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Obesity and insulin resistance increases sensitivity to sepsis-induced hepatotoxicity

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      Abstract

      Introduction. Sepsis in the setting of obesity and insulin resistance is associated with increased morbidity and mortality. The liver is a key intermediary in sepsis through production of cytokines and the up regulation of the inducible nitric oxide synthase (iNOS). Based on the significant fatty changes that occur in obesity, we hypothesized that the liver would exhibit an altered response to endotoxin injection. Methods. The obese Zucker rat was utilized as an accepted model of obesity and insulin-resistance. Obese rats were injected intraperitoneally with 1 mg/kg LPS. Lean controls received either 1 (low dose) or 2 mg/kg (high dose). Serum and tissue samples were obtained at baseline, 4h, and 24 h following LPS administration to measure liver enzyme levels, histopathology, and inflammatory mediators. Results. Obese Zucker rats demonstrated exquisite sensitivity to LPS injection with 100% mortality at doses of 2.5, 5, and 10 mg/kg at 24 h compared to 0% in lean controls. AST and ALT were significantly elevated at 4 h in the obese animals (1687 ± 541 IU/L and 713 ± 170 IU/L, respectively, n ≥ 4/group) compared to the low-dose (796 ± 733 and 265 ± 150) and high-dose controls (571 ± 349 and 272 ± 134; P < 0.05). Serum TNFα levels at 4 h were similarly elevated to 587 pg/mL versus 271 and 211 in the low and high dose controls (P < 0.05). LPS administration in obese rats also increased iNOS protein expression at 4 h (see Figure)
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      Graphical Abstract
      and circulating NO levels compared to lean controls. Conclusions. These findings demonstrate an exaggerated innate immune response in obese rats and suggest that the fatty liver displays an exaggerated susceptibility to injury during endotoxemia.
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