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Fact is, that the whole story of PGC-1 and inflammation is a huge mess. Although initially there was one study by Wenz et al in PNAS suggesting that PGC-1 is anti-inflammatory, there is now much more evidence that it is pro-inflammatory. There is a new article by Henriette Pilegaard, a leading scientist in the topic, in PLOS ONE 2012. She found that PGC-1 activates NF kappa B, also known as p65. p65 phosphorylation is then increased and p65 increases the expression of TNF alpha. Independently of her work, other groups elucidated the mechanistic background for this pro-inflammatory action of PGC-1, thereby delivering direct mechanistic proof for her findings: -Romanino, K et al PNAS 2012 showed in the same rodent model of muscle specific overexpression of PGC-1 increases in skeletal muscle Akt protein levels and phosphorylation. Akt, also known as Protein kinase B (PKB) is known to phosphorylate p65 (shown by two independent groups: Viatour, P et al Trends Biochem Sci 2005 and Chen, LF et al Nat Rev Mol Cell Biol 2004). Therefore, there is increased phosphorylation of p65 in PGC-1 muscle-specific transgenic mice through higher Akt levels and phosphorylation. -Summermatter, S et al AJP 2012 demonstrated in the same model that calcineurin activity is increased. Calcineurin activates p65 and this has directly been clearly demonstrated (shown by two independent groups: Harris, CD et al Cellular and Molecular Life Science 2005 and Alzuherri, H and Cheng KC Cell Signal 2003). NF kappa B is an important mediator of inflammation. There is more evidence that PGC-1 in the muscle itself is pro-inflammatory. Now, there is however another aspect: Mice transgenic for PGC-1 have massively elevated angiogenesis and higher capillary densities than control wild-type animals (Arany Z et al, Nature 2008 for PGC-1alpha and Rowe GC et al, Am J Physiol Endocrinol Metab 2011 for PGC-1beta). Therefore, there are much more blood and blood components (macrophages) in the muscles of those transgenic animals. Also there is more endothelial surface/volume available for the uptake of macrophages in those transgenic animals. This messes the whole thing even more up. Finally, it has been demonstrated years ago (Yakeu et al, Atherosclerosis 2010) that PGC-1alpha and PGC-1beta mediate PPARγ/PGC-1α/β-driven macrophage M2 polarisation. M2 macrophages are more anti-inflammatory. PGC-1α and PGC-1β on the other hand were shown to downregulate pro-inflammatory M1 markers. Moreover, plasma levels of Th2 cytokines increased when PGC-1 was high, while those of Th1 cytokines decreased. Thus, PGC-1 may prime monocytes for differentiation towards an M2 macrophage phenotype via PPARγ. Already in 2006 Vats, D et al Cell Metabolism has shown that PGC-1 and oxidative metabolism promote M2 polarization of macrophages. They published that expression of PGC-1 primes macrophages for alternative activation and strongly inhibits proinflammatory cytokine production, whereas inhibition of oxidative metabolism or RNAi-mediated knockdown of PGC-1beta attenuates this immune response. A more recent publication by Chan MM, PPAR Res, 2012 showed that PPAR gamma coactivator-1 (PGC-1) protein through the STAT-6 pathway polarizes the monocytes into alternatively activated (M2) macrophages with anti-inflammatory properties. By its transcriptional activity, it mediates the expression of arginase-1 (Arg1) and CD36. Arginine metabolism away from production of NO compromises the ability of infected macrophage to clear the intracellular pathogens. It is certain that the overexpression of PGC-1 in skeletal muscle is leaky. Probably there is also an overexpression in macrophages priming them to M2 So, nothing is really clear