title: Calorie restriction attenuates LPS-induced sickness behavior and shifts hypothalamic signaling pathways to an anti-inflammatory bias.
abstract: Calorie restriction (CR) 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 μg/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 κB-α (IκB-α), cyclooxygenase-2 (COX-2), prostaglandin E(2) (PGE(2)), 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 IκB-α 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.
authors.affiliation: School of Psychological Science, La Trobe University, Bundoora, VIC 3086, Australia.
authors.forename: Leah
authors.initials: L
authors.lastname: MacDonald
authors.forename: Morgan
authors.initials: M
authors.lastname: Radler
authors.forename: Antonio G
authors.initials: AG
authors.lastname: Paolini
authors.forename: Stephen
authors.initials: S
authors.lastname: Kent
mesh_terms: D000818:Animals; D001831:Body Temperature / Q000187:drug effects / Q000502:physiology; D001835:Body Weight / Q000187:drug effects / Q000502:physiology; D031204:Caloric Restriction; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004195:Disease Models, Animal; D004435:Eating / Q000187:drug effects / Q000502:physiology; D007031:Hypothalamus / Q000187:drug effects / Q000502:physiology*; D055809:Illness Behavior / Q000502:physiology*; D007249:Inflammation / Q000378:metabolism / Q000503:physiopathology*; D019746:Intramolecular Oxidoreductases / Q000378:metabolism; D020738:Leptin / Q000378:metabolism; D008070:Lipopolysaccharides / Q000009:adverse effects* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D011333:Pro-Opiomelanocortin / Q000378:metabolism; D000071876:Prostaglandin-E Synthases; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism
chemical_list: D020738:Leptin; D008070:Lipopolysaccharides; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D011333:Pro-Opiomelanocortin; D051546:Cyclooxygenase 2; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases