Roux-en-Y gastric bypass improves glucose homeostasis, reduces oxidative stress and inflammation in livers of obese rats and in Kupffer cells via an AMPK-dependent pathway

Abstract

Oxidative stress and inflammation are implicated in the pathogenesis of steatohepatitis. We hypothesize that Roux-en-Y gastric bypass reduces oxidative stress and inflammation in the liver of obese rats via activation of AMPK-α. Obese Sprague-Dawley male rats underwent either sham operation or Roux-en-Y gastric bypass. Hepatic TNF-α, NF-κB, IRS-2, PI3 kinase, PKC-ζ, NOX2, and AMPK-α were measured. Mechanistic studies were done in a rat Kupffer cell line (RKC1) that was treated with free fatty acids to mimic lipotoxicity and then transfected with AMPK-α siRNA. Reactive oxygen species, TNF-α, NF-κB, AMPK-α, p-AMPK-α, PPAR-γ, and NOX2 were measured. A t test was used. Roux-en-Y gastric bypass lowered nonfasting serum glucose, improved the glucose tolerance test, and induced IRS2/PI3 kinase interaction. Additionally, Roux-en-Y gastric bypass decreased hepatic NOX2, PKC-ζ, TNF-α expression and activation of NF-κB. Free fatty acids increased reactive oxygen species, TNF-α protein, NOX2 protein, and activated NF-κB. Rosiglitazone attenuated the free fatty acids-induced increase in reactive oxygen species, TNF-α, NOX2, and NF-κB; blocking AMPK-α by siRNA abolished the effects of rosiglitazone. Roux-en-Y gastric bypass exhibits antidiabetic properties and is associated with downregulation of proinflammation genes and oxidative stress in the liver and within Kupffer cells via activation of AMPK-α.