Cytokines and Hypermetabolism

Hypermetabolism, i.e. an increase in resting energy expenditure, occurs in many cachectic diseases [46]. Several cytokines, including TNF-a, IL-1 p and IL-6 [47-49], have been shown to stimulate energy expenditure and to induce fever as part of their effects on CNS mechanisms of defence and/or energy balance control.

Similar to the cytokine anorectic effects (see above), cytokine-induced hypermetabolism appears to result from synergistic and sequential interactions [50] and to involve the same principles of action of cir culating cytokines on the CNS [51-53] (see Fig. 1 and above). Some discrepancy exists as to whether the vagus is involved in the hypermetabolic effect of cytokines. Whereas some studies provide evidence for a vagal mediation [54-56],others do not [57,58].Dif-ferent routes of administration (i.e.,intraperitoneal vs. intravenous) [59] and/or different doses [60] of the involved cytokine may contribute to some of the observed discrepancies. In addition, the time and duration of measurement may be crucial because some evidence suggests that vagal afferents are involved in the immediate fever effect of peripheral cytokines,but not in their longer-term actions [55].

An alternative pathway of metabolic stimulation has recently been demonstrated for IFNy. A study in experimentally induced murine toxoplas-mosis showed that the hypermetabolism in this animal model depends on IFN-y and is due to a stimulation of extramitochondrial lipid oxidation in macrophage-rich tissues [61]. This suggests that IFN-y-dependent stimulation of the oxidative burst in macrophages can be a major contributor to the hypermetabolic response in some pathological situations.

Neurochemicals

COX2, PG

BBB endothelial cells

Neurochemicals

Immune cell ■ migration

Cytokine receptors

Insulin resistance and peripheral metabolic, neural and hormonal responses

Other intermediates

BBB endothelial cells

Immune cell ■ migration

Cytokine receptors

Other intermediates

Cytokines

Cytokines t

Monocytes, macrophage^, mast cells-

Cell surface structures (e.g. CD14, TLRs)

Cell surface structures (e.g. CD14, TLRs)

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