Evidence that lipopolysaccharide-induced anorexia depends upon central, rather than peripheral, inflammatory signals.
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-1beta 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-1beta and TNFalpha 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.
Division of Metabolism, Harborview Medical Center, Seattle, WA 98104-2499, USA. bewisse@u.washington.edu
Brent E
BE
Wisse
Kayoko
K
Ogimoto
Jingjing
J
Tang
Marvin K
MK
Harris
Elaine W
EW
Raines
Michael W
MW
Schwartz
D000818:Animals; D000855:Anorexia / Q000139:chemically induced*; D001823:Body Composition / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D016026:Bone Marrow Transplantation / Q000502:physiology; D002478:Cells, Cultured; D004435:Eating / Q000187:drug effects; D005260:Female; D007031:Hypothalamus / Q000378:metabolism / Q000502:physiology*; D007107:Immune System / Q000378:metabolism / Q000502:physiology; D018836:Inflammation Mediators / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*; D013154:Spleen / Q000378:metabolism / Q000502:physiology*
D018836:Inflammation Mediators; D008070:Lipopolysaccharides; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88