| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Division of Metabolism, Endocrinology, and Nutrition, 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.
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
After the discovery of cytokines and the signal transduction pathways that mediate their cellular effects, mutant mouse models were generated to identify molecules that are necessary for inflammatory anorexia and weight loss. Among these is Toll-like receptor 4 (TLR4), a pattern recognition receptor involved in the host response to bacterial pathogens. Mice lacking TLR4 are resistant to anorexia caused by lipopolysaccharide (LPS), a major component of the Gram-negative bacterial cell wall (11) and a potent inducer of systemic inflammation. Similarly, IL-1 receptor I (IL1RI)-deficient mice resist negative energy balance induced by IL-1ß, a major proinflammatory cytokine (12). Both TLR4 and IL1RI share a common signal transduction pathway that uses the intracellular adaptor molecule MyD88 to rapidly elicit cellular inflammatory responses, including activation of the key transcription factor nuclear factor-
B (NFB) (13, 14). In addition to the pathway involving MyD88, however, activation of either TLR4 or IL1RI can induce NFB activation via MyD88-independent signaling pathways in some cells (15, 16).
To further clarify how inflammatory mediators affect energy balance, we investigated whether MyD88 signaling is necessary for anorexia and weight loss in response to stimuli that activate TLR4, IL1RI, or other inflammatory signal transduction pathways. Our findings demonstrate that although the absence of MyD88 signaling confers complete protection against anorexia induced by either LPS or IL1ß in mice, protection from weight loss is incomplete. In addition, our results show that the peripheral inflammatory response to LPS is surprisingly intact in mice lacking MyD88, suggesting that increased plasma levels of key cytokines, including several that do not signal through MyD88, are insufficient to cause anorexia in the absence of MyD88 signaling.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Study protocols
Protocol 1: effect of ip administration of inflammatory mediators on food intake and body weight in MyD88-deficient mice.
On consecutive days, MyD88–/– mice (n = 8–12) and MyD88+/+ littermate controls (n = 8–12) received a single daily ip injection, vehicle (0.3 ml normal saline), on d 1 and 2, followed by LPS (50 ng/g ip, Escherichia coli serotype 055:B5, trichloroacetic acid precipitated, filtrated by gel chromatography and 
-irradiated; Sigma, St. Louis, MO) on d 3. All ip injections were given 30 min before the onset of the dark cycle. Food was returned at dark cycle onset and cumulative food intake was measured at 2 and 4 h into the dark cycle and again at 20 h after ip injections. Body weight was measured both before and 20 h after ip injections. To study the response to IL-1ß or TNF
, an identical protocol was used, except that IL-1ß (10 ng/g ip; Upstate Biotechnology, Lake Placid, NY) or TNF (65 ng/g ip; Chemicon, Temecula, CA) were substituted for LPS in separate groups of mutant and wild-type mice.
Protocol 2: effects of LPS on determinants of energy expenditure in MyD88-deficient mice.
One week after surgery to implant ip temperature transponders (Mini Mitter, Sun River, OR), MyD88–/– mice (n = 8) and MyD88+/+ littermate controls (n = 8) were placed individually into metabolic cages equipped for continuous, online measurements of food intake, water intake, core body temperature, ambulatory activity (determined using infrared activity sensors), and the rate of oxygen consumption (Columbus Instruments, Columbus, OH). During these studies, mice were maintained on a 12-h light, 12-h dark cycle (1800 h/0600 h) in a temperature- (25 C) and humidity-controlled environment and had ad libitum access to pulverized standard chow (Pico Rodent D5053M; Animal Specialties, Inc., Hubbard, OR) and water. Ambulatory activity was measured as frequency with which two adjacent infrared beams were broken by the animal’s movement (17). Food and water intake, body temperature, and locomotor activity were all continuously recorded over 24 h except during calibration and when animals were briefly removed at the end of the light cycle for body weight measurements and ip injections of vehicle or test compounds as described. All animals were adapted to the novel environment for 48 h before study. On d 1 and 2 after habituation, mice received an ip injection of vehicle (0.3 ml normal saline), whereas on d 3 they received LPS (50 ng/g ip).
Protocol 3: effects of LPS on serum corticosterone and cytokine concentrations and hypothalamic and splenic cytokine mRNA expression in MyD88-deficient and wild-type mice.
