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

• Published in: American journal of physiology. Regulatory, integrative and comparative physiology integrative and comparative physiology, 2011-07, Vol.301 (1), p.R172-R184
• Main Authors: MacDonald, Leah, Radler, Morgan, Paolini, Antonio G, Kent, Stephen
• Format: Article
• Language: English
• Subjects: Animals; Anorexia; Body Temperature - drug effects; Body Temperature - physiology; Body Weight - drug effects; Body Weight - physiology; Caloric Restriction; Cyclooxygenase 2 - metabolism; Cytokines; Disease Models, Animal; Eating - drug effects; Eating - physiology; Fever; Hypothalamus - drug effects; Hypothalamus - physiology; Illness Behavior - physiology; Inflammation - metabolism; Inflammation - physiopathology; Intramolecular Oxidoreductases - metabolism; Leptin - metabolism; Lipopolysaccharides - adverse effects; Lipopolysaccharides - pharmacology; Male; Mice; Mice, Inbred C57BL; Motor Activity - drug effects; Motor Activity - physiology; Pro-Opiomelanocortin - metabolism; Prostaglandin-E Synthases; Ribonucleic acid; RNA; Rodents; Signal Transduction - drug effects; Signal Transduction - physiology; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins - metabolism
• ISSN: 0363-6119; 1522-1490
• DOI: 10.1152/ajpregu.00057.2011

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.