Obesity is associated with an increased incidence of infection, diabetes, and cardiovascular disease, which together account for most obesity-related morbidity and mortality. Decreased expression of leptin or of functional leptin receptors results in hyperphagia, decreased energy expenditure, and obesity. It is unclear, however, whether defective leptin-dependent signal transduction directly promotes any of the conditions that frequently complicate obesity. Abnormalities in tumor necrosis factor alpha expression have been noted in each of the above comorbid conditions, so leptin deficiency could promote these complications if leptin had immunoregulatory activity. Studies of rodents with genetic abnormalities in leptin or leptin receptors revealed obesity-related deficits in macrophage phagocytosis and the expression of proinflammatory cytokines both in vivo and in vitro. Exogenous leptin up-regulated both phagocytosis and the production of proinflammatory cytokines. These results identify an important and novel function for leptin: up-regulation of inflammatory immune responses, which may provide a common pathogenetic mechanism that contributes to several of the major complications of obesity.

Obesity is associated with an increased incidence of infection, diabetes, and cardiovascular disease, which together account for most obesity‐related morbidity and mortality. Decreased expression of leptin or of functional leptin receptors results in hyperphagia, decreased energy expenditure, and obesity. It is unclear, however, whether defective leptin‐dependent signal transduction directly promotes any of the conditions that frequently complicate obesity. Abnormalities in tumor necrosis factor α expression have been noted in each of the above comorbid conditions, so leptin deficiency could promote these complications if leptin had immunoregulatory activity. Studies of rodents with genetic abnormalities in leptin or leptin receptors revealed obesity‐related deficits in macrophage phagocytosis and the expression of proinflammatory cytokines both in vivo and in vitro. Exogenous leptin up‐regulated both phagocytosis and the production of proinflammatory cytokines. These results identify an important and novel function for leptin: up‐regulation of inflammatory immune responses, which may provide a common pathogenetic mechanism that contributes to several of the major complications of obesity.—Loffreda, S., Yang, S. Q., Lin, H. Z., Karp, C. L., Brengman, M. L., Wang, D. J., Klein, A. S., Bulkley, G. B., Bao, C., Noble, P. W., Lane, M. D., Diehl, A. M. Leptin regulates proinflammatory immune responses. FASEB J. 12, 57–65 (1998)

that synchronize the regenerative response to liver injury Tumor necrosis factor a (TNF), initiates a cytokine and implies that hepatocytes and liver nonparenchymal cells cascade that promotes hepatocyte proliferation after are both the sources of, and the targets for, various growth-70% partial hepatectomy (PH) but the mechanisms reguregulatory cytokines. Thus, to understand how liver regenerlating TNF production after PH are unknown. We preation is regulated, it is critical to delineate the cytokine netviously reported that gadolinium chloride (GdCl), an works that modify the phenotypes of liver cells during this agent that depletes the liver of phagocytically active growth response. Kupffer cells, enhances hepatic expression of TNF mesSeveral lines of evidence suggest that tumor necrosis factor senger RNA (mRNA) and promotes liver regeneration (TNF) a, is likely to be a key component of the paracrine after subsequent PH. This suggests that GdCl interferes network that promotes hepatocyte proliferation during liver with Kupffer cell mechanisms that normally constrain TNF production after PH. To evaluate this, the pre-and regeneration. The possibility that TNF may play a hepatopost-PH expression of TNF, TNF-inducible cytokines (in-trophic role is somewhat counterintutitive, given its wellterleukin [IL]-1, IL-6) and cytokines (transforming documented cytotoxic effects in other settings.2 However, this growth factor [TGF] b 1 and IL-10) that down-regulate theory is supported by data which show that liver DNA syn-TNF were compared in controls and GdCl-treated rats. thesis and hepatocyte mitoses increase in healthy adult rats In controls, TNF, IL-1, IL-6, and IL-10 increase within 3 after intravenous administration of human recombinant hours after PH, whereas TGF-b 1 is induced much later TNF 3 and evidence that pretreatment of rats with neutraliz-(ú24 hours after PH). GdCl causes sustained overex-ing antibodies to TNF 4 or soluble TNF receptors (Rai RM, et pression of TNF mRNA and transient overexpression of al., Unpublished data, May 1996) inhibits hepatocyte DNA circulating TNF protein after PH; both TNF-inducible synthesis after PH. To date, the mechanisms which control cytokines are also relatively overexpressed. Cytokines TNF production during liver regeneration have not been that down-regulate TNF are effected differentially by characterized. GdCl. Regenerative induction of IL-10 is abolished butIsolated Kupffer cells are known to produce TNF when TGF-b 1 induction is unaltered. Because IL-10 is known to stimulated by lipopolysaccharide 5 and are generally preshorten the half-life of TNF mRNA, these results suggest sumed to be an important source of hepatic TNF during an that Kupffer cell production of IL-10 is an important inflammatory response.6 Thus, we were surprised to discover mechanism that down-regulates TNF production during that gadolinium chloride (GdCl), an agent that depletes the liver regeneration. (HEPATOLOGY 1997;25:889-895.) liver of phagocytically active Kupffer cells, 7 increases hepatic l...