MyD88–/– mice and MyD88+/+ littermate controls were injected with either vehicle (0.3 ml normal saline ip) or LPS (50 ng/g ip) 30 min before the onset of the dark cycle. At either 6 or 12 h after injections, mice were killed by decapitation after brief exposure to inhaled CO2, creating a total of seven groups of animals, as follows: 1) 6 h/vehicle/wild-type (n = 7); 2) 6 h/ vehicle/MyD88–/– (n = 4); 3) 6 h/LPS/wild-type (n = 5); 4) 6 h/LPS/MyD88–/– (n = 4); 5) 12 h/vehicle/wild-type (n = 6); 6) 12 h/LPS/MyD88–/– (n = 5); and 7) 12 h/LPS/wild-type (n = 5).
Blood collection and tissue processing
Brains were removed and immediately frozen under crushed dry ice. Mediobasal hypothalamus was dissected and stored at –80 C before RNA extraction as previously described (18). Trunk blood was collected in chilled heparinized tubes, centrifuged, and plasma collected and frozen at –80 C. Plasma cytokine concentrations were measured using a mouse cytokine multiplex immunoassay (Linco Research Inc., St. Charles, MO). Plasma corticosterone concentrations were determined using a mouse corticosterone RIA assay (MP Biomedical, Orangeburg, NY).
Determination of cytokine mRNA levels by real-time PCR
Splenic and hypothalamic RNA extraction, quantification, and reverse transcription were performed as previously described (18). PCR was optimized for IL-1ß, TNF, proopiomelanocortin (POMC), neuropeptide Y (NPY), agouti gene-related peptide (Agrp), and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), using the following primer sequences: IL-1ß: forward, 5'-tacaaggagagacaagcaacgaca-3'; IL-1ß reverse, 5'-gatccacactctccagctgca-3'; TNF: forward, 5'-catcttctcaaaactcgagtgacaa-3', TNF reverse, 5'-tgggagtagataaggtacagccc-3'; NPY forward, 5'-accaggcagagatatggcaaga-3', NPY reverse, 5'-ggacattttctgtgctttctctcatta-3'; POMC forward, 5'-cgctcctactctatggagcactt-3', POMC reverse, 5'-tcacctaccagctccctcttg-3'; Agrp forward, 5'-agggcatcagaaggcctgaccagg-3', Agrp reverse, 5'-cattgaagaagcggcagtagcacgt-3'; GAPDH forward, 5'-aacgaccccttcattgac-3', GAPDH reverse, 5'-tccacgacatactcagcac-3' as previously described (18) using an ABI prism 7900HT (Applied Biosystems, Foster City, CA) and ABI SYBR Green PCR master mix (Applied Biosystems). PCR data were analyzed using the Sequence Detection System software (SDS version 2.2; Applied Biosystems). IL-1ß and TNF mRNA expression levels were normalized to Gapdh mRNA content, and nontemplate controls were incorporated into each PCR run. Correct amplification of IL-1ß mRNA by PCR was verified by sequencing of the PCR product (data not shown).
Statistical methods
Comparisons between group mean values were performed by two-way ANOVA using within-subjects comparison for treatment effect and between-subjects comparisons for genotype effect, and the Tukey honestly significant difference (HSD) post hoc test for multiple comparisons. Statistical analyses were performed using Statistica software (version 4.1; StatSoft Inc., Tulsa, OK). The null hypothesis of no difference between groups was rejected at P < 0.05. All values are presented as the mean ± SEM.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
) relative to vehicle-injected MyD88+/+ mice (2 h, 1.5 ± 0.1 g; 4 h, 2.3 ± 0.1 g; and 20 h, 5.2 ± 0.2 g) (Fig. 1A, P < 0.001 vs. LPS-treated MyD88+/+ mice at all time points). In contrast, administration of LPS to MyD88–/– mice had no effect on food intake at any of these three time points (2 h, 1.3 ± 0.1 g; 4 h, 2.3 ± 0.1 g; and 20 h, 5.4 ± 0.3 g) relative to vehicle-injected MyD88–/– mice (2 h, 1.5 ± 0.1 g; 4 h, 2.3 ± 0.1 g; and 20 h, 5.4 ± 0.3 g) (Fig 1A). Surprisingly, despite complete protection from anorexia, LPS administration resulted in weight loss in both genotypes, although weight loss of MyD88–/– mice was significantly less (–0.4 ± 0.1 g, P < 0.01 vs. vehicle) than in MyD88+/+ controls (–1.4 ± 0.1 g, P < 0.001 vs. LPS-treated MyD88–/– mice). Vehicle injection was associated with modest weight gain independent of genotype (+0.4 ± 0.2 g in MyD88–/– and +0.4 ± 0.2 g in MyD88+/+ mice). For all outcome measures described above, the response to vehicle injection did not differ according to genotype (Fig. 1, A and B).
|
). Consistent with the results of experiment 1, MyD88–/–mice demonstrated complete resistance to LPS-induced anorexia (Fig 2B), but, as in the first experiment, these animals nonetheless exhibited significant weight loss (–0.5 ± 0.1 g, P < 0.05). In MyD88–/– mice, LPS administration had no effect on body temperature relative to vehicle, whereas MyD88+/+ littermate controls exhibited the expected febrile response (maximum 1.2 C higher than control) that was sustained for a period of 4 h (Fig. 2C) to LPS. Relative to vehicle injection, LPS administration also failed to reduce ambulatory activity, as measured by cumulative laser beam breaks, in MyD88–/– mice (103% of control at 20 h, P = ns, Fig. 2E), whereas LPS-treated MyD88+/+ mice showed a pronounced reduction in ambulatory activity (60% of control at 20 h, P < 0.001, Fig. 2E). Similarly, cumulative oxygen consumption over 20 h was not altered by LPS treatment in MyD88–/– mice relative to vehicle injection (98% of control at 20 h, P = ns, Fig. 2D), whereas in MyD88+/+ littermates, LPS administration caused a significant reduction in oxygen consumption (87% of control at 20 h, P < 0.001, Fig. 2D) that was detected within 1 h of LPS administration and remained below rates in the other three groups for 10 consecutive hours. Thus, MyD88–/– mice are completely protected against LPS-induced fever, anorexia, adipsia, and reductions of both ambulatory activity and oxygen consumption but not against LPS-induced weight loss.
|
). At 6 h after LPS administration, corticosterone levels were not significantly different in MyD88–/– mice (93 ± 33 ng/ml) relative to vehicle-injected animals (43 ± 15 ng/ml and 56 ± 24 ng/ml, respectively, for MyD88–/– and MyD88+/+ animals injected with vehicle; P = 0.1), whereas LPS-treated MyD88+/+ mice showed the expected, pronounced increase of circulating corticosterone levels (459 ± 120 ng/ml, P < 0.05 vs. all other groups). At 12 h after LPS administration, plasma corticosterone levels remained elevated in MyD88+/+ animals (106 ± 58 ng/ml), compared with MyD88–/–, LPS-treated mice (30 ± 11 ng/ml), and vehicle-injected wild-type animals (33 ± 21 ng/ml), although this difference was no longer statistically significant (P = 0.1 vs. both groups).
|
). Despite the absence of MyD88 signaling, LPS induced markedly increased plasma levels of several key cytokines in MyD88–/– mice. For example, the plasma concentration of the proinflammatory cytokine IL-6 was increased at both 6 and 12 h to the same degree in MyD88+/+ and MyD88–/– mice, rising 30- to 50-fold above the IL-6 values measured in vehicle-injected MyD88+/+ mice. The plasma concentration of TNF was also increased 6 h after LPS administration in MyD88–/– mice relative to vehicle-injected mice and remained elevated in MyD88–/– mice at 12 h, a time point at which the plasma TNF concentration in the majority of LPS-treated MyD88+/+ mice was no longer detectable. Interestingly, a similar pattern of sustained (12 h) elevation of circulating cytokine concentrations after LPS administration in MyD88–/– mice was seen for the antiinflammatory cytokine IL-10 and the chemokine monocyte chemotactic protein (MCP)-1. Unlike for IL-6 and TNF, however, plasma concentration of MCP-1 at 6 h was higher in LPS-treated MyD88+/+ animals than MyD88–/– mice, although MCP-1 values for both LPS-treated groups were greater than those in vehicle-injected mice. No effect of LPS on plasma values of IL-2, IL-4, and IL-15 was evident in either genotype, and whereas LPS-stimulated IL-1 and interferon- values were 2- to 3-fold greater in MyD88+/+ mice than LPS-treated MyD88–/– mice and vehicle-injected groups, these differences failed to reach statistical significance.
