vitro. They found that transgenic mice overexpressing Pgc1b exhibited increased expression of medium-chain acyl-CoA dehydrogenase (ACADM; 607008), an ERR target and a pivotal enzyme in mitochondrial beta oxidation in skeletal muscle. As a result, transgenic mice were hyperphagic, showed elevated energy expenditure, and were resistant to obesity induced by a high-fat diet or by genetic abnormality. Kamei et al. (2003) concluded that PGC1B functions as an ERR ligand and contributes to the control of energy balance in vivo.
To examine the influence of genetic and environmental factors on the expression of PPARGC1A and PPARGC1B in human skeletal muscle, Ling et al. (2004) studied mRNA expression of these transcriptional coactivators in muscle biopsies from young and elderly monozygotic and dizygotic twins before and after a hyperinsulinemic euglycemic clamp and found that insulin increased and aging reduced PPARGC1A and PPARGC1B mRNA levels. Expression of PPARGC1A in muscle was positively related to insulin-stimulated glucose uptake and oxidation, whereas PPARGC1B expression was positively related to fat oxidation and nonoxidative glucose metabolism. Ling et al. (2004) concluded that insulin stimulates and aging reduces skeletal muscle expression of PPARGC1A and PPARGC1B, and suggested that they have different regulatory functions on glucose and fat oxidation in muscle cells. The authors suggested that this could provide an explanation by which an environmental trigger (age) modifies genetic susceptibility to type II diabetes (see 125853).
Lin et al. (2005) found that high-fat feeding stimulated expression of both Pgc1-beta and Srebp1a/1c (SREBF1; 184756) in mouse liver. Pgc1-beta coactivated the Srebp transcription factor family and stimulated lipogenic gene expression. Furthermore, Pgc1-beta was required for Srebp-mediated lipogenic gene expression. However, unlike Srebp itself, Pgc1-beta reduced fat accumulation in liver while greatly increasing circulating triglycerides and cholesterol in very low density lipoprotein particles. Lin et al. (2005) determined that the stimulation of lipoprotein transport upon Pgc1-beta expression was likely due to the simultaneous coactivation of the liver nuclear hormone receptor, Lxr-alpha (NR1H3; 602423). These data suggested a mechanism through which dietary saturated fats can stimulate hyperlipidemia and atherogenesis.
Ishii et al. (2009) found that knockdown of Ppargc1b in primary mouse osteoclasts impaired their differentiation and mitochondrial biogenesis. Transferrin receptor-1 (TFRC; 190010) expression was induced in osteoclasts via iron regulatory protein-2 (IREB2; 147582), and Tfrc-mediated iron uptake promoted osteoclast differentiation and bone-resorbing activity, which was associated with the induction of mitochondrial respiration, production of reactive oxygen species, and accelerated Ppargc1b transcription. Iron chelation inhibited osteoclastic bone resorption and protected female mice against bone loss following estrogen deficiency resulting from ovariectomy. Ishii et al. (2009) concluded that mitochondrial biogenesis, which is induced by PPARGC1B and supported by TFRC-mediated iron uptake for utilization by mitochondrial respiratory proteins, is fundamental to osteoclast activation and bone metabolism.
Srivastava et al. (2009) tested the potential effect of increased mitochondrial biogenesis in cells derived from patients harboring oxidative phosphorylation defects due to either nuclear or mitochondrial DNA mutations. Adenoviral-mediated expression of PPARGC1A and/or PPARGC1B improved mitochondrial respiration in fibroblasts harboring a complex III deficiency (124000) or complex IV deficiency (220110) as well as in transmitochondrial cybrids harboring a mutation in the MTTL1 gene (590050.0001), resulting in MELAS syndrome (540000). The respiratory function improvement was found to be associated with increased levels of mitochondrial components per cell, although this increase was not homogeneous.
Sahin et al. (2011) used transcriptomic network analyses in mice null for either Tert (187270) or Terc (602322), which exhibit telomere dysfunction, to identify common mechanisms operative in hematopoietic stem cells, heart, and liver. Their studies revealed profound repression of peroxisome proliferator-activated receptor-gamma (PPARG; 601487), PCG1-alpha (604517) and PGC1-beta, and the downstream network. Consistent with PGCs as master regulators of mitochondrial physiology and metabolism, telomere dysfunction was associated with impaired mitochondrial biogenesis and function, decreased gluconeogenesis, cardiomyopathy, and increased reactive oxygen species. In the setting of telomere dysfunction, enforced Tert or PGC1-alpha expression or germline deletion of p53 (191170) substantially restored PGC network expression, mitochondrial respiration, cardiac function, and gluconeogenesis. Sahin et al. (2011) demonstrated that telomere dysfunction activates p53 which in turn binds and represses PGC1-alpha and PGC1-beta promoters, thereby forging a direct link between telomere and mitochondrial biology. Sahin et al. (2011) proposed that this telomere-p53-PGC axis contributes to organ and metabolic failure and to diminishing organismal fitness in the setting of telomere dysfunction.
Lin et al. (2002) reported that the human PPARGC1B gene maps to 5q33. Kressler et al. (2002) identified the PPARGC1B gene on chromosome 5.
In a case-control study of 7,790 individuals, Andersen et al. (2005) found that the pro203 allele of PPARGC1B (608886.0001) was significantly less frequent among obese participants than normal or overweight subjects (p = 0.004). Andersen et al. (2005) concluded that variation of PPARGC1B may contribute to the pathogenesis of obesity, with the widespread ala203 allele being a risk factor for the development of this common disorder.
Lai et al. (2008) found that survival rates of Pgc1b -/- mice were reduced compared with wildtype mice, although they appeared normal and had normal heart function, similar to Pgc1a -/- mice. However, Pgc1b -/- mice showed reduced ability to adapt to thermal or exercise challenge, and Pgc1b -/- mice upregulated Pgc1a expression in heart and brown adipose tissue, suggesting a compensatory response to increase ATP synthesis during physiologic challenge. In contrast, Pgc1a/Pgc1b double-knockout mice died shortly after birth with small hearts, bradycardia, intermittent heart block, and markedly reduced cardiac output. Cardiac-specific ablation of the Pgc1b gene on a Pgc1a -/- background phenocopied Pgc1a/Pgc1b double-knockout mice. The hearts of double-knockout mice exhibited features of a maturational defect, including reduced growth, late fetal arrest in mitochondria biogenesis, and persistence of a fetal pattern of gene expression. Brown adipose tissue of double-knockout mice also exhibited a severe abnormality in function and mitochondrial density. Lai et al. (2008) concluded that PGC1A and PGC1B share roles necessary for postnatal metabolic and functional maturation of the heart and brown adipose tissue.
Ishii et al. (2009) found that Ppargc1b -/- mice displayed enhanced bone mass due to impaired bone resorption. Ppargc1b -/- osteoclasts appeared abnormal and their bone-resorbing activity was significantly impaired.
In a case-control study of 7,790 individuals, Andersen et al. (2005) found that alleles carrying a 649G-C transversion in exon 5 of the PPARGC1B gene, resulting in an ala203-to-pro (A203P) substitution, were significantly less frequent among obese participants than normal or overweight subjects (p = 0.004). The ala/ala genotype was found in 84%, 85%, and 88% of normal, overweight, and obese subjects, respectively. Andersen et al. (2005) concluded that variation of PPARGC1B may contribute to the pathogenesis of obesity, with the widespread ala203 allele being a risk factor for the development of this common disorder. The authors noted that they used the most abundant human isoform, PPARGC1B1a, for numbering codons.
