Interleukin-6 and leptin mediate lipopolysaccharide-induced fever and sickness behavior

Harden, Lois M.; Plessis, Irné du; Poole, Stephen; Laburn, Helen P.

doi:10.1016/j.physbeh.2006.05.016

Cited by 138 publications

(98 citation statements)

References 54 publications

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“…While the intensity of this measure is consistent with differences in leptin levels across groups, our previous work directly manipulating leptin levels does not support the hypothesis that leptin mediates sickness-induced anorexia in Siberian hamsters (Carlton and Demas, 2014). Although some research has linked leptin with sickness-induced anorexia (Sachot et al, 2004;Harden et al, 2006), other studies have suggested that these variables have little relation to each other (Faggioni et al, 1997;Lugarini et al, 2005). Thus, the role of leptin in modulating sickness-induced anorexia in Siberian hamsters and other species remains unresolved.…”

Section: Discussionmentioning

confidence: 54%

Body mass affects seasonal variation in sickness intensity in a seasonally-breeding rodent

Carlton

Demas

2015

Journal of Experimental Biology

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Species that display seasonal variation in sickness intensity show the most intense response in the season during which they have the highest body mass, suggesting that sickness intensity may be limited by an animal's energy stores. Siberian hamsters (Phodopus sungorus) display lower body masses and less intense sickness when housed in short, winter-like days as opposed to long, summer-like days. To determine whether reduced sickness intensity displayed by short-day hamsters is a product of seasonal changes in body mass, we food restricted long-day hamsters so that they exhibited body mass loss that mimicked the natural photoperiod-induced loss of body mass in short-day hamsters. We then experimentally induced sickness with lipopolysaccharide (LPS) and compared sickness responses among long-day food-restricted and long-and short-day ad libitum fed groups, predicting that long-day food-restricted hamsters would show sickness responses comparable to those of short-day ad libitum fed hamsters and attenuated in comparison to long-day ad libitum fed hamsters. We found that long-day food-restricted hamsters showed attenuated LPSinduced anorexia, loss of body mass and hypothermia compared with long-day ad libitum fed animals; however, anorexia remained elevated in long-day food-restricted animals compared with short-day ad libitum fed animals. Additionally, LPS-induced anhedonia and decreases in nest building were not influenced by body mass. Results of hormone assays suggest that cortisol levels could play a role in the attenuation of sickness in long-day food-restricted hamsters, indicating that future research should target the roles of glucocorticoids and natural variation in energy stores in seasonal sickness variation.

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Section: Discussionmentioning

confidence: 54%

Body mass affects seasonal variation in sickness intensity in a seasonally-breeding rodent

Carlton

Demas

2015

Journal of Experimental Biology

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“…In addition, it has been recognized that POMC derived melanocortin peptides reduce food intake via the activation of the melanocortin 4-receptor, and that reduced POMC expression can lead to hyperphagia and obesity (67). Leptin has been widely demonstrated to have proinflammatory properties and has been shown to mediate the reduction in food intake following LPS (28,50,65). The attenuated increase in POMC and leptin at 2 h post-LPS, seen in the CR50% animals, may contribute to the CR animals' attenuated anorexia and weight loss.…”

Section: Cr Sickness Behavior and A Potential Mechanismmentioning

confidence: 99%

Calorie restriction attenuates LPS-induced sickness behavior and shifts hypothalamic signaling pathways to an anti-inflammatory bias

MacDonald

Radler

Paolini

et al. 2011

American Journal of Physiology-Regulatory, Integrative and Comp

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MacDonald L, Radler M, Paolini AG, Kent S. Calorie restriction attenuates LPS-induced sickness behavior and shifts hypothalamic signaling pathways to an anti-inflammatory bias. Am J Physiol Regul Integr Comp Physiol 301: R172-R184, 2011. First published April 27, 2011 doi:10.1152/ajpregu.00057.2011 has been demonstrated to alter cytokine levels; however, its potential to modify sickness behavior (fever, anorexia, cachexia) has not. The effect of CR on sickness behavior was examined in male C57BL/6J mice fed ad libitum or restricted 25% (CR25%) or restricted 50% (CR50%) in food intake for 28 days and injected with 50 g/kg of LPS on day 29. Changes in body temperature, locomotor activity, body weight, and food intake were determined. A separate cohort of mice were fed ad libitum or CR50% for 28 days, and hypothalamic mRNA expression of inhibitory factor B-␣ (I B-␣), cyclooxygenase-2 (COX-2), prostaglandin E 2 (PGE2), suppressor of cytokine signaling 3 (SOCS3), IL-10, neuropeptide Y (NPY), leptin, proopiomelanocortin (POMC), and corticotrophin-releasing hormone (CRH) were determined at 0, 2, and 4 h post-LPS. CR50% mice did not develop fevers, whereas the CR25% mice displayed a fever shorter in duration but with the same peak as the controls. Both CR25% and CR50% mice showed no sign of anorexia and reduced cachexia after LPS administration. Hypothalamic mRNA expression of NPY and CRH were both increased by severalfold in CR50% animals preinjection compared with controls. The CR50% mice did not demonstrate the expected rise in hypothalamic mRNA expression of COX-2, microsomal prostaglandin E synthase-1, POMC, or CRH 2 h post-LPS, and leptin expression was decreased at this time point. Increases in SOCS3, IL-10, and I B-␣ expression in CR50% animals were enhanced compared with ad libitum-fed controls at 4 h post-LPS. CR results in a suppression of sickness behavior in a dose-dependent manner, which may be due to CR attenuating proinflammatory pathways and enhancing anti-inflammatory pathways. fever; suppressor of cytokine signaling 3; cyclooxygenase-2; microsomal prostaglandin E synthase-1; leptin CALORIE RESTRICTION (CR), a dietary regimen low in calories, while avoiding malnutrition, is the only manipulation that has consistently been shown to extend the mean and maximum life span in a range of species (2,42,71,76). In addition to an increase in life span, CR attenuates the normal immunosenscence seen with age (52), along with reducing the occurrence of other age-related diseases (14,39,43,53,54,79).It has been postulated that the mechanism by which CR extends the mean and maximum life span is by reducing oxidative stress caused by unregulated increases in reactive oxygen species (3,19,31,42,69), as well as by limiting the age-related increase in basal pro-inflammatory cytokine levels (73). One possible mechanism by which CR exerts its antiinflammatory effect are glucocorticoids, which are increased after CR (33, 47) and act to increase the transcription of anti-inflammatory cytokines and decrease the transcripti...

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“…While genetic ablation of a particular cytokine or its receptor often does not substantially attenuate the anorectic effect of peripheral LPS (for review, see Langhans, 2004), acute pharmacological or immunological antagonism of cytokines appears to be generally more effective (Bluthe et al 1992;Porter et al 1998aPorter et al , 2000Swiergiel & Dunn, 1999;Laye et al 2000;Harden et al 2006). These seemingly discrepant findings may be related to the redundant and overlapping actions of the cytokines, which could permit unusually extensive developmental compensation.…”

Section: Role Of Cytokinesmentioning

confidence: 99%

Signals generating anorexia during acute illness

Langhans

2007

Proc. Nutr. Soc.

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Anorexia is part of the body's acute-phase response to illness. Microbial products such as lipopolysaccharides (LPS), which are also commonly used to model acute illness, trigger the acute-phase response and cause anorexia mainly through pro-inflammatory cytokines. LPS stimulate cytokine production through the cell-surface structural molecule CD14 and toll-like receptor-4. Cytokines ultimately change neural activity in brain areas controlling food intake and energy balance. The blood-brain barrier endothelial cells (BBB EC) are an important site of cytokine action in this context. BBB EC and perivascular cells (microglia and macrophages) form a complex regulatory interface that modulates neuronal activity by the release of messengers (e.g. PG, NO) in response to peripheral challenges. Serotonergic neurons originating in the raphe nuclei and glucagon-like peptide-1-expressing neurons in the hindbrain may be among the targets of these messengers, because serotonin (5-HT), acting through the 5-HT 2C receptor, and glucagon-like peptide-1 have recently emerged as neurochemical mediators of LPS anorexia. The central melanocortin system, which is a downstream target of serotonergic neurons, also appears to be involved in mediation of LPS anorexia. Interestingly, LPS also reduce orexin expression and the activity of orexin neurons in the lateral hypothalamic area of fasted mice. As the eating-stimulatory properties of orexin are apparently related to arousal, the inhibitory effect of LPS on orexin neurons might be involved in LPS-induced inactivity and anorexia. In summary, the immune signalling pathways of LPS-induced, and presumably acute illness-induced, anorexia converge on central neural signalling systems that control food intake and energy balance in healthy individuals.

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Interleukin-6 and leptin mediate lipopolysaccharide-induced fever and sickness behavior

Cited by 138 publications

References 54 publications

Body mass affects seasonal variation in sickness intensity in a seasonally-breeding rodent

Body mass affects seasonal variation in sickness intensity in a seasonally-breeding rodent

Calorie restriction attenuates LPS-induced sickness behavior and shifts hypothalamic signaling pathways to an anti-inflammatory bias

Signals generating anorexia during acute illness

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