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Evidence that Lipopolysaccharide-Induced Anorexia Depends upon Central, Rather than Peripheral, Inflammatory Signals

Division of Metabolism (B.E.W., K.O., M.K.H., M.W.S.), Endocrinology and Nutrition, Departments of Medicine and Pathology (J.T., E.W.R.), Harborview Medical Center, University of Washington, Seattle, Washington 98108

Address all correspondence and requests for reprints to: Brent E. Wisse, M.D., Harborview Medical Center, 325 Ninth Avenue, Box 359757, Seattle, Washington 98104-2499. E-mail: bewisse{at}u.washington.edu.

Systemic inflammatory stimuli cause anorexia and weight loss by disrupting the physiological regulation of energy balance. Mice lacking MyD88, an intracellular mediator of signal transduction activated by Toll-like receptor 4 or IL-1β receptors, are resistant to anorexia induced by the bacterial endotoxin lipopolysaccharide (LPS), despite a significant circulating cytokine response. Thus, we hypothesized that induction of a peripheral inflammatory response is insufficient to cause LPS-induced anorexia when MyD88 signaling in the central nervous system and other tissues is absent. To test this hypothesis, we used bone marrow transplantation (BMT) to determine if LPS-induced anorexia can be restored to MyD88-deficient mice by reconstituting their bone marrow with wild-type (WT) immune cells. We found that restoring WT circulating immune cells to mice lacking MyD88 conferred only a mild, short-lived anorexia in response to LPS, such that food intake was fully normalized by 20 h post injection (LPS 4.1 ± 0.5 g vs. vehicle 4.3 ± 0.3 g), whereas LPS-induced anorexia was profound and sustained in WT controls after either autologous BMT or sham BMT. Similarly, LPS-mediated induction of hypothalamic mRNA encoding IL-1β and TNF was robust in both WT control groups but was absent in chimeric MyD88 mice, despite comparable peripheral inflammatory responses across the three groups. We conclude that LPS reduces food intake via a mechanism dependent on MyD88 signaling within brain and/or other tissues and that in the absence of this effect, robust stimulation of circulating immune cells cannot induce sustained anorexia.