MyD88 is a key mediator of anorexia, but not weight loss, induced by lipopolysaccharide and interleukin-1 beta.
Systemic inflammatory signals can disrupt the physiological regulation of energy balance, causing anorexia and weight loss. In the current studies, we investigated whether MyD88, the primary, but not exclusive, intracellular signal transduction pathway for Toll-like receptor 4 and IL-1 receptor I, is necessary for anorexia and weight loss to occur in response to stimuli that activate these key innate immune receptors. Our findings demonstrate that the absence of MyD88 signaling confers complete protection against anorexia induced by either lipopolysaccharide (LPS) (20 h food intake in MyD88-/- mice 5.4 +/- 0.3 vs. 3.3 +/- 0.4 g in MyD88+/+ control mice, P < 0.001) or IL-1 beta (20 h food intake in MyD88-/- mice 4.9 +/- 0.5 vs. 4.0 +/- 0.3 g in MyD88+/+ control mice, P < 0.001). However, absent MyD88 signaling does not prevent these inflammatory mediators from causing weight loss (LPS, -0.4 +/- 0.1 g; IL1 beta, -0.1 +/- 0.1 g, both P < 0.01 vs. vehicle-injected MyD88-/- mice, +0.4 +/- 0.2 g). Furthermore, LPS-induced weight loss occurs in the absence of adipsia, fever, or hypothalamus-pituitary-adrenal axis activation in MyD88-deficient mice. In addition, the peripheral inflammatory response to LPS is surprisingly intact in mice lacking MyD88. Together, these observations indicate that LPS reduces food intake via a mechanism that is dissociated from its effect on peripheral cytokine production, and whereas the presence of circulating proinflammatory cytokines per se is insufficient to cause anorexia in the absence of MyD88 signaling, it may contribute to LPS-induced weight loss.
Ogimoto
Kayoko
K
Division of Metabolism, Endocrinology, and Nutrition, Harborview Medical Center, 325 Ninth Avenue, Box 359757, Seattle, Washington 98104-2499, USA.
Harris
Marvin K
MK
Wisse
Brent E
BE
D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000502:physiology*; D000818:Animals; D000855:Anorexia / Q000209:etiology / Q000503:physiopathology* / Q000517:prevention & control; D001831:Body Temperature / Q000187:drug effects; D003345:Corticosterone / Q000097:blood; D016207:Cytokines / Q000097:blood / Q000235:genetics; D004435:Eating / Q000187:drug effects / Q000502:physiology; D004734:Energy Metabolism / Q000187:drug effects; D005260:Female; D007031:Hypothalamus / Q000737:chemistry; D007375:Interleukin-1 / Q000494:pharmacology*; D015850:Interleukin-6 / Q000097:blood; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88; D009479:Neuropeptides / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D017472:Receptors, Interleukin-1 / Q000502:physiology; D015398:Signal Transduction; D013154:Spleen / Q000737:chemistry; D051197:Toll-Like Receptor 4 / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015431:Weight Loss / Q000187:drug effects / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D016207:Cytokines; D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D009479:Neuropeptides; D012333:RNA, Messenger; D017472:Receptors, Interleukin-1; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D003345:Corticosterone