scholarly journals MyD88 Is a Key Mediator of Anorexia, But Not Weight Loss, Induced by Lipopolysaccharide and Interleukin-1β

Endocrinology ◽  
2006 ◽  
Vol 147 (9) ◽  
pp. 4445-4453 ◽  
Author(s):  
Kayoko Ogimoto ◽  
Marvin K. Harris ◽  
Brent E. Wisse
Keyword(s):  
Weight Loss ◽  
Food Intake ◽  
Signal Transduction Pathway ◽  
Toll Like Receptor 4 ◽  
Physiological Regulation ◽  
Intracellular Signal Transduction Pathway ◽  
Intracellular Signal ◽  
Myd88 Signaling ◽  
Deficient Mice ◽  
Pituitary Adrenal Axis

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-1β (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; IL1β, −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.

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

Endocrinology ◽  
2007 ◽  
Vol 148 (11) ◽  
pp. 5230-5237 ◽  
Author(s):  
Brent E. Wisse ◽  
Kayoko Ogimoto ◽  
Jingjing Tang ◽  
Marvin K. Harris ◽  
Elaine W. Raines ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Food Intake ◽  
Immune Cells ◽  
Inflammatory Responses ◽  
Toll Like Receptor 4 ◽  
Physiological Regulation ◽  
Inflammatory Stimuli ◽  
The Central Nervous System ◽  
Myd88 Signaling ◽  
Deficient Mice

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 TNFα 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.

Transactivation of gene expression by nuclear and cytoplasmic rel proteins

1989 ◽  
Vol 9 (10) ◽  
pp. 4323-4336
Author(s):  
M Hannink ◽  
H M Temin
Keyword(s):  
Gene Expression ◽  
Transcriptional Activation ◽  
Signal Transduction Pathway ◽  
Cellular Transformation ◽  
C Terminus ◽  
Intracellular Signal Transduction Pathway ◽  
Transforming Activity ◽  
A Cell ◽  
Rat Fibroblasts ◽  
Intracellular Signal

Transcriptional activation of gene expression by oncogenic proteins can lead to cellular transformation. It has recently been demonstrated that the protein encoded by the v-rel oncogene from reticuloendotheliosis virus strain T can transactivate gene expression from certain promoters in a cell-specific manner. We have examined the cytological location, transforming properties, and transactivation properties of proteins encoded by chimeric turkey v-rel/chicken c-rel genes. We found that whereas the v-rel protein was nuclear in both chicken embryo and rat fibroblasts, the presence of the C terminus of the c-rel protein inhibited nuclear localization of the rel protein in these fibroblasts. Cytoplasmic rel proteins containing C-terminal c-rel sequences transactivated gene expression from the polyomavirus late promoter as efficiently as did similar rel proteins located in the nucleus. These results indicate that the cellular location of rel proteins is not important for transactivation of gene expression and suggest that transactivation by rel proteins is indirect, perhaps by affecting an intracellular signal transduction pathway that eventually results in the alteration of gene expression. The transforming properties of the rel protein were unaltered by the presence of the c-rel C terminus, but, as previously reported for turkey c-rel sequences, substitution of chicken c-rel sequences for internal v-rel sequences reduced the transforming activity of the rel protein and eliminated the immortalization ability. However, all of the chimeric v/c-rel proteins were able to transactivate gene expression, indicating that transactivation does not correlate with transformation. These results suggest that transactivation may be necessary but is not sufficient for transformation by rel proteins.

scholarly journals Transactivation of gene expression by nuclear and cytoplasmic rel proteins.

1989 ◽  
Vol 9 (10) ◽  
pp. 4323-4336 ◽  
Author(s):  
M Hannink ◽  
H M Temin
Keyword(s):  
Gene Expression ◽  
Transcriptional Activation ◽  
Signal Transduction Pathway ◽  
Cellular Transformation ◽  
C Terminus ◽  
Intracellular Signal Transduction Pathway ◽  
Transforming Activity ◽  
A Cell ◽  
Rat Fibroblasts ◽  
Intracellular Signal

Transcriptional activation of gene expression by oncogenic proteins can lead to cellular transformation. It has recently been demonstrated that the protein encoded by the v-rel oncogene from reticuloendotheliosis virus strain T can transactivate gene expression from certain promoters in a cell-specific manner. We have examined the cytological location, transforming properties, and transactivation properties of proteins encoded by chimeric turkey v-rel/chicken c-rel genes. We found that whereas the v-rel protein was nuclear in both chicken embryo and rat fibroblasts, the presence of the C terminus of the c-rel protein inhibited nuclear localization of the rel protein in these fibroblasts. Cytoplasmic rel proteins containing C-terminal c-rel sequences transactivated gene expression from the polyomavirus late promoter as efficiently as did similar rel proteins located in the nucleus. These results indicate that the cellular location of rel proteins is not important for transactivation of gene expression and suggest that transactivation by rel proteins is indirect, perhaps by affecting an intracellular signal transduction pathway that eventually results in the alteration of gene expression. The transforming properties of the rel protein were unaltered by the presence of the c-rel C terminus, but, as previously reported for turkey c-rel sequences, substitution of chicken c-rel sequences for internal v-rel sequences reduced the transforming activity of the rel protein and eliminated the immortalization ability. However, all of the chimeric v/c-rel proteins were able to transactivate gene expression, indicating that transactivation does not correlate with transformation. These results suggest that transactivation may be necessary but is not sufficient for transformation by rel proteins.

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