Peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α is a transcriptional coactivator described as a master regulator of mitochondrial biogenesis and function, including oxidative phosphorylation and reactive oxygen species detoxification. PGC-1α is highly expressed in tissues with high energy demands, and it is clearly associated with the pathogenesis of metabolic syndrome and its principal complications including obesity, type 2 diabetes mellitus, cardiovascular disease, and hepatic steatosis. We herein review the molecular pathways regulated by PGC-1α, which connect oxidative stress and mitochondrial metabolism with inflammatory response and metabolic syndrome. PGC-1α regulates the expression of mitochondrial antioxidant genes, including manganese superoxide dismutase, catalase, peroxiredoxin 3 and 5, uncoupling protein 2, thioredoxin 2, and thioredoxin reductase and thus prevents oxidative injury and mitochondrial dysfunction. Dysregulation of PGC-1α alters redox homeostasis in cells and exacerbates inflammatory response, which is commonly accompanied by metabolic disturbances. During inflammation, low levels of PGC-1α downregulate mitochondrial antioxidant gene expression, induce oxidative stress, and promote nuclear factor kappa B activation. In metabolic syndrome, which is characterized by a chronic low grade of inflammation, PGC-1α dysregulation modifies the metabolic properties of tissues by altering mitochondrial function and promoting reactive oxygen species accumulation. In conclusion, PGC-1α acts as an essential node connecting metabolic regulation, redox control, and inflammatory pathways, and it is an interesting therapeutic target that may have significant benefits for a number of metabolic diseases.

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Obesity is associated with local and systemic complications in acute pancreatitis. PPARγ co-activator 1α (PGC-1α) is a transcriptional co-activator and master regulator of mitochondrial biogenesis that exhibits dysregulation in obese subjects. Our aims were 1) to study PGC-1α levels in pancreas from lean or obese rats and mice with acute pancreatitis; and 2) to determine the role of PGC-1α in the inflammatory response during acute pancreatitis elucidating the signaling pathways regulated by PGC-1α. Lean and obese Zucker rats and lean and obese C57BL6 mice were used first, and subsequently wild-type and PGC-1α knock-out (KO) mice with cerulein-induced pancreatitis were used to assess the inflammatory response and expression of target genes. Ppargc1a mRNA and protein levels were markedly down-regulated in pancreas of obese mice versus lean mice. PGC-1α protein levels increased in pancreas of lean mice with acute pancreatitis, but not in obese mice with pancreatitis. Il6 mRNA levels were dramatically up-regulated in pancreas of PGC-1α KO mice after cerulein-induced pancreatitis in comparison with wild type mice with pancreatitis. Edema and the inflammatory infiltrate were more intense in pancreas from PGC-1α KO mice than in wild type mice. The lack of PGC-1α markedly enhanced nuclear translocation of phospho-p65 and recruitment of p65 to Il6 promoter. PGC-1α bound phospho-p65 in pancreas during pancreatitis in wild type mice. Glutathione depletion in cerulein-induced pancreatitis was more severe in KO mice than in wild type mice. PGC-1α KO mice with pancreatitis, but not wild type mice, exhibited increased MPO activity in the lungs together with alveolar wall thickening and collapse, which were abrogated by blockade of the IL-6 receptor gp130 with LMT-28. In conclusion, obese rodents exhibit PGC-1α deficiency in the pancreas. PGC-1α acts as selective repressor of NF-κB towards IL-6 in pancreas. PGC-1α deficiency markedly enhanced NF-κB-mediated up-regulation of Il6 in pancreas in pancreatitis, leading to severe inflammatory response.

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Macrophage polarization refers to the process by which macrophages can produce two distinct functional phenotypes: M1 or M2. The balance between both strongly affects the progression of inflammatory disorders. Here, we review how redox signals regulate macrophage polarization and reprogramming during acute inflammation. In M1, macrophages augment NADPH oxidase isoform 2 (NOX2), inducible nitric oxide synthase (iNOS), synaptotagmin-binding cytoplasmic RNA interacting protein (SYNCRIP), and tumor necrosis factor receptor-associated factor 6 increase oxygen and nitrogen reactive species, which triggers inflammatory response, phagocytosis, and cytotoxicity. In M2, macrophages down-regulate NOX2, iNOS, SYNCRIP, and/or up-regulate arginase and superoxide dismutase type 1, counteract oxidative and nitrosative stress, and favor anti-inflammatory and tissue repair responses. M1 and M2 macrophages exhibit different metabolic profiles, which are tightly regulated by redox mechanisms. Oxidative and nitrosative stress sustain the M1 phenotype by activating glycolysis and lipid biosynthesis, but by inhibiting tricarboxylic acid cycle and oxidative phosphorylation. This metabolic profile is reversed in M2 macrophages because of changes in the redox state. Therefore, new therapies based on redox mechanisms have emerged to treat acute inflammation with positive results, which highlights the relevance of redox signaling as a master regulator of macrophage reprogramming.