The liver responds to injury with regulated tissue regeneration. During early regeneration, the liver accumulates fat. Neither the mechanisms responsible for nor the functional significance of this transient steatosis have been determined. In this study, we examined patterns of gene expression associated with hepatic fat accumulation in regenerating liver and tested the hypothesis that disruption of hepatic fat accumulation would be associated with impaired hepatic regeneration. First, microarray-based gene expression analysis revealed that several genes typically induced during adipocyte differentiation were specifically upregulated in the regenerating liver prior to peak hepatocellular fat accumulation. These observations suggest that hepatic fat accumulation is specifically regulated during liver regeneration. Next, 2 methods were employed to disrupt hepatocellular fat accumulation in the regenerating liver. Because exogenous leptin supplementation reverses hepatic steatosis in leptin-deficient mice, the effects of leptin supplementation on liver regeneration in wildtype mice were examined. The data showed that leptin supplementation resulted in suppression of hepatocellular fat accumulation and impairment of hepatocellular proliferation during liver regeneration. Second, because glucocorticoids regulate cellular fat accumulation during adipocyte differentiation, the effects of hepatocyte-specific disruption of the glucocorticoid receptor were similarly evaluated. The results showed that hepatic fat accumulation and hepatocellular proliferation were also suppressed in mice with liver specific disruption of glucocorticoid receptor. In conclusion, suppression of hepatocellular fat accumulation is associated with impaired hepatocellular proliferation following partial hepatectomy, indicating that hepatocellular fat accumulation is specifically regulated during and may be essential for normal liver regeneration. (HEPATOLOGY 2004;40:1322-1332.) T he liver regenerates in response to a variety of injuries. [1][2][3] The rodent partial hepatectomy model has been a useful tool with which to investigate the signals that regulate this regenerative response. Following partial hepatectomy, most of the remaining quiescent hepatocytes in the remnant liver tissue quickly proliferate leading to rapid restoration of appropriate liver mass. 4 Analyses of genetically and pharmacologically manipulated mice using this model have begun to identify the coordinated signaling events that regulate hepatic regeneration. These signals include activation of tumor necrosis factor β£ (TNFβ£) interleukin (IL)-6 signaling, 5-7 generation of mitochondrial reactive oxygen species 8 and prostaglandins 9 , and activation of stress-and mitogenactivated-protein kinase cascades. 10 These signals lead to activation of nuclear factor B (NFB) and other transcription factors, which direct an immediate early gene expression program culminating in growth factor-dependent hepatocellular reentry into and progression through the cell cycle [11][12][13] . Once this has occurred and normal hepatic mass is restored, the regenerative response is ter-