Different tumor necrosis factor-α-associated leptin expression in rats with dimethylnitrosamine and bile duct ligation-induced liver cirrhosis

Although serum leptin concentrations are reported by several studies to increase in patients with liver cirrhosis, the mechanisms underpinning this increase remain unclear. Circulating tumor necrosis factor α (TNF-α) concentrations are also recognized to increase in liver cirrhosis. Furthermore, TNF-α administration to rodents results in increased expression and secretion of leptin from adipose tissue in a manner dependent on type 1 TNF-α receptor (TNF-RI). The present study was undertaken to examine adipose leptin expression and to explore potential relationships between leptin expression and TNF-α in subjects with liver cirrhosis. Liver cirrhosis was induced in male Sprague-Dawley rats by dimethylnitrosamine (DMN) administration or by common bile duct ligation (BDL). Ad libitum and pair-fed animals constituted controls. Serum leptin and TNF-α concentrations were determined by immunoassay. Gene expression was determined by the reverse transcription-polymerase chain reaction, and protein levels were measured by Western blotting. Serum leptin values after adjustment of body fat mass in DMN-treated rats were significantly higher than in pair-fed or ad libitum groups. Leptin mRNA and protein levels in epididymal fat in DMN rats increased by 1.8-fold and 2.3-fold, respectively, as compared with ad libitum controls, and by 4-fold and 6-fold, respectively, as compared with the pair-fed group. Epididymal TNF-α and membranous TNF-RI (mTNF-RI) concentrations were both 2.3 times higher in DMN rats than in ad libitum controls but did not differ between ad libitum and pair-fed groups. Adipose leptin protein levels correlated directly with TNF-α and mTNF-RI concentrations in combined DMN, ad libitum, and pair-fed rats (r = 0.64 and r = 0.49, respectively; P < .05). In BDL-treated rats, however, serum and adipose leptin concentrations were identical to those in ad libitum controls despite 2.1-fold and 2.4-fold increase in epididymal TNF-α and mTNF-RI, respectively. TNF-α administration to fasting control animals increased serum and adipose leptin concentrations significantly. The observed TNF-α-associated leptin up-regulation in DMN-induced, but not in BDL-induced, cirrhotic rats is consistent with distinctly different roles for TNF-α in rats with nonbiliary, as opposed to biliary, cirrhosis.