Obesity causes PGC-1α deficiency in the pancreas leading to marked IL-6 upregulation via NF-κB in acute pancreatitis

Obesity is associated with local and systemic complications in acute pancreatitis. PPAR gamma coactivator 1 alpha (PGC-1 alpha) is a transcriptional coactivator and master regulator of mitochondrial biogenesis that exhibits dysregulation in obese subjects. Our aims were: (1) to study PGC-1 alpha levels in pancreas from lean or obese rats and mice with acute pancreatitis; and (2) to determine the role of PGC-1 alpha in the inflammatory response during acute pancreatitis elucidating the signaling pathways regulated by PGC-1 alpha. Lean and obese Zucker rats and lean and obese C57BL6 mice were used first; subsequently, wild-type and PGC-1 alpha knockout (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 downregulated in pancreas of obese rats and mice versus lean animals. PGC-1 alpha protein levels increased in pancreas of lean mice with acute pancreatitis, but not in obese mice with pancreatitis. Interleukin-6 (Il6) mRNA levels were dramatically upregulated in pancreas of PGC-1 alpha 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-1 alpha KO mice than in wild-type mice. The lack of PGC-1 alpha markedly enhanced nuclear translocation of phospho-p65 and recruitment of p65 to Il6 promoter. PGC-1 alpha 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-1 alpha KO mice with pancreatitis, but not wild-type mice, exhibited increased myeloperoxidase activity in the lungs, together with alveolar wall thickening and collapse, which were abrogated by blockade of the IL-6 receptor glycoprotein 130 with LMT-28. In conclusion, obese rodents exhibit PGC-1 alpha deficiency in the pancreas. PGC-1 alpha acts as selective repressor of nuclear factor-kappa B (NF-kappa B) towards IL-6 in pancreas. PGC-1 alpha deficiency markedly enhanced NF-kappa B-mediated upregulation of Il6 in pancreas in pancreatitis, leading to a severe inflammatory response. Copyright (c) 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.