|
in both spleen and mediobasal hypothalamus of LPS-treated mutant and wild-type mice (Fig. 5). Among MyD88–/– mice, LPS failed to induce IL-1ß mRNA expression in either spleen or hypothalamus, whereas LPS injection increased IL-1ß mRNA expression by 4-fold in the spleen and 8-fold in the hypothalamus of MyD88+/+ animals. In contrast, the effect of LPS to increase splenic TNF mRNA expression did not differ by genotype (Fig. 5A). Hypothalamic TNF mRNA expression was also induced by LPS in MyD88–/– mice but to a lesser degree (3-fold) than was observed in MyD88+/+ mice (8-fold, P < 0.01, Fig. 5B). Reduced hypothalamic proinflammatory cytokine production could therefore contribute to protection against LPS-induced anorexia in mice lacking MyD88.
|
). Hypothalamic NPY mRNA content was increased in LPS-treated MyD88–/– mice only at 6 h after LPS administration (150% of vehicle-injected MyD88–/– mice, P < 0.05). LPS-induced NPY mRNA content at 12 h and POMC mRNA expression at both time points were no different from vehicle-injected controls for both genotypes (Table 1).
|
) relative to vehicle: 2 h (1.2 ± 0.1 g), 4 h (2.1 ± 0.1 g), and 20 h (4.6 ± 0.2 g) (Fig. 6A, P < 0.001 vs. IL-1ß-treated MyD88+/+ mice for all time points). In contrast, IL-1ß-administration had no effect on food intake in MyD88–/– mice at 2 h (1.1 ± 0.1 g), 4 h (2.2 ± 0.2 g), or 20 h (4.9 ± 0.5 g) (Fig. 6A) relative to vehicle-injected MyD88–/– mice: 2 h (1.0 ± 0.1 g), 4 h (2.0 ± 0.2 g), and 20 h (4.5 ± 0.4 g) (Fig. 6A). By comparison, despite complete protection from anorexia, IL-1ß-administration caused weight loss in MyD88–/– mice (–0.1 ± 0.1 g, P < 0.01 vs. vehicle-injected MyD88–/– mice, Fig. 6B), although this effect was attenuated, compared with weight loss caused by IL-1ß in MyD88+/+ littermate controls (–0.5 ± 0.1 g, P < 0.001 vs. IL-1ß-treated MyD88–/– mice). As in experiment 1, vehicle injection was associated with modest weight gain independent of genotype (+0.1 ± 0.1 g in MyD88–/– and +0.2 ± 0.1 g in MyD88+/+ mice). Thus, as for LPS, MyD88 deficiency confers complete protection from anorexia, but not weight loss, induced by IL-1ß.
|
administration on food intake and body weight in MyD88-deficient and wild-type mice, a MyD88-independent inflammatory stimulus, on energy balance in MyD88-deficient mice and controls. As expected, TNF administration (65 ng/g ip) reduced cumulative food intake in MyD88+/+ mice at 2 h (0.5 ± 0.1 g), 4 h (1.1 ± 0.2 g), and 20 h (3.4 ± 0.3 g) (Fig. 7A) relative to vehicle-injected MyD88+/+ mice: 2 h (1.3 ± 0.1 g), 4 h (1.9 ± 0.1 g), and 20 h (4.7 ± 0.1 g) (Fig. 7A, P < 0.001 vs. TNF-treated MyD88+/+ mice at all time points). Unlike the response to LPS or IL-1ß, however, TNF administration reduced food intake comparably in MyD88–/– mice: 2 h (0.8 ± 0.1 g), 4 h (1.2 ± 0.1 g), and 20 h (3.4 ± 0.1 g) (Fig. 7A) relative to vehicle at 2 h (1.4 ± 0.1 g), 4 h (1.8 ± 0.1 g), and 20 h (4.5 ± 0.2 g) (Fig. 7A). Similarly, the weight-reducing effect of TNF administration was comparable between MyD88+/+ (–0.4 ± 0.1 g) and MyD88–/– mice (–0.4 ± 0.1 g, Fig. 7B), whereas vehicle injection was associated with weight gain in both genotypes (+0.5 ± 0.1 g in MyD88–/– and +0.6 ± 0.1 g in MyD88+/+ mice). Thus, MyD88-deficient mice are fully sensitive to TNF-induced anorexia and weight loss, consistent with the MyD88-independent signaling mechanisms that mediate the response to this cytokine.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Circulating cytokines are widely viewed as key mediators of inflammatory anorexia (19, 20, 21, 22), and based on evidence that the presence of cytokines in the central nervous system (CNS) is a prerequisite for inflammatory anorexia to occur (7, 23), several studies have sought to explain how peripheral cytokines enter the brain and affect neuronal pathways involved in food intake regulation (24, 25). However, blocking individual cytokine signaling pathways in the CNS has not proven effective in preventing inflammatory anorexia (12), presumably because of the wide variety of cytokines that are able to participate in this response. A logical extension of this model is that the protective effect of genetic deletion of TLR4 or IL1RI on LPS- or IL-1ß-induced anorexia, respectively, arises from blockade of the peripheral inflammatory response to these potent stimulators of cytokine production, rather than by interfering with the CNS response to anorexigenic cytokines. Consistent with this model is the observation that genetic deletion of IL1RI or IL-1 converting enzyme does not block peripheral LPS-mediated sickness, suggesting that TLR4-mediated stimulation of the cytokine cascade overwhelms the downstream protective effect of impaired IL-1ß signaling (12, 26).
Our finding that LPS stimulates circulating cytokines in MyD88–/– mice without causing anorexia challenges this view. Whereas the cytokine response to LPS in mutant animals is different from that in MyD88+/+ mice and may be missing critical inflammatory factors, the pronounced increases in several serum cytokines, including MyD88-independent, anorexia-causing mediators such as IL-6 and TNF, suggest that MyD88 deficiency protects mice against LPS-induced anorexia by a mechanism other than impaired cytokine synthesis. Rather, MyD88-dependent signaling appears to play a vital role in the perception of inflammatory signals within the CNS.
Our finding that LPS triggers cytokine production in the absence of MyD88 signaling is compatible with previous work demonstrating that in inflammatory cells, LPS activates both MyD88-dependent and MyD88-independent signal transduction pathways (14). The latter pathway involves coupling between TLR4 and the Toll/IL-1 receptor domain-containing adaptor-inducing interferon-ß (TRIF) pathway, a second messenger system initially discovered as a mediator of interferon signaling (15). The TRIF pathway is capable of activating the transcription factor NFB (27), albeit in a delayed fashion relative to MyD88-dependent signaling, consistent with our finding that LPS-induced plasma cytokine concentration elevations in mice lacking MyD88 appear to lag behind the response seen in animals with intact MyD88 signaling. One previous in vivo study has also documented that IL-18 production can occur in mice lacking MyD88 in response to LPS (28), and whereas an earlier study reported an attenuated peripheral cytokine response to LPS in MyD88-deficient mice (27), this assessment was based principally on data obtained from early time points and, unlike our study, did not measure the delayed plasma cytokine response in these mice. Thus, whereas diminished peripheral cytokine production may account for protection from inflammatory anorexia in MyD88–/– mice at early time points (2 and 4 h), the sustained protection from anorexia demonstrated at time points when circulating proinflammatory cytokines are stimulated by LPS suggests that other MyD88-dependent signals are critical to the transmission of inflammatory signals into the CNS.
Another finding of interest from our study was the absence of an LPS-induced increase in circulating corticosterone levels in mice lacking MyD88. Because this response originates within the brain, this finding supports our interpretation that MyD88-dependent signaling is required for the perception of inflammatory signals within the CNS of animals treated with LPS. In addition, it is possible that reduced plasma concentrations of corticosterone, a potent antiinflammatory hormone, may contribute to the prolonged time course of inflammatory cytokine expression exhibited by MyD88–/– mice.
Our finding that weight loss induced by LPS or IL-1ß can be dissociated from the feeding effects of these inflammatory mediators sheds new light on mechanisms whereby inflammatory mediators affect energy balance. Collectively, our findings indicate that although MyD88-dependent inflammatory effects including anorexia, adipsia, and fever, are important contributors to weight loss, MyD88-independent signals can induce weight loss even in the absence of other sickness characteristics. Furthermore, because water intake remained normal in LPS-treated MyD88-deficient mice, the possibility that weight loss was principally due to dehydration seems unlikely, although further work is need to determine whether weight loss induced by LPS or IL-1ß in mice lacking MyD88 is a consequence of reduced fat mass, lean mass, or free fluid. An interesting possibility is that this weight loss was caused by inflammatory cachexia, the specific wasting of lean tissue, and future studies examining skeletal muscle physiology in these animals are warranted to investigate this hypothesis.
As described for TLR4 above, IL-1ß signaling through IL1RI can also occur via a MyD88-independent mechanism, evidently via activation of phosphatidylinositol 3 kinase, an enzyme which can also activate NFB signaling (16). Because NFB activation is proposed to be a critical determinant of muscle wasting (29), it will be of interest to determine whether LPS and IL-1ß activate NFB in skeletal muscle in mice lacking MyD88.
As expected, we found that the presence or absence of MyD88 signaling does not alter the ability of a pharmacological dose of TNF to cause anorexia and weight loss. Thus, the inflammatory response to pharmacological administration of this cytokine overcame the protective effect conferred by deficiency of MyD88, at least where anorexia and weight loss are concerned. This conclusion has interesting implications for our finding that in MyD88-deficient animals, LPS administration increased TNF mRNA expression in both the spleen and hypothalamus, and markedly increased circulating TNF concentrations. How does the absence of MyD88 signaling protect against LPS-mediated anorexia, despite pronounced activation of TNF signaling, if the anorexic response to exogenous TNF is intact in this setting? One possibility is that ip TNF administration triggers neural responses distinct from those generated by endogenous TNF production from circulating cells, e.g. activation of vagal afferent fibers. Alternatively, the ability of exogenous TNF to cause anorexia in our study may reflect a pharmacological effect that is not recapitulated by more physiological increases of TNF induced by LPS. A third possibility is that the delayed time course of endogenous TNF production in MyD88-deficient animals may block the anorexic response.
In conclusion, we report that anorexia can be dissociated from weight loss in an acute model of inflammatory sickness and that the absence of MyD88 signaling protects against LPS-induced anorexia, even when known anorexia-inducing inflammatory cytokines are present in the circulation. These findings imply a key role for MyD88 signaling in the CNS as a mediator of changes of body weight and appetite related to inflammatory conditions, a concept that may lead to novel therapies for patients with inflammatory anorexia and wasting illness.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
Disclosure summary: The authors have nothing to disclose.
First Published Online June 15, 2006
Abbreviations: Agrp, Agouti gene-related peptide; CNS, central nervous system; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; HPA, hypothalamus-pituitary-adrenal; HSD, honestly significant difference; IL1RI, IL-1 receptor I; LPS, lipopolysaccharide; MCP, monocyte chemotactic protein; NFB, nuclear factor-B; NPY, neuropeptide Y; ns, not significant; POMC, proopiomelanocortin; TLR4, Toll-like receptor 4.
Received April 11, 2006.
Accepted for publication May 30, 2006.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
in lipopolysaccharide-induced sickness behaviour: a study with interleukin-1 type I receptor-deficient mice. Eur J Neurosci 12:4447–4456[CrossRef][Medline]B activation causes severe muscle wasting in mice. Cell 119:285–298[CrossRef][Medline]This article has been cited by other articles:
 |
|
 |
|
  T. Hayashi, H. B. Cottam, M. Chan, G. Jin, R. I. Tawatao, B. Crain, L. Ronacher, K. Messer, D. A. Carson, and M. Corr Mast cell-dependent anorexia and hypothermia induced by mucosal activation of Toll-like receptor 7 Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2008; 295(1): R123 - R132. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. R. Johnson, C. L. Sherry, J. M. York, and G. G. Freund Acute Hypoxia, Diabetes, and Neuroimmune Dysregulation: Converging Mechanisms in the Brain Neuroscientist, June 1, 2008; 14(3): 235 - 239. [Abstract] [PDF]
|
|
|
|
 |
|
 M. Depke, G. Fusch, G. Domanska, R. Geffers, U. Volker, C. Schuett, and C. Kiank Hypermetabolic Syndrome as a Consequence of Repeated Psychological Stress in Mice Endocrinology, June 1, 2008; 149(6): 2714 - 2723. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. E. Wisse, K. Ogimoto, J. Tang, M. K. Harris Jr., E. W. Raines, and M. W. Schwartz Evidence that Lipopolysaccharide-Induced Anorexia Depends upon Central, Rather than Peripheral, Inflammatory Signals Endocrinology, November 1, 2007; 148(11): 5230 - 5237. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. P. Zorrilla, M. Sanchez-Alavez, S. Sugama, M. Brennan, R. Fernandez, T. Bartfai, and B. Conti Interleukin-18 controls energy homeostasis by suppressing appetite and feed efficiency PNAS, June 26, 2007; 104(26): 11097 - 11102. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Granado, A. I Martin, M{a} A. Villanua, and A. Lopez-Calderon Experimental arthritis inhibits the insulin-like growth factor-I axis and induces muscle wasting through cyclooxygenase-2 activation Am J Physiol Endocrinol Metab, June 1, 2007; 292(6): E1656 - E1665. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
