Differential roles of tumor necrosis factor-alpha and interferon-gamma in mouse hypermetabolic and anorectic responses induced by LPS

Lipopolysaccharide (LPS)-induced effects on energy balance are characterize d by alterations in energy expenditure (hypermetabolism) and food intake (a norexia). To study the role of tumour necrosis factor alpha (TNF-alpha) on some of these metabolic responses to endotoxin, we have used transgenic mic e expressing soluble tumour necrosis factor receptor-1 IgG fusion protein ( TNFR1-IgG) as well as TNF-alpha knockout (KO), lymphotoxin-alpha (LT-alpha) KO, and interferon-gamma receptor (IFN-gammaR) KO mice. The results from T NFR1-IgG transgenic mice suggest that the hypermetabolic and anorectic resp onses induced by LPS are independently regulated since, in the absence of T NF-alpha or LT-alpha, the LPS-induced hypermetabolism is almost prevented b ut not the anorexia. The anorectic response shows the strongest association with IFN-gamma since both IFN-gammaR KO mice and mice treated with anti-IF N-gamma antibody showed marked reduction in the LPS-induced anorexia compar ed to other mice, IFN-gammaR KO mice also have an attenuated thermogenic re sponse to endotoxin, Anti-Asialo GM1 antibody treatment attenuated both the hypermetabolic and anorectic responses to LPS, to an extent comparable to that observed in IFN-gammaR KO mice. This finding suggests that natural kil ler cells (lymphocytic subsets) may be involved in IFN-gamma production and play an important role in the metabolic alterations induced by LPS, We als o showed that the hypermetabolic response of control mice is associated wit h an upregulation of cytokine expression within the brain and an increase i n permeability of the blood bl ain barrier, LPS-induced anorexia appears to involve peripheral cytokine expression.