Andersen, G., Wegner, L., Yanagisawa, K., Rose, C. S., Glumer, C., Drivsholm, T., Borch-Johnsen, K., Jorgensen, T., Hansen, T., Spiegelman, B. M., Pedersen, O. Evidence of an association between genetic variation of the coactivator PGC-1-beta and obesity. J. Med. Genet. 42: 402-407, 2005. [PubMed: 15863669] [Full Text: https://doi.org/10.1136/jmg.2004.026278]
Hentschke, M., Susens, U., Borgmeyer, U. PGC-1 and PERC, coactivators of the estrogen receptor-related receptor gamma. Biochem. Biophys. Res. Commun. 299: 872-879, 2002. [PubMed: 12470660] [Full Text: https://doi.org/10.1016/s0006-291x(02)02753-5]
Ishii, K., Fumoto, T., Iwai, K., Takeshita, S., Ito, M., Shimohata, N., Aburatani, H., Taketani, S., Lelliott, C. J., Vidal-Puig, A., Ikeda, K. Coordination of PGC-1-beta and iron uptake in mitochondrial biogenesis and osteoclast activation. Nature Med. 15: 259-266, 2009. [PubMed: 19252502] [Full Text: https://doi.org/10.1038/nm.1910]
Kamei, Y., Ohizumi, H., Fujitani, Y., Nemoto, T., Tanaka, T., Takahashi, N., Kawada, T., Miyoshi, M., Ezaki, O., Kakizuka, A. PPAR-gamma coactivator 1-beta/ERR ligand 1 is an ERR protein ligand, whose expression induces a high-energy expenditure and antagonizes obesity. Proc. Nat. Acad. Sci. 100: 12378-12383, 2003. [PubMed: 14530391] [Full Text: https://doi.org/10.1073/pnas.2135217100]
Kressler, D., Schreiber, S. N., Knutti, D., Kralli, A. The PGC-1-related protein PERC is a selective coactivator of estrogen receptor-alpha. J. Biol. Chem. 277: 13918-13925, 2002. [PubMed: 11854298] [Full Text: https://doi.org/10.1074/jbc.M201134200]
Lai, L., Leone, T. C., Zechner, C., Schaeffer, P. J., Kelly, S. M., Flanagan, D. P., Medeiros, D. M., Kovacs, A., Kelly, D. P. Transcriptional coactivators PGC-1-alpha and PGC-1-beta control overlapping programs required for perinatal maturation of the heart. Genes Dev. 22: 1948-1961, 2008. [PubMed: 18628400] [Full Text: https://doi.org/10.1101/gad.1661708]
Lin, J., Puigserver, P., Donovan, J., Tarr, P., Spiegelman, B. M. Peroxisome proliferator-activated receptor gamma coactivator 1-beta (PGC-1-beta), a novel PGC-1-related transcription coactivator associated with host cell factor. J. Biol. Chem. 277: 1645-1648, 2002. [PubMed: 11733490] [Full Text: https://doi.org/10.1074/jbc.C100631200]
Lin, J., Yang, R., Tarr, P. T., Wu, P.-H., Handschin, C., Li, S., Yang, W., Pei, L., Uldry, M., Tontonoz, P., Newgard, C. B., Spiegelman, B. M. Hyperlipidemic effects of dietary saturated fats mediated through PGC-1-beta coactivation of SREBP. Cell 120: 261-273, 2005. [PubMed: 15680331] [Full Text: https://doi.org/10.1016/j.cell.2004.11.043]
Ling, C., Poulsen, P., Carlsson, E., Ridderstrale, M., Almgren, P., Wojtaszewski, J., Beck-Nielsen, H., Groop, L., Vaag, A. Multiple environmental and genetic factors influence skeletal muscle PGC-1-alpha and PGC-1-beta gene expression in twins. J. Clin. Invest. 114: 1518-1526, 2004. [PubMed: 15546003] [Full Text: https://doi.org/10.1172/JCI21889]
Sahin, E., Colla, S., Liesa, M., Moslehi, J., Muller, F. L., Guo, M., Cooper, M., Kotton, D., Fabian, A. J., Walkey, C., Maser, R. S., Tonon, G., and 18 others. Telomere dysfunction induces metabolic and mitochondrial compromise. Nature 470: 359-365, 2011. Note: Erratum: Nature 475: 254 only, 2011. [PubMed: 21307849] [Full Text: https://doi.org/10.1038/nature09787]
Srivastava, S., Diaz, F., Iommarini, L., Aure, K., Lombes, A., Moraes, C. T. PGC-1-alpha/beta induced expression partially compensates for respiratory chain defects in cells from patients with mitochondrial disorders. Hum. Molec. Genet. 18: 1805-1812, 2009. [PubMed: 19297390] [Full Text: https://doi.org/10.1093/hmg/ddp093]