Obesity causes Pgc-1α deficiency in the pancreas leading to marked Il-6 up-regulation via NF-κB in acute pancreatitis.

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.