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...