TNF-alpha tolerance blocks LPS-induced hypophagia but LPS tolerance fails to prevent TNF-alpha-induced hypophagia.

To investigate the role of tumor necrosis factor-alpha (TNF-alpha) in bacterial lipopolysaccharide (LPS)-induced hypophagia, we tested whether a cross tolerance between LPS and TNF-alpha exists with respect to their anorectic effects. Only the first of three subsequent intraperitoneal injections of LPS (100 micrograms/kg body wt) given every second day at dark onset (12:12-h light-dark cycle) led to a significant reduction of food intake in male rats. Likewise, intraperitoneal injections of human recombinant TNF-alpha (150 micrograms > or = 3 x 10(6) U/kg body wt) also resulted in tolerance to its hypophagic effect. LPS tolerance did not alter the hypophagic response to subsequently injected TNF-alpha (n = 14). However, TNF-alpha pretreatment completely blocked the hypophagic response to LPS (n = 14). The results demonstrate that tolerance to the hypophagic effect of exogenous TNF-alpha is sufficient to eliminate LPS-induced hypophagia. This is consistent with the hypothesis that endogenous TNF-alpha plays a major role in LPS-induced hypophagia. The ineffectiveness of LPS tolerance to attenuate TNF-alpha-induced hypophagia is compatible with findings demonstrating that reduced TNF-alpha production is an important feature of LPS tolerance.