The importance of leptin in mice and man

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Background/Aims: Profound impairment of liver generation in rodents with dysfunctional leptin signal-g has been attributed to non-alcohol-induced fat liver disorders (NAFLD). Our aim was to establish whether defective liver regeneration in ob/ob mice is direct consequence of leptin-dependent, intracellular signaling mechanisms controlling cell-cycle regulation in hepatocytes. Methods: After exposure to a sing hepatotoxic dose of (CCl(4)), the regenerative response hepatic injury was studied in leptin-deficient ob/ob and control mice. The effects of leptin supplementation (100 mug kg(-1) per day) were examined. We assessed try into and progression through the cell cycle and activation of key signaling intermediates and transcriptional regulators. Results: CCl(4)-induced liver injury is equally severe in ob/ob and control mice. In leptin-deficient mice, it was associated with exaggerated activation of NF-kappa B and STAT3 during the priming phase, abrogation of tumor necrosis factor (TNF) and interleukin (IL)-6 release at the time of G1/S transition, and failure of hepatocyte induction of cyclin D1 and cell-cycle entry. Leptin replacement corrected these defects in ob/ob mice by restoring TNF and IL-6 release and inducing cyclin D1. Hepatocytes entered S phase and progressed, as in wild-type mice, to vigorous mitosis and normal hepatic regenerative response. In ob/ob mice, low doses of TNF before CCl(4) also were associated with restitution of TNF release and proliferative capabilities inclusions: Impaired liver regeneration in ob/ob mice caused by leptin deficiency. We propose that alter( cytokine production in ob/ob mice is part of the mechanisms responsible for impaired proliferation response to hepatic injury. (C) 2003 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.




Jaeschke, H., & McCuskey, R. S. (2004). The importance of leptin in mice and man. Journal of Hepatology. Elsevier